Phase 2a, AMP Challenge, Dose Escalation Study to Assess the Dose Response for Topical Efficacy and Systemic Activity in Asthmatic Subjects

An Escalating Dose, Randomized, Placebo-controlled, Incomplete-block, 2-period Cross-over Study to Assess the Dose Response for Topical Efficacy Via Airway Responsiveness to Adenosine-5'-Monophosphate (AMP) Challenge and the Dose Response for Systemic Activity Via 24h Plasma Cortisol Suppression and Thereby the Relative Therapeutic Index for Fluticasone Furoate (FF), Fluticasone Propionate (FP) and Budesonide (BUD) in Asthmatic Subjects

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02991859

Enrollment

Registered

2016-12-14

Start date

2017-02-09

Completion date

2018-12-20

Last updated

2020-07-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

Keywords

Dose-response, AMP challenge, cortisol suppression, dose escalation, therapeutic index

Brief summary

This is a randomized, placebo-controlled, 2-period crossover, escalating repeat dose study, aiming to investigate whether higher potency of different inhaled corticosteroid confers an improvement in the topical efficacy to systemic activity ratio in asthmatic subjects. It will compare the dose response for topical efficacy via airway responsiveness (to adenosine-5'-monophosphate \[AMP\] challenge), and the dose response for systemic activity via 24 hour plasma cortisol suppression, and thereby compare the relative therapeutic index, for the following inhaled corticosteroids: fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD). There will be a screening visit 4 - 42 days before the first dose of study treatment, and AMP challenge Provocative concentration 20 (PC20) of \<=80 milligrams per milliliter (mg/mL) at screening visit 2 i.e. at 4 - 14 days before the first dose of study treatment. Subjects will be randomized to one of 5 or 12 treatment sequences, and will have one or two treatment periods, each comprising 5 consecutive 7-day phases of escalating doses of either FF, FP, BUD or placebo. There will be a 25- to 42-day washout period between treatment periods. The study duration for each subject will be approximately 13 or 24 weeks including the follow-up period.

Interventions

DRUGFluticasone furoate (FF) Dry Powder Inhaler

Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods

DRUGFluticasone propionate (FP) Dry Powder Inhaler

Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods

DRUGBudesonide (BUD) Turbuhaler

Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.

DRUGPlacebo (ELLIPTA or DISKUS)

Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

- Subjects must be 18 to 65 years of age inclusive, at the time of signing the informed Consent. - Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit - Pre-bronchodilator FEV1 \>=65% of predicted at screening; the pre-dose baseline FEV1 should not have changed significantly in the opinion of the investigator from the screening baseline value and should be \>=65% predicted for the subject to continue - Documented sensitivity to AMP with a provocative concentration of AMP resulting in a fall of \>=20% FEV1 with a PC20 AMP \<=80 mg/mL at the screening visit - Current therapy could include short-acting Beta2-agonists (SABA) prescribed SABA for at least 12 weeks prior to screening, if needed; subjects receiving low-dose ICS may take part after a 4-week ICS washout prior to AMP challenge. The subject's asthma symptoms must remain stable during this 4-week period as assessed at screening visit 2. Stable asthma is defined as no more than 2 consecutive days where \>=12 inhalations/day of salbutamol were used; or no severe asthma exacerbations requiring use of systemic corticosteroids (tablets, suspension, or injection) or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids; or no clinical asthma worsening which in the opinion of the investigator requires additional asthma treatment other than study medication or salbutamol; subjects taking Long-acting beta2-agonist (LABA), long-acting muscarinic antagonist (LAMA), leukotriene receptor antagonist (LTRA) therapy within three months prior to the start of the study are not eligible; subjects taking biological therapies within 6 months prior to start of the study are not eligible. - Bodyweight \>=50 Kilogram (kg) and BMI within the range 18.0-35.0 kg/meter (m)\^2 (inclusive) - Male and female. Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin \[HCG\] test), not lactating, and at least one of the following conditions applies prior to randomization: • Non-reproductive potential defined as pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea, in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. • Reproductive potential and agrees to follow one of the highly effective methods for avoiding pregnancy in females of reproductive potential from 30 days prior to the first dose of study medication and until at least five terminal half-lives after the last dose of study medication. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. - Aspartate aminotransferase and Alanine transaminase \<2x upper limit of normal (ULN); alkaline phosphatase and bilirubin ≤1.5 x ULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) - Light smokers, who smoke \<=20 cigarettes per week or equivalent unit dose of other tobacco products or e-cigarettes, are eligible for the study. Smokers who intend to stop, reduce or increase their smoking habit during the study period are not eligible. - Having provided written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion criteria

- A history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years. - Other significant pulmonary diseases to include (but not limited to) severe pneumonia within 6 months of the screening visit, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, tuberculosis or other respiratory abnormalities other than asthma. - Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear within 4 weeks of screening that: In the opinion of the investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study. - A subject will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening. - Any asthma exacerbation requiring oral corticosteroids within 12 weeks of screening or that resulted in overnight hospitalization requiring additional treatment for asthma within 6 months prior to randomization. - Use of prohibited medications including, anti-depressant drugs, and anti-asthma drugs (other than short acting inhaled beta-agonists supplied as rescue medication, oral contraceptives, non-steroidal anti-inflammatory drugs, stable doses of antihistamines, and paracetamol) for 1 week prior to screening and throughout the course of the study. Anti-histamines should be withheld 4 days prior to AMP challenge; subjects must also be able to abstain from short acting inhaled beta-agonists, for 8 hours prior to spirometry. - Subjects undergoing de-sensitization therapy - Current smokers who smoke \> 20 cigarettes per week or the equivalent unit dose of other tobacco products or e-cigarettes, or smokers with a smoking history of \>=10 pack years. - History of regular alcohol consumption exceeding 21 units per week for men and 14 units per week for females (1 unit =5 ounces \[150 mL\] of wine or 12 ounces \[360 mL\] of beer or 1.5 ounces \[45 mL\] of spirits) within 6 months of screening. - All subjects who are currently or in the last month have worked night-shifts are excluded from the study - Exposure to more than four new chemical entities within 12 months prior to the first dosing day or received an investigational product within 30 days of study start, or 5 half-lives of study drug if that is longer. - A subject has any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the study results if the condition/disease exacerbated during the study. (e.g. stroke or myocardial infarction within 3 months, uncontrolled hypertension, congestive heart failure, uncontrolled diabetes mellitus.) - Evidence of cancer or history of cancer in the past 5 years other than adequately treated basal or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix. - Pregnant females as determined by positive urine HCG test at screening or by positive urine HCG test prior to dosing and lactating females. - Subjects with active or chronic infections including hepatitis B or C, human immunodeficiency virus. A positive serology at screening. - Allergies: History of severe milk protein allergy Drug Allergy defined as any adverse reaction including immediate or delayed hypersensitivity to intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of FF, FP or BUD (i.e., lactose or magnesium stearate etc.) Historical Allergy defined as history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. - Significant abnormality in the 12-lead electrocardiogram (ECG) performed at screening. The mean of the three individual ECGs will be taken. Mean QT interval corrected for heart rate (QTc) \>450 millisecond (msec) for males or QTc\>470 msec for female subjects and \>480 in subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF).

Design outcomes

Primary

Measure	Time frame	Description
Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	12 hours post last dose on Day 7	The percentage fall in FEV1 was calculated using highest FEV1 (post saline) minus highest FEV1 (post AMP) divided by highest FEV1 (post saline)\*100 where highest FEV1 (post saline) is the highest value of two FEV1 measurements at 60 and 180 seconds after the saline control, highest FEV1 (post AMP) is the highest value of the two FEV1 measurements at 60 and 180 seconds after the dose of AMP. Results are presented treatment wise. The analysis method was a 3 parameter Emax model with log 2 transformed AMP PC20 as the outcome variable, assuming common Emax across FF, FP and BUD, and with an unstructured variance-covariance matrix. Mean and 95% Confidence Interval (CI) presented are predicted estimate.
Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	Pre-dose PM dose on Day 6 to pre-dose PM dose Day 7	Blood samples for measurement of plasma cortisol were collected at given time point. The weighted means were derived by calculating the area under the curve (AUC) over the 0-24-hour period using the trapezoidal rule, and then dividing it by the actual time interval. Results are presented treatment wise. Mean and 95% CI presented are predicted estimate. The analysis method was an inhibitory exponential power-law model with log e transformed cortisol as the outcome variable, assuming 100% inhibition at highest doses.
Theraputic Index of FF	12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7	Therapeutic Index was calculated by ED20 for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter\[nmol/L\]) divided by Dose at which 80% of the maximum effect is reached (ED80) for AMP PC20 for FF 25 mcg, FF 100 mcg, FF 200 mcg, FF 400 mcg, FF 800 mcg. Theraputic index has been presented. Only those participants with data available at the specified time points were analyzed. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively.
Theraputic Index of FP	12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7	Therapeutic Index was calculated by Dose at which 20% of the maximum effect is reached (ED20) for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter\[nmol/L\]) divided by ED80 for AMP PC20 for FP 50 mcg, FP 200 mcg, FP 500 mcg, FP 1000 mcg, FP 2000 mcg. Theraputic index has been presented. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively.
Theraputic Index of BUD	12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7	Therapeutic Index was calculated by ED20 for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter\[nmol/L\]) divided by ED80 for AMP PC20 for BUD 100 mcg, BUD 400 mcg, BUD 800 mcg, BUD 1600 mcg, BUD 3200 mcg. Theraputic index has been presented. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively.

Secondary

Measure	Time frame	Description
PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 2 to 8 PM, Day 9 to 14 AM and PM, Day 15 PM, Day 16 to 21 AM and PM, Day 22 PM,Day 23 to 28 AM and PM, Day 29 PM,Day 30 to 35 AM and PM in Period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Participants recorded their PEFR measurement before each dose in a paper diary. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1	Day 2,3,4,5,6,7 PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2	Day 2,3,4,5,6,7 PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 8,9,10,11,12,13,14 PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 8,9,10,11,12,13,14 PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Days 22,23,24,25,26,27,28 PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Days 29,30,31,32,33,34,35 PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 29,30,31,32,33,34,35 PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1	Day 2,3,4,5,6,7 PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 2,3,4,5,6,7 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Days 8,9,1,0,11,12,13,14 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 8,9,1,0,11,12,13,14 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 15 PM, Day 16,17,18,19,20,21,22,23,24,25,26,27,28 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. One participant who was supposed to receive FP 1000 mg during day 22-28 and FP 2000 mg during day 28-35 but this participant continued the 3rd escalation phase dose (FP 500 mg) in fourth escalation phase and took FP 1000 mg (4th phase dose) in the fifth escalation phase (days 28-35).
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 15 PM, Day 16,17,18,19,20,21 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 22 PM, Day 23,24,25,26,27,28,29,30,31,32,33,34,35 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. One participant who was supposed to receive FP 1000 mg during day 22-28 and FP 2000 mg during day 28-35 but this participant continued the 3rd escalation phase dose (FP 500 mg) in fourth escalation phase and took FP 1000 mg (4th phase dose) in the fifth escalation phase (days 28-35).
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 2 to 6 AM and PM, Day 7 PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2	Day 2,3,4,5,6,7 PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 8 PM, Day 9 to 14 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 8 PM, Day 9 to 14 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 15,16, 17, 18, 19, 20, 21 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 15 PM, Day 16, 17, 18, 19, 20, 21 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Number of Participants With Clinically Significant Abnormal Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Up to Week 18	SBP and DBP were measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.
Number of Participants With Clinically Significant Abnormal Vital Signs: Pulse Rate	Up to Week 18	Pulse rate was measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.
Number of Participants With Clinically Significant Abnormal Vital Signs: Respiratory Rate	Up to Week 18	Respiratory rate was measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.
Number of Participants With Clinically Significant Abnormal Vital Signs: Temperature	Up to Week 18	Temperature was measured after participants have been rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.
Number of Participants With Abnormal Physical Examination	Up to Week 18	Physical examinations included assessment of the cardiovascular, respiratory, gastrointestinal, skin, abdomen (liver and spleen), and neurological systems. This analysis was planned and data was not collected and captured in the database. Results are presented treatment wise.
Number of Participants With Clinically Significant Abnormal Hematology Parameters	Up to Week 18	Blood samples were collected for assessement of following hematology parameters: basophils, eosinophils, Erythrocyte mean corpuscular volume (MCV), hemoglobin, hematocrit, Erythrocyte mean corpuscular hemoglobin (MCH), leukocytes, lymphocytes, monocytes, platelets. Results are presented treatment wise. Only participants with clinically significant abnormal hematology data was reported.
Number of Participants With Clinically Significant Abnormal Chemistry Parameters	Up to Week 18	Blood samples were collecte for assessment of following chemistry parametres:Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, alkaline phosphatase, bilirubin, calcium, creatinine, glucose, direct bilirubin, potassium, protein, sodium, urea. Results are presented treatment wise. Only participants with clinically significant abnormal chemistry data was reported.
Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	Up to Week 18	Urine sample were collected to assess following urine parameters: potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick. Results are presented treatment wise. Only participants with clinically significant abnormal urinalysis data was reported.
Forced Expiratory Volume in 1 Second (FEV 1) in Period 1	Day 1 (pre-dose) in Period 1	FEV1 was measured with participants in a sitting position using a calibrated spirometer in accordance with American Thoracic Society (ATS) guidelines using European Respiratory Society (ERS)guidelines for predicted values. Results are presented treatment wise.
Forced Expiratory Volume in 1 Second (FEV 1) in Period 2	Day 1 (pre-dose) in Period 2	FEV1 was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 15,16,17,18,19,20,21 PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Forced Vital Capacity (FVC) in Period 2	Day 1 (pre-dose) in Period 2	FVC was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise.
Forced Vital Capacity (FVC) in Period 1	Day 1 (pre-dose) in Period 1	FVC was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 15,16,17,18,19,20 PM, Day 21 AM and PM in period 2	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Days 22,23,24,25,26,27,28 PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.
Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Up to Week 18	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward medical occurrence that at any dose results in death, Is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect. Results are presented treatment wise.
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 2 to 8 PM, Day 9 to 14 AM and PM, Day 15 PM, Day 16 to 21 AM and PM, Day 22 PM,Day 23 to 28 AM and PM, Day 29 PM,Day 30 to 35 AM and PM in period 1	PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Participants recorded their PEFR measurement before each dose in a paper diary. Results are presented treatment wise.Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Countries

Germany, United Kingdom

Participant flow

Recruitment details

A total of 56 participants were enrolled across 1 center in Germany and 2 centers in the United Kingdom.

Pre-assignment details

A total of 165 participants were screened of which 109 failed screening and 56 participants were enrolled in study. Of the 56 participants enrolled,only 54 were randomized and received at least one dose of study medication. Only 7 participants were withdrawn from the study, 2 participants who were not withdrawn, entered Period 2 esc Phase 1.

Participants by arm

Arm	Count
Arm AB - FF Followed by FP Participants received evening (PM) dose of 1 puff of Fluticasone Furoate (FF) 25 microgram (mcg) (Total daily dose \[TDD\] = 25 mcg) in first dose escalation phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puff of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puff of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, participants received PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by morning (AM) and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period was of 25-42 days.	2
AC - FF Followed by BUD Participants will receive PM dose of 1 puff of FF 25mcg (TDD=25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD=100 mcg) in second phase; PM dose of 1 puff of FF 200mcg (TDD=200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD =800 mcg) in fifth phase. In TP 2, participants will receive PM dose of 1 puff of BUD 100 mcg (TDD=100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD=400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD=800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD=1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD=3200 mcg) in fifth phase. Washout period will be of 25-42 days	3
Arm AD - FF Followed by ELLIPTA Placebo Participants received PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, participants received PM dose of 1 puff of ELLIPTA Placebo in first, second and third phases followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. Washout period was of 25-42 days.	2
Arm BA - FP Followed by FF Participants received PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, participants received PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period was of 25-42 days.	2
Arm BC - FP Followed by BUD Participants received PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, participants received PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD = 400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period was of 25-42 days.	3
Arm BE - FP Followed by DISKUS Placebo Participants received PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, participants received PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each DISKUS Placebo in second, third and fourth phase; AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. Washout period was of 25-42 days.	3
Arm CA - BUD Followed by FF Participants received PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, participants received PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period was of 25-42 days.	2
Arm CB - BUD Followed by FP Participants received PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, participants received PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD =500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period was of 25-42 days.	2
Arm CE - BUD Followed by DISKUS Placebo Participants received PM dose of 1 puff of BUD as 100 mcg in first phase followed by BUD 200 mcg 1 puff AM and PM (TDD=400 mcg), in third phase BUD 400 mcg 1 puff AM and PM (TDD=800 mcg) followed by BUD 400 mcg 2 puffs AM and PM(TDD=1600mcg) in fourth phase followed by BUD 400 mcg 4puffs AM and PM (TDD=3200mcg) in TP1. In TP 2 participants received DISKUS placebo 1 puff PM in first phase followed by DISKUS placebo 1 puff AM and PM in second phase followed by DISKUS placebo 1 puff AM and PM in third phase followed by DISKUS placebo 1 puff AM and PM in fourth phase followed by DISKUS placebo 2 puffs AM and PM in fifth phase. Washout period was of 25-42 days.	2
Arm DA - ELLIPTA Placebo Followed by FF Participants received PM dose of 1 puff of ELLIPTA Placebo in first, second and third phase followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. In TP 2, participants will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period was of 25-42 days.	3
EB - DISKUS Placebo Followed by FP Participants received PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each of DISKUS Placebo in second, third and fourth phase; AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. In TP 2, participants received PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period was of 25-42 days.	2
Arm DC - ELLIPTA Placebo Followed by BUD Participants received PM dose of 1 puff of ELLIPTA Placebo in first, second and third phase followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. In TP 2, participants received PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period was of 25-42 days.	2
Fluticasone Furoate (FF) Participants received evening (PM) dose of 1 puff of FF 25 microgram (mcg) (Total daily dose \[TDD\] = 25 mcg) in first dose escalation phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puff of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puff of FF 200 mcg (TDD = 800 mcg) in fifth phase.	7
Fluticasone Propionate (FP) Participants received PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by morning (AM) and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase.	7
Budesonide (BUD) Participants received PM dose of 1 puff of BUD 100 mcg (TDD=100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD=400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD=800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD=1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD=3200 mcg) in fifth phase.	6
ELLIPTA Participants received PM dose of 1 puff of ELLIPTA Placebo in first, second and third phases followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase.	3
DISKUS Participants received PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each DISKUS Placebo in second, third and fourth phase; AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase.	3
Total	54

Withdrawals & dropouts

Period	Reason	FG001	FG004	FG005	FG008	FG009	FG012	FG013
Period 1,Escalation Phase 1,Upto Day 7	Withdrawal by Subject	1	1	0	0	0	0	0
Period1, Escalation Phase3, Upto Day21	Withdrawal by Subject	0	0	0	0	0	1	1
Period2, Escalation Phase4, Upto Day 105	Withdrawal by Subject	0	0	0	1	0	0	0
Wash Out, Up to Day 77	Lost to Follow-up	0	0	0	0	1	0	0
Wash Out, Up to Day 77	Withdrawal by Subject	0	0	1	0	0	0	0

Baseline characteristics

Characteristic	Total	Arm AB - FF Followed by FP	AC - FF Followed by BUD	Arm AD - FF Followed by ELLIPTA Placebo	Arm BA - FP Followed by FF	Arm BC - FP Followed by BUD	Arm BE - FP Followed by DISKUS Placebo	Arm CA - BUD Followed by FF	Arm CB - BUD Followed by FP	Arm CE - BUD Followed by DISKUS Placebo	Arm DA - ELLIPTA Placebo Followed by FF	EB - DISKUS Placebo Followed by FP	Arm DC - ELLIPTA Placebo Followed by BUD	Fluticasone Furoate (FF)	Fluticasone Propionate (FP)	Budesonide (BUD)	ELLIPTA	DISKUS
Age, Customized 18 to 64 years	50 Participants	2 Participants	3 Participants	2 Participants	2 Participants	3 Participants	3 Participants	2 Participants	2 Participants	1 Participants	2 Participants	2 Participants	2 Participants	7 Participants	7 Participants	5 Participants	3 Participants	2 Participants
Age, Customized <=18 years	3 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Age, Customized 65 to 84 years	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized AFRICAN AMERICAN/AFRICAN HERITAGE	7 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	2 Participants	1 Participants	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized ASIAN - CENTRAL/SOUTH ASIAN HERITAGE	4 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized ASIAN - EAST ASIAN HERITAGE	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized MULTIPLE	2 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized WHITE - ARABIC/NORTH AFRICAN HERITAGE	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized WHITE - WHITE/CAUCASIAN/EUROPEAN HERITAGE	39 Participants	0 Participants	3 Participants	1 Participants	2 Participants	3 Participants	1 Participants	1 Participants	1 Participants	1 Participants	3 Participants	2 Participants	2 Participants	5 Participants	6 Participants	4 Participants	2 Participants	2 Participants
Sex: Female, Male Female	13 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants	1 Participants	1 Participants	0 Participants	0 Participants	2 Participants	3 Participants	1 Participants	0 Participants	0 Participants
Sex: Female, Male Male	41 Participants	2 Participants	2 Participants	1 Participants	2 Participants	3 Participants	2 Participants	2 Participants	0 Participants	1 Participants	2 Participants	2 Participants	2 Participants	5 Participants	4 Participants	5 Participants	3 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk	EG012 affected / at risk	EG013 affected / at risk	EG014 affected / at risk	EG015 affected / at risk
deaths Total, all-cause mortality	0 / 17	0 / 20	0 / 19	0 / 19	0 / 18	0 / 18	0 / 21	0 / 20	0 / 20	0 / 18	0 / 17	0 / 18	0 / 18	0 / 18	0 / 18	0 / 18
other Total, other adverse events	10 / 17	6 / 20	8 / 19	7 / 19	6 / 18	7 / 18	10 / 21	4 / 20	4 / 20	8 / 18	6 / 17	6 / 18	8 / 18	5 / 18	6 / 18	3 / 18
serious Total, serious adverse events	0 / 17	0 / 20	0 / 19	0 / 19	0 / 18	0 / 18	0 / 21	0 / 20	0 / 20	0 / 18	0 / 17	0 / 18	0 / 18	0 / 18	0 / 18	0 / 18

Outcome results

Primary

Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis

Blood samples for measurement of plasma cortisol were collected at given time point. The weighted means were derived by calculating the area under the curve (AUC) over the 0-24-hour period using the trapezoidal rule, and then dividing it by the actual time interval. Results are presented treatment wise. Mean and 95% CI presented are predicted estimate. The analysis method was an inhibitory exponential power-law model with log e transformed cortisol as the outcome variable, assuming 100% inhibition at highest doses.

Time frame: Pre-dose PM dose on Day 6 to pre-dose PM dose Day 7

Population: PD population. Only those participants with data available for each dose escalation phase were analyzed.

Arm	Measure	Value (MEAN)
FF 25 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	172.73 nanomoles per liter
FF 100 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	163.03 nanomoles per liter
FF 200 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	150.95 nanomoles per liter
FF 400 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	129.40 nanomoles per liter
FF 800 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	95.09 nanomoles per liter
FP 50 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	173.04 nanomoles per liter
FP 200 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	164.22 nanomoles per liter
FP 500 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	147.89 nanomoles per liter
FP 1000 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	124.21 nanomoles per liter
FP 2000 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	87.62 nanomoles per liter
BUD 100 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	169.87 nanomoles per liter
BUD 400 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	152.50 nanomoles per liter
BUD 800 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	132.06 nanomoles per liter
BUD 1600 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	99.05 nanomoles per liter
BUD 3200 mcg	Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis	55.71 nanomoles per liter

95% CI: [162.87, 190.38]

95% CI: [698.36, 1101.62]

95% CI: [162.87, 190.38]

95% CI: [1574.7, 2397.39]

95% CI: [162.87, 190.38]

95% CI: [1698.47, 2156.37]

Primary

Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis

The percentage fall in FEV1 was calculated using highest FEV1 (post saline) minus highest FEV1 (post AMP) divided by highest FEV1 (post saline)\*100 where highest FEV1 (post saline) is the highest value of two FEV1 measurements at 60 and 180 seconds after the saline control, highest FEV1 (post AMP) is the highest value of the two FEV1 measurements at 60 and 180 seconds after the dose of AMP. Results are presented treatment wise. The analysis method was a 3 parameter Emax model with log 2 transformed AMP PC20 as the outcome variable, assuming common Emax across FF, FP and BUD, and with an unstructured variance-covariance matrix. Mean and 95% Confidence Interval (CI) presented are predicted estimate.

Time frame: 12 hours post last dose on Day 7

Population: Pharmacodymanic (PD) population. Participants who were randomized and received at least one dose of trial medication and also have at least one post dose PD measurement. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (MEAN)
FF 25 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	33.45 Milligrams per milliliter
FF 100 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	81.45 Milligrams per milliliter
FF 200 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	115.69 Milligrams per milliliter
FF 400 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	145.97 Milligrams per milliliter
FF 800 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	167.26 Milligrams per milliliter
FP 50 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	15.19 Milligrams per milliliter
FP 200 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	20.47 Milligrams per milliliter
FP 500 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	31.39 Milligrams per milliliter
FP 1000 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	48.67 Milligrams per milliliter
FP 2000 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	76.35 Milligrams per milliliter
BUD 100 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	16.00 Milligrams per milliliter
BUD 400 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	23.91 Milligrams per milliliter
BUD 800 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	34.62 Milligrams per milliliter
BUD 1600 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	54.33 Milligrams per milliliter
BUD 3200 mcg	Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis	84.17 Milligrams per milliliter

95% CI: [9.39, 19.39]

95% CI: [8.21, 25.4]

95% CI: [18.21, 129.32]

95% CI: [9.39, 19.39]

95% CI: [8.21, 25.4]

95% CI: [448, 2609.66]

95% CI: [9.39, 19.39]

95% CI: [8.21, 25.4]

95% CI: [546.51, 3939.84]

Primary

Theraputic Index of BUD

Therapeutic Index was calculated by ED20 for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter\[nmol/L\]) divided by ED80 for AMP PC20 for BUD 100 mcg, BUD 400 mcg, BUD 800 mcg, BUD 1600 mcg, BUD 3200 mcg. Theraputic index has been presented. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively.

Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7

Population: PD population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (NUMBER)
FF 25 mcg	Theraputic Index of BUD	0.11 Ratio

95% CI: [546.79, 694.2]

95% CI: [2186.03, 15759.35]

Primary

Theraputic Index of FF

Therapeutic Index was calculated by ED20 for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter\[nmol/L\]) divided by Dose at which 80% of the maximum effect is reached (ED80) for AMP PC20 for FF 25 mcg, FF 100 mcg, FF 200 mcg, FF 400 mcg, FF 800 mcg. Theraputic index has been presented. Only those participants with data available at the specified time points were analyzed. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively.

Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7

Population: PD population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (NUMBER)
FF 25 mcg	Theraputic Index of FF	1.49 Ratio

95% CI: [224.82, 354.64]

95% CI: [72.82, 517.28]

Primary

Theraputic Index of FP

Therapeutic Index was calculated by Dose at which 20% of the maximum effect is reached (ED20) for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter\[nmol/L\]) divided by ED80 for AMP PC20 for FP 50 mcg, FP 200 mcg, FP 500 mcg, FP 1000 mcg, FP 2000 mcg. Theraputic index has been presented. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively.

Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7

Population: PD population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (NUMBER)
FF 25 mcg	Theraputic Index of FP	0.15 Ratio

95% CI: [506.94, 771.79]

95% CI: [1792.02, 10438.64]

Secondary

Forced Expiratory Volume in 1 Second (FEV 1) in Period 1

FEV1 was measured with participants in a sitting position using a calibrated spirometer in accordance with American Thoracic Society (ATS) guidelines using European Respiratory Society (ERS)guidelines for predicted values. Results are presented treatment wise.

Time frame: Day 1 (pre-dose) in Period 1

Population: All Subjects Population.

Arm	Measure	Value (MEAN)	Dispersion
FF 25 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 1	3.18 Liter	Standard Error 0.151
FF 100 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 1	3.02 Liter	Standard Error 0.166
FF 200 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 1	3.50 Liter	Standard Error 0.269
FF 400 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 1	3.29 Liter	Standard Error 0.274

Secondary

Forced Expiratory Volume in 1 Second (FEV 1) in Period 2

FEV1 was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise.

Time frame: Day 1 (pre-dose) in Period 2

Population: All Subjects Population.

Arm	Measure	Value (MEAN)	Dispersion
FF 25 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 2	2.67 Liter	Standard Error 0.482
FF 100 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 2	3.44 Liter	Standard Error 0.431
FF 200 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 2	2.68 Liter	Standard Error 0.278
FF 400 mcg	Forced Expiratory Volume in 1 Second (FEV 1) in Period 2	3.46 Liter	Standard Error 0.257

Secondary

Forced Vital Capacity (FVC) in Period 1

FVC was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise.

Time frame: Day 1 (pre-dose) in Period 1

Population: All Subjects Population.

Arm	Measure	Value (MEAN)	Dispersion
FF 25 mcg	Forced Vital Capacity (FVC) in Period 1	4.55 Liter	Standard Error 0.221
FF 100 mcg	Forced Vital Capacity (FVC) in Period 1	4.36 Liter	Standard Error 0.222
FF 200 mcg	Forced Vital Capacity (FVC) in Period 1	5.15 Liter	Standard Error 0.287
FF 400 mcg	Forced Vital Capacity (FVC) in Period 1	4.70 Liter	Standard Error 0.406

Secondary

Forced Vital Capacity (FVC) in Period 2

Time frame: Day 1 (pre-dose) in Period 2

Population: All Subjects Population.

Arm	Measure	Value (MEAN)	Dispersion
FF 25 mcg	Forced Vital Capacity (FVC) in Period 2	4.11 Liter	Standard Error 0.57
FF 100 mcg	Forced Vital Capacity (FVC) in Period 2	4.85 Liter	Standard Error 0.602
FF 200 mcg	Forced Vital Capacity (FVC) in Period 2	4.09 Liter	Standard Error 0.386
FF 400 mcg	Forced Vital Capacity (FVC) in Period 2	4.90 Liter	Standard Error 0.41

Secondary

Number of Participants With Abnormal Physical Examination

Physical examinations included assessment of the cardiovascular, respiratory, gastrointestinal, skin, abdomen (liver and spleen), and neurological systems. This analysis was planned and data was not collected and captured in the database. Results are presented treatment wise.

Time frame: Up to Week 18

Population: All subjects Population.

Secondary

Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward medical occurrence that at any dose results in death, Is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect. Results are presented treatment wise.

Time frame: Up to Week 18

Population: All Subjects Population was consisted of all participants who were randomized and who received at least one dose of trial medication.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
FF 25 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	10 Participants
FF 25 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FF 100 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FF 100 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	6 Participants
FF 200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	8 Participants
FF 200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FF 400 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FF 400 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	7 Participants
FF 800 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FF 800 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	6 Participants
FP 50 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	7 Participants
FP 50 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FP 200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FP 200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	10 Participants
FP 500 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FP 500 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	4 Participants
FP 1000 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	4 Participants
FP 1000 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
FP 2000 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	8 Participants
FP 2000 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
BUD 100 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	6 Participants
BUD 100 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
BUD 400 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	6 Participants
BUD 400 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
BUD 800 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	8 Participants
BUD 800 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
BUD 1600 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	5 Participants
BUD 1600 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
BUD 3200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	6 Participants
BUD 3200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
BUD 3200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any SAEs	0 Participants
BUD 3200 mcg	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)	Any AEs	3 Participants

Secondary

Number of Participants With Clinically Significant Abnormal Chemistry Parameters

Blood samples were collecte for assessment of following chemistry parametres:Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, alkaline phosphatase, bilirubin, calcium, creatinine, glucose, direct bilirubin, potassium, protein, sodium, urea. Results are presented treatment wise. Only participants with clinically significant abnormal chemistry data was reported.

Time frame: Up to Week 18

Population: All subjects Population.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
FF 25 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FF 100 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FF 200 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FF 400 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FF 800 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FP 50 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FP 200 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FP 500 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FP 1000 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
FP 2000 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
BUD 100 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
BUD 400 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
BUD 800 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
BUD 1600 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
BUD 3200 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants
BUD 3200 mcg	Number of Participants With Clinically Significant Abnormal Chemistry Parameters	0 Participants

Secondary

Number of Participants With Clinically Significant Abnormal Hematology Parameters

Blood samples were collected for assessement of following hematology parameters: basophils, eosinophils, Erythrocyte mean corpuscular volume (MCV), hemoglobin, hematocrit, Erythrocyte mean corpuscular hemoglobin (MCH), leukocytes, lymphocytes, monocytes, platelets. Results are presented treatment wise. Only participants with clinically significant abnormal hematology data was reported.

Time frame: Up to Week 18

Population: All subjects Population.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
FF 25 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FF 100 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FF 200 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FF 400 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FF 800 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FP 50 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FP 200 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FP 500 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FP 1000 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
FP 2000 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
BUD 100 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
BUD 400 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
BUD 800 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
BUD 1600 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
BUD 3200 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants
BUD 3200 mcg	Number of Participants With Clinically Significant Abnormal Hematology Parameters	0 Participants

Secondary

Number of Participants With Clinically Significant Abnormal Urinalysis Parameters

Urine sample were collected to assess following urine parameters: potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick. Results are presented treatment wise. Only participants with clinically significant abnormal urinalysis data was reported.

Time frame: Up to Week 18

Population: All subjects Population.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
FF 25 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FF 100 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FF 200 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FF 400 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FF 800 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FP 50 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FP 200 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FP 500 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FP 1000 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
FP 2000 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
BUD 100 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
BUD 400 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
BUD 800 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
BUD 1600 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
BUD 3200 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants
BUD 3200 mcg	Number of Participants With Clinically Significant Abnormal Urinalysis Parameters	0 Participants

Secondary

Number of Participants With Clinically Significant Abnormal Vital Signs: Pulse Rate

Pulse rate was measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.

Time frame: Up to Week 18

Population: All subjects Population

Secondary

Number of Participants With Clinically Significant Abnormal Vital Signs: Respiratory Rate

Respiratory rate was measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.

Time frame: Up to Week 18

Population: All subjects Population.

Secondary

Number of Participants With Clinically Significant Abnormal Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

SBP and DBP were measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.

Time frame: Up to Week 18

Population: All subjects Population.

Secondary

Number of Participants With Clinically Significant Abnormal Vital Signs: Temperature

Temperature was measured after participants have been rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event.

Time frame: Up to Week 18

Population: All subjects Population.

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 2 to 6 AM and PM, Day 7 PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 2 AM, n=1	600.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 2 PM, n=12	512.9 Liters per minute	Standard Error 33.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 3 AM, n=1	600.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 3 PM, n=12	517.1 Liters per minute	Standard Error 31.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 4 AM, n=1	625.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 4 PM, n=12	524.2 Liters per minute	Standard Error 32.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 5 AM, n=1	600.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 5 PM, n=12	520.8 Liters per minute	Standard Error 32.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 6 AM, n=1	600.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 6 PM, n=12	523.3 Liters per minute	Standard Error 33.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1	Day 7 PM, n=12	527.5 Liters per minute	Standard Error 33.4

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 2,3,4,5,6,7 PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2	Day 4 PM, n=4	545.0 Liters per minute	Standard Error 27.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2	Day 5 PM, n=4	552.5 Liters per minute	Standard Error 46
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2	Day 2 PM, n=4	557.5 Liters per minute	Standard Error 28.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2	Day 3 PM, n=4	547.5 Liters per minute	Standard Error 60.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2	Day 6 PM, n=4	577.5 Liters per minute	Standard Error 26.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2	Day 7 PM, n=3	603.3 Liters per minute	Standard Error 32.8

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 22 PM	506.4 Liters per minute	Standard Error 33.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 23 AM	496.4 Liters per minute	Standard Error 29.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 23 PM	512.7 Liters per minute	Standard Error 32.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 24 AM	498.2 Liters per minute	Standard Error 34.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 24 PM	510.5 Liters per minute	Standard Error 34.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 25 AM	500.5 Liters per minute	Standard Error 32.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 25 PM	514.1 Liters per minute	Standard Error 33.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 26 AM	499.1 Liters per minute	Standard Error 31.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 26 PM	512.3 Liters per minute	Standard Error 35.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 27 AM	491.4 Liters per minute	Standard Error 31
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 27 PM	497.7 Liters per minute	Standard Error 37.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 28 AM	476.8 Liters per minute	Standard Error 27.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1	Day 28 PM	526.8 Liters per minute	Standard Error 33.9

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 22 PM	594.0 Liters per minute	Standard Error 47.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 23 AM	578.0 Liters per minute	Standard Error 40
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 23 PM	586.0 Liters per minute	Standard Error 46.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 24 AM	556.0 Liters per minute	Standard Error 37.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 24 PM	556.0 Liters per minute	Standard Error 45.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 25 AM	564.0 Liters per minute	Standard Error 50.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 25 PM	594.0 Liters per minute	Standard Error 45.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 26 AM	584.0 Liters per minute	Standard Error 45.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 26 PM	568.0 Liters per minute	Standard Error 51.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 27 AM	568.0 Liters per minute	Standard Error 52.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 27 PM	584.0 Liters per minute	Standard Error 35.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 28 AM	574.0 Liters per minute	Standard Error 30.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2	Day 28 PM	630.0 Liters per minute	Standard Error 46

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 29 PM, n=10	493.0 Liters per minute	Standard Error 31.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 30 AM, n=10	482.0 Liters per minute	Standard Error 33.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 30 PM, n=10	502.0 Liters per minute	Standard Error 33.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 31 AM, n=10	482.0 Liters per minute	Standard Error 34
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 31 PM, n=10	496.0 Liters per minute	Standard Error 32.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 32 AM, n=10	482.0 Liters per minute	Standard Error 30.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 32 PM, n=10	488.0 Liters per minute	Standard Error 33
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 33 AM, n=10	483.0 Liters per minute	Standard Error 29.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 33 PM, n=10	490.0 Liters per minute	Standard Error 35
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 34 AM, n=10	489.0 Liters per minute	Standard Error 31.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 34 PM, n=9	522.2 Liters per minute	Standard Error 33.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 35 AM, n=10	474.0 Liters per minute	Standard Error 33.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1	Day 35 PM, n=10	488.0 Liters per minute	Standard Error 30.6

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 32 AM, n=4	592.5 Liters per minute	Standard Error 38.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 32 PM, n=4	587.5 Liters per minute	Standard Error 18.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 29 PM, n=5	596.0 Liters per minute	Standard Error 43.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 30 AM, n=5	604.0 Liters per minute	Standard Error 22.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 30 PM, n=5	586.0 Liters per minute	Standard Error 41.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 31 AM, n=4	562.5 Liters per minute	Standard Error 33.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 31 PM, n=4	547.5 Liters per minute	Standard Error 43.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 33 AM, n=4	567.5 Liters per minute	Standard Error 30.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 33 PM, n=4	565.0 Liters per minute	Standard Error 42.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 34 AM, n=4	585.0 Liters per minute	Standard Error 38.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 34 PM, n=4	583.8 Liters per minute	Standard Error 29.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 35 AM, n=4	577.5 Liters per minute	Standard Error 35.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2	Day 35 PM, n=4	597.5 Liters per minute	Standard Error 38.6

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 8 PM, Day 9 to 14 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 8 PM, n=12	521.7 Liters per minute	Standard Error 31.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 9 AM, n=10	473.0 Liters per minute	Standard Error 30.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 9 PM, n=12	515.4 Liters per minute	Standard Error 34.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 10 AM, n=10	470.0 Liters per minute	Standard Error 33.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 10 PM, n=12	512.9 Liters per minute	Standard Error 32.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 11 AM, n=10	466.7 Liters per minute	Standard Error 36
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 11 PM, n=11	492.5 Liters per minute	Standard Error 35.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 12 AM, n=9	451.1 Liters per minute	Standard Error 28.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 12 PM, n=11	509.5 Liters per minute	Standard Error 33.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 13 AM, n=9	457.8 Liters per minute	Standard Error 33.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 13 PM, n=11	506.8 Liters per minute	Standard Error 33.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 14 AM, n=11	480.5 Liters per minute	Standard Error 30.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1	Day 14 PM, n=11	496.4 Liters per minute	Standard Error 32.1

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 8 PM, Day 9 to 14 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 8 PM	560.0 Liters per minute	Standard Error 43.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 9 AM	552.0 Liters per minute	Standard Error 40.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 9 PM	560.0 Liters per minute	Standard Error 34.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 10 AM	552.0 Liters per minute	Standard Error 34.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 10 PM	556.0 Liters per minute	Standard Error 30.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 11 AM	562.0 Liters per minute	Standard Error 26.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 11 PM	574.0 Liters per minute	Standard Error 30.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 12 AM	568.0 Liters per minute	Standard Error 29.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 12 PM	578.0 Liters per minute	Standard Error 44.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 13 AM	562.0 Liters per minute	Standard Error 28.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 13 PM	588.0 Liters per minute	Standard Error 37.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 14 AM	586.0 Liters per minute	Standard Error 22.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2	Day 14 PM	590.0 Liters per minute	Standard Error 44.6

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 15,16, 17, 18, 19, 20, 21 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 15 AM, n=1	610.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 15 PM, n=11	515.5 Liters per minute	Standard Error 30.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 16 AM, n=11	494.5 Liters per minute	Standard Error 31.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 16 PM, n=11	507.3 Liters per minute	Standard Error 34.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 17 AM, n=11	484.1 Liters per minute	Standard Error 33.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 17 PM, n=11	505.0 Liters per minute	Standard Error 34.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 18 AM, n=11	492.7 Liters per minute	Standard Error 33.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 18 PM, n=11	503.2 Liters per minute	Standard Error 36.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 19 AM, n=11	483.2 Liters per minute	Standard Error 29.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 19 PM, n=11	487.7 Liters per minute	Standard Error 38
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 20 AM, n=11	483.6 Liters per minute	Standard Error 31.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 20 PM, n=11	517.7 Liters per minute	Standard Error 33.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 21 AM, n=11	490.5 Liters per minute	Standard Error 27.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1	Day 21 PM, n=11	509.1 Liters per minute	Standard Error 32.9

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 15 PM, Day 16, 17, 18, 19, 20, 21 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 15 PM	578.0 Liters per minute	Standard Error 32
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 16 AM	568.0 Liters per minute	Standard Error 37.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 16 PM	572.0 Liters per minute	Standard Error 45.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 17 AM	572.0 Liters per minute	Standard Error 27.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 17 PM	558.0 Liters per minute	Standard Error 46
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 18 AM	558.0 Liters per minute	Standard Error 45.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 18 PM	568.0 Liters per minute	Standard Error 53.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 19 AM	572.0 Liters per minute	Standard Error 46.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 19 PM	584.0 Liters per minute	Standard Error 47.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 20 AM	590.0 Liters per minute	Standard Error 37.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 20 PM	590.0 Liters per minute	Standard Error 37.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 21 AM	574.0 Liters per minute	Standard Error 23.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2	Day 21 PM	606.0 Liters per minute	Standard Error 38

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. One participant who was supposed to receive FP 1000 mg during day 22-28 and FP 2000 mg during day 28-35 but this participant continued the 3rd escalation phase dose (FP 500 mg) in fourth escalation phase and took FP 1000 mg (4th phase dose) in the fifth escalation phase (days 28-35).

Time frame: Day 22 PM, Day 23,24,25,26,27,28,29,30,31,32,33,34,35 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 23 PM, n=11	516.4 Liters per minute	Standard Error 38.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 24 AM, n=11	521.8 Liters per minute	Standard Error 38
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 24 PM, n=11	520.9 Liters per minute	Standard Error 37.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 25 AM, n=11	489.5 Liters per minute	Standard Error 35.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 25 PM, n=10	521.0 Liters per minute	Standard Error 42.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 26 AM, n=11	502.7 Liters per minute	Standard Error 37
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 32 PM, n=1	550.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 33 AM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 33 PM, n=1	540.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 34 AM, n=1	510.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 34 PM, n=1	520.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 35 AM, n=1	540.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 35 PM, n=1	550.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 22 PM, n=6	523.2 Liters per minute	Standard Error 30.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 23 AM, n=11	511.8 Liters per minute	Standard Error 36.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 26 PM, n=11	517.3 Liters per minute	Standard Error 35.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 27 AM, n=11	493.6 Liters per minute	Standard Error 33
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 27 PM, n=11	523.6 Liters per minute	Standard Error 37.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 28 AM, n=11	500.0 Liters per minute	Standard Error 40.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 28,PM, n=11	516.4 Liters per minute	Standard Error 33.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 29 PM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 30 AM, n=1	520.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 30 PM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 31 AM, n=1	510.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 31 PM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1	Day 32 AM, n=1	520.0 Liters per minute	—

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 22 PM, n=6	493.3 Liters per minute	Standard Error 42.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 23 AM, n=6	480.0 Liters per minute	Standard Error 43.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 23 PM, n=6	506.7 Liters per minute	Standard Error 43.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 24 AM, n=6	481.7 Liters per minute	Standard Error 39.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 24 PM, n=6	505.0 Liters per minute	Standard Error 45.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 25 AM, n=6	491.7 Liters per minute	Standard Error 43.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 25 PM, n=6	510.0 Liters per minute	Standard Error 51.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 26 AM, n=6	485.0 Liters per minute	Standard Error 45.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 26 PM, n=6	501.7 Liters per minute	Standard Error 49.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 27 AM, n=6	475.0 Liters per minute	Standard Error 42.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 27 PM, n=6	490.0 Liters per minute	Standard Error 43.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 28 AM, n=5	452.0 Liters per minute	Standard Error 47.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2	Day 28,PM, n=5	476.0 Liters per minute	Standard Error 56.8

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 29 PM, n=10	520.5 Liters per minute	Standard Error 36.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 30 AM, n=10	505.0 Liters per minute	Standard Error 39
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 30 PM, n=10	520.0 Liters per minute	Standard Error 40.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 31 AM, n=10	507.0 Liters per minute	Standard Error 37
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 31 PM, n=10	521.0 Liters per minute	Standard Error 41.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 32 AM, n=10	500.0 Liters per minute	Standard Error 39.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 32 PM, n=10	524.0 Liters per minute	Standard Error 41.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 33 AM, n=10	511.0 Liters per minute	Standard Error 40.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 33 PM, n=10	511.5 Liters per minute	Standard Error 43.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 34 AM, n=10	519.0 Liters per minute	Standard Error 38.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 34 PM, n=10	517.0 Liters per minute	Standard Error 38.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 35 AM, n=9	514.4 Liters per minute	Standard Error 40.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1	Day 35 PM, n=9	543.9 Liters per minute	Standard Error 44.1

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 29 PM	506.7 Liters per minute	Standard Error 45.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 30 AM	493.3 Liters per minute	Standard Error 45
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 30 PM	496.7 Liters per minute	Standard Error 46.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 31 AM	486.7 Liters per minute	Standard Error 48
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 31 PM	485.0 Liters per minute	Standard Error 41.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 32 AM	488.3 Liters per minute	Standard Error 44.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 32 PM	513.3 Liters per minute	Standard Error 52.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 33 AM	495.0 Liters per minute	Standard Error 45.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 33 PM	498.3 Liters per minute	Standard Error 44.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 34 AM	481.7 Liters per minute	Standard Error 46
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 34 PM	498.3 Liters per minute	Standard Error 47.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 35 AM	483.3 Liters per minute	Standard Error 44.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2	Day 35 PM	493.3 Liters per minute	Standard Error 46.3

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1

Time frame: Day 15 PM, Day 16,17,18,19,20,21,22,23,24,25,26,27,28 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 15 PM, n=14	527.5 Liters per minute	Standard Error 29.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 16 AM, n=13	503.8 Liters per minute	Standard Error 31.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 16 PM, n=14	520.4 Liters per minute	Standard Error 29.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 17 AM, n=13	510.0 Liters per minute	Standard Error 30.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 17 PM, n=14	508.6 Liters per minute	Standard Error 31.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 18 AM, n=12	497.5 Liters per minute	Standard Error 34.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 18 PM, n=13	505.8 Liters per minute	Standard Error 28.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 19 AM, n=12	505.8 Liters per minute	Standard Error 35.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 19 PM, n=13	506.9 Liters per minute	Standard Error 29.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 20 AM, n=11	518.2 Liters per minute	Standard Error 35.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 20 PM, n=13	517.3 Liters per minute	Standard Error 30.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 21 AM, n=13	501.9 Liters per minute	Standard Error 32.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 21 PM, n=11	493.6 Liters per minute	Standard Error 30
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 22 AM, n=1	520.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 22 PM, n=1	540.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 23 AM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 23 PM, n=1	550.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 24 AM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 24 PM, n=1	540.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 25 AM, n=1	510.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 25 PM, n=1	500.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 26 AM, n=1	520.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 26 PM, n=1	550.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 27 AM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 27 PM, n=1	580.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 28 AM, n=1	530.0 Liters per minute	—
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1	Day 28 PM, n=1	500.0 Liters per minute	—

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 15 PM, Day 16,17,18,19,20,21 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 15 PM, n=6	486.7 Liters per minute	Standard Error 43.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 16 AM, n=6	476.7 Liters per minute	Standard Error 43.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 16 PM, n=6	503.3 Liters per minute	Standard Error 46.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 17 AM, n=6	493.3 Liters per minute	Standard Error 44
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 17 PM, n=6	500.0 Liters per minute	Standard Error 45.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 18 AM, n=6	476.7 Liters per minute	Standard Error 39.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 18 PM, n=6	495.0 Liters per minute	Standard Error 42.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 19 AM, n=5	454.0 Liters per minute	Standard Error 44.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 19 PM, n=6	500.0 Liters per minute	Standard Error 45.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 20 AM, n=5	524.0 Liters per minute	Standard Error 43.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 20 PM, n=6	501.7 Liters per minute	Standard Error 50.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 21 AM, n=6	490.0 Liters per minute	Standard Error 44.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2	Day 21 PM, n=6	496.7 Liters per minute	Standard Error 48.4

Secondary

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Participants recorded their PEFR measurement before each dose in a paper diary. Results are presented treatment wise.Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Time frame: Day 2 to 8 PM, Day 9 to 14 AM and PM, Day 15 PM, Day 16 to 21 AM and PM, Day 22 PM,Day 23 to 28 AM and PM, Day 29 PM,Day 30 to 35 AM and PM in period 1

Population: All subjects Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 15, PM, n=12	530.8 Liters per minute	Standard Error 26
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 16, AM, n=5	588.0 Liters per minute	Standard Error 36.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 19, AM, n=5	568.0 Liters per minute	Standard Error 38.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 19,PM, n=12	535.8 Liters per minute	Standard Error 29.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 20, AM, n=5	596.0 Liters per minute	Standard Error 37.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 20,PM, n=12	544.2 Liters per minute	Standard Error 28.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 21, AM, n=5	580.0 Liters per minute	Standard Error 31.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 21,PM, n=12	534.2 Liters per minute	Standard Error 32.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 22,PM, n=11	544.5 Liters per minute	Standard Error 29
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 23, AM, n=4	577.5 Liters per minute	Standard Error 37.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 23,PM, n=11	530.0 Liters per minute	Standard Error 27.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 24, AM, n=4	567.5 Liters per minute	Standard Error 39.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 24,PM, n=11	526.4 Liters per minute	Standard Error 26.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 25, AM, n=4	585.0 Liters per minute	Standard Error 39.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 25,PM, n=11	530.9 Liters per minute	Standard Error 29.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 26, AM, n=4	582.5 Liters per minute	Standard Error 40
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 26,PM, n=11	518.2 Liters per minute	Standard Error 30
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 27, AM, n=4	587.5 Liters per minute	Standard Error 40
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 27,PM, n=11	539.1 Liters per minute	Standard Error 29.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 28, AM, n=4	587.5 Liters per minute	Standard Error 43
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 28,PM, n=10	547.0 Liters per minute	Standard Error 30.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 29,PM, n=11	547.3 Liters per minute	Standard Error 28.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 30, AM, n=4	567.5 Liters per minute	Standard Error 38.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 30,PM, n=11	527.3 Liters per minute	Standard Error 26.6
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 31, AM, n=4	562.5 Liters per minute	Standard Error 33.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 31,PM, n=11	537.3 Liters per minute	Standard Error 26.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 32, AM, n=4	582.5 Liters per minute	Standard Error 40.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 32,PM, n=11	537.3 Liters per minute	Standard Error 26.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 33, AM, n=4	597.5 Liters per minute	Standard Error 40
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 33,PM, n=11	528.2 Liters per minute	Standard Error 30.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 34, AM, n=4	580.0 Liters per minute	Standard Error 39.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 34,PM, n=11	531.4 Liters per minute	Standard Error 31.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 35, AM, n=4	565.0 Liters per minute	Standard Error 38.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 35,PM, n=11	501.8 Liters per minute	Standard Error 26.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 2, PM, n=12	522.5 Liters per minute	Standard Error 25.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 3, PM, n=12	517.5 Liters per minute	Standard Error 27
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 4, PM, n=12	514.2 Liters per minute	Standard Error 27.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 5,PM, n=12	521.7 Liters per minute	Standard Error 24.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 6, PM, n=12	522.5 Liters per minute	Standard Error 29.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 7, PM, n=12	539.2 Liters per minute	Standard Error 32.3
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 8, PM, n=12	530.8 Liters per minute	Standard Error 27.8
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 9, AM, n=5	576.0 Liters per minute	Standard Error 37.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 9, PM, n=12	531.3 Liters per minute	Standard Error 27.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 10, AM, n=5	572.0 Liters per minute	Standard Error 34.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 10, PM, n=12	535.0 Liters per minute	Standard Error 22
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 11, AM, n=5	578.0 Liters per minute	Standard Error 35.9
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 11, PM, n=12	533.8 Liters per minute	Standard Error 29
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 12, AM, n=5	578.0 Liters per minute	Standard Error 37.2
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 12 PM, n=12	527.5 Liters per minute	Standard Error 26.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 13, AM, n=5	580.0 Liters per minute	Standard Error 37.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 13, PM, n=12	540.8 Liters per minute	Standard Error 25.1
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 14, AM, n=5	572.0 Liters per minute	Standard Error 34.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 14, PM, n=12	543.3 Liters per minute	Standard Error 26.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 16,PM, n=12	528.3 Liters per minute	Standard Error 24.4
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 17, AM, n=5	586.0 Liters per minute	Standard Error 31.7
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 17,PM, n=12	521.7 Liters per minute	Standard Error 32.5
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 18, AM, n=5	586.0 Liters per minute	Standard Error 35
FF 25 mcg	Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1	Day 18,PM, n=12	540.0 Liters per minute	Standard Error 26.9

Secondary

PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 8,9,10,11,12,13,14 PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 8, PM, n=13	497.3 Liters per minute	Standard Error 24.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 9, PM, n=13	500.4 Liters per minute	Standard Error 28.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 10, PM, n=13	491.2 Liters per minute	Standard Error 31
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 11, PM, n=12	507.5 Liters per minute	Standard Error 30.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 12, PM, n=13	500.2 Liters per minute	Standard Error 30.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 13, PM, n=13	515.4 Liters per minute	Standard Error 29.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1	Day 14, PM, n=13	505.8 Liters per minute	Standard Error 28.7

Secondary

PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 8,9,10,11,12,13,14 PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 8, PM	540.0 Liters per minute	Standard Error 43.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 9, PM	567.5 Liters per minute	Standard Error 42.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 10, PM	556.7 Liters per minute	Standard Error 43.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 11, PM	561.7 Liters per minute	Standard Error 44.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 12, PM	573.3 Liters per minute	Standard Error 50
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 13, PM	563.3 Liters per minute	Standard Error 53
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2	Day 14, PM	555.8 Liters per minute	Standard Error 46.9

Secondary

PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 15,16,17,18,19,20,21 PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 15,PM, n=13	500.8 Liters per minute	Standard Error 30.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 16,PM, n=13	500.0 Liters per minute	Standard Error 28.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 17,PM, n=13	506.2 Liters per minute	Standard Error 29.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 18,PM, n=13	514.2 Liters per minute	Standard Error 31.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 19,PM, n=13	505.4 Liters per minute	Standard Error 29
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 20,PM, n=12	505.8 Liters per minute	Standard Error 30.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1	Day 21,PM, n=12	485.0 Liters per minute	Standard Error 28.2

Secondary

PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 15,16,17,18,19,20 PM, Day 21 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 15,PM, n=6	575.0 Liters per minute	Standard Error 52.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 16,PM, n=6	575.0 Liters per minute	Standard Error 48.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 17,PM, n=6	564.2 Liters per minute	Standard Error 46.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 18,PM, n=6	573.3 Liters per minute	Standard Error 56.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 19,PM, n=6	556.7 Liters per minute	Standard Error 53.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 20,PM, n=6	571.7 Liters per minute	Standard Error 50
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 21,AM, n=1	670.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2	Day 21,PM, n=6	560.0 Liters per minute	Standard Error 38.3

Secondary

PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 2,3,4,5,6,7 PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n= X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1	Day 2, PM, n=14	479.6 Liters per minute	Standard Error 30.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1	Day 3, PM, n=14	475.7 Liters per minute	Standard Error 32.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1	Day 4, PM, n=14	473.0 Liters per minute	Standard Error 31.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1	Day 5,PM, n=14	476.1 Liters per minute	Standard Error 26.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1	Day 6, PM, n=13	503.1 Liters per minute	Standard Error 24.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1	Day 7, PM, n=13	502.3 Liters per minute	Standard Error 28.1

Secondary

PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 2,3,4,5,6,7 PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n= X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2	Day 6, PM, n=6	550.8 Liters per minute	Standard Error 52.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2	Day 7, PM, n=6	560.0 Liters per minute	Standard Error 45.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2	Day 2, PM, n=5	572.0 Liters per minute	Standard Error 48.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2	Day 3, PM, n=5	570.0 Liters per minute	Standard Error 54.5
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2	Day 4, PM, n=5	568.0 Liters per minute	Standard Error 55
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2	Day 5,PM, n=5	573.0 Liters per minute	Standard Error 54.9

Secondary

PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Days 22,23,24,25,26,27,28 PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Day 22 PM	496.7 Liters per minute	Standard Error 30.5
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Day 23 PM	481.0 Liters per minute	Standard Error 25.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Day 24 PM	484.6 Liters per minute	Standard Error 25.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Day 25 PM	488.3 Liters per minute	Standard Error 26.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Day 26 PM	496.7 Liters per minute	Standard Error 28.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Day 27 PM	508.8 Liters per minute	Standard Error 28.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1	Day 28 PM	486.7 Liters per minute	Standard Error 23.7

Secondary

PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Days 22,23,24,25,26,27,28 PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Day 22 PM	556.7 Liters per minute	Standard Error 46.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Day 23 PM	566.7 Liters per minute	Standard Error 47.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Day 24 PM	571.7 Liters per minute	Standard Error 50.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Day 25 PM	568.3 Liters per minute	Standard Error 52.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Day 26 PM	565.0 Liters per minute	Standard Error 43
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Day 27 PM	540.0 Liters per minute	Standard Error 43.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2	Day 28 PM	541.7 Liters per minute	Standard Error 41.2

Secondary

PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Days 29,30,31,32,33,34,35 PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Day 30 PM	487.1 Liters per minute	Standard Error 25.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Day 31 PM	488.3 Liters per minute	Standard Error 24.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Day 32 PM	481.3 Liters per minute	Standard Error 25.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Day 33 PM	481.5 Liters per minute	Standard Error 24.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Day 34 PM	487.5 Liters per minute	Standard Error 28.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Day 35 PM	471.0 Liters per minute	Standard Error 26.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1	Day 29 PM	496.7 Liters per minute	Standard Error 27

Secondary

PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 29,30,31,32,33,34,35 PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 29 PM	576.7 Liters per minute	Standard Error 44.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 30 PM	560.0 Liters per minute	Standard Error 48.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 31 PM	553.3 Liters per minute	Standard Error 45
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 32 PM	565.0 Liters per minute	Standard Error 50.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 33 PM	580.0 Liters per minute	Standard Error 48.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 34 PM	568.3 Liters per minute	Standard Error 42.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2	Day 35 PM	556.7 Liters per minute	Standard Error 44.9

Secondary

PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Days 8,9,1,0,11,12,13,14 AM and PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 10 AM, n=10	521.0 Liters per minute	Standard Error 39
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 10 PM, n=14	513.2 Liters per minute	Standard Error 28.5
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 11 AM, n=11	476.4 Liters per minute	Standard Error 35.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 11 PM, n=14	512.1 Liters per minute	Standard Error 30
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 12 AM, n=11	506.8 Liters per minute	Standard Error 38
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 12 PM, n=13	528.8 Liters per minute	Standard Error 34.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 13 AM, n=11	500.0 Liters per minute	Standard Error 38.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 13 PM, n=14	514.6 Liters per minute	Standard Error 31.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 14 AM, n=13	496.2 Liters per minute	Standard Error 31.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 8 AM, n=1	540.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 8 PM, n=13	532.7 Liters per minute	Standard Error 33.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 9 AM, n=11	500.9 Liters per minute	Standard Error 38.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day 9 PM, n=14	517.9 Liters per minute	Standard Error 26.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1	Day14 PM, n=13	522.7 Liters per minute	Standard Error 32.9

Secondary

PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 8,9,1,0,11,12,13,14 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 8 PM, n=6	500.0 Liters per minute	Standard Error 43.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 9 AM, n=5	506.0 Liters per minute	Standard Error 39.5
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 9 PM, n=6	488.3 Liters per minute	Standard Error 43.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 10 AM, n=4	515.0 Liters per minute	Standard Error 44
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 10 PM, n=6	490.0 Liters per minute	Standard Error 47.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 11 AM, n=5	504.0 Liters per minute	Standard Error 36.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 11 PM, n=6	485.0 Liters per minute	Standard Error 42.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 12 AM, n=5	508.0 Liters per minute	Standard Error 41.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 12 PM, n=6	493.3 Liters per minute	Standard Error 42.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 13 AM, n=5	500.0 Liters per minute	Standard Error 40.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 13 PM, n=6	495.0 Liters per minute	Standard Error 45.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 14 AM, n=5	438.0 Liters per minute	Standard Error 46.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 14 PM, n=6	495.8 Liters per minute	Standard Error 48.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2	Day 8 AM, n=1	610.0 Liters per minute	—

Secondary

PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 2,3,4,5,6,7 PM in period 1

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1	Day 2 PM, n=15	529.3 Liters per minute	Standard Error 28
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1	Day 3 PM, n=14	533.6 Liters per minute	Standard Error 30.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1	Day 4 PM, n=15	532.3 Liters per minute	Standard Error 30.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1	Day 5 PM, n=15	524.0 Liters per minute	Standard Error 29.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1	Day 6 PM, n=14	519.3 Liters per minute	Standard Error 26.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1	Day 7 PM, n=14	502.9 Liters per minute	Standard Error 35.1

Secondary

PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Time frame: Day 2,3,4,5,6,7 AM and PM in period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 2 AM, n=1	600.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 2 PM, n=6	490.0 Liters per minute	Standard Error 40.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 3 AM, n=1	600.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 3 PM, n=6	486.7 Liters per minute	Standard Error 42.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 4 PM, n=1	590.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 4 PM, n=6	491.7 Liters per minute	Standard Error 42.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 5 AM, n=1	600.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 5 PM, n=6	491.7 Liters per minute	Standard Error 44.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 6 PM, n=1	600.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 6 PM, n=6	490.0 Liters per minute	Standard Error 44.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 7 PM, n=1	600.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2	Day 7 PM, n=6	466.0 Liters per minute	Standard Error 48.9

Secondary

PEFR as a Measure of Safety and Tolerability of Placebo in Period 2

Time frame: Day 2 to 8 PM, Day 9 to 14 AM and PM, Day 15 PM, Day 16 to 21 AM and PM, Day 22 PM,Day 23 to 28 AM and PM, Day 29 PM,Day 30 to 35 AM and PM in Period 2

Population: All subjects Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (MEAN)	Dispersion
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 2, PM, n=4	422.5 Liters per minute	Standard Error 28.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 3, PM, n=4	415.0 Liters per minute	Standard Error 27.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 4, PM, n=4	398.8 Liters per minute	Standard Error 26.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 5,PM, n=4	407.5 Liters per minute	Standard Error 37.5
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 6, PM, n=4	411.3 Liters per minute	Standard Error 29
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 7, PM, n=4	410.0 Liters per minute	Standard Error 36.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 8, PM, n=4	415.0 Liters per minute	Standard Error 36.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 9, AM, n=2	430.0 Liters per minute	Standard Error 80
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 18,PM,n=3	423.3 Liters per minute	Standard Error 34.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 19, AM, n=2	415.0 Liters per minute	Standard Error 65
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 28,PM, n=3	430.0 Liters per minute	Standard Error 49.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 29,PM, n=3	380.0 Liters per minute	Standard Error 75.5
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 30, AM, n=1	460.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 30,PM, n=3	388.3 Liters per minute	Standard Error 78
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 31, AM, n=1	480.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 31,PM, n=3	390.0 Liters per minute	Standard Error 85
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 9, PM, n=4	411.3 Liters per minute	Standard Error 45.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 10, AM, n=2	425.0 Liters per minute	Standard Error 65
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 10, PM, n=4	403.8 Liters per minute	Standard Error 37.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 11, AM, n=2	410.0 Liters per minute	Standard Error 60
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 11, PM, n=4	395.0 Liters per minute	Standard Error 29
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 12, AM, n=2	400.0 Liters per minute	Standard Error 50
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 12, PM, n=4	398.8 Liters per minute	Standard Error 28.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 13, AM, n=2	415.0 Liters per minute	Standard Error 95
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 13, PM, n=4	425.0 Liters per minute	Standard Error 35.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 14, AM, n=2	425.0 Liters per minute	Standard Error 65
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 14, PM, n=3	420.0 Liters per minute	Standard Error 40.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 15, PM, n=4	416.3 Liters per minute	Standard Error 37
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 16, AM, n=2	405.0 Liters per minute	Standard Error 75
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 16,PM, n=4	405.0 Liters per minute	Standard Error 32
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 17, AM, n=2	390.0 Liters per minute	Standard Error 70
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 17,PM, n=4	405.0 Liters per minute	Standard Error 28.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 18, AM, n=1	450.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 19,PM, n=4	402.5 Liters per minute	Standard Error 30.1
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 20, AM, n=2	402.5 Liters per minute	Standard Error 57.5
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 20,PM, n=4	398.8 Liters per minute	Standard Error 36.3
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 21, AM, n=2	400.0 Liters per minute	Standard Error 60
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 21,PM, n=4	395.0 Liters per minute	Standard Error 38.6
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 22,PM, n=4	397.5 Liters per minute	Standard Error 34.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 23, AM, n=1	480.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 23,PM, n=3	415.0 Liters per minute	Standard Error 39
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 24, AM, n=1	460.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 24,PM, n=3	423.3 Liters per minute	Standard Error 38.4
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 25, AM, n=1	460.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 25,PM, n=3	416.7 Liters per minute	Standard Error 33.8
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 26, AM, n=1	450.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 26,PM, n=3	418.3 Liters per minute	Standard Error 36.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 27, AM, n=1	460.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 27,PM, n=3	433.3 Liters per minute	Standard Error 49.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 28, AM, n=1	460.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 32, AM, n=1	500.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 32,PM, n=3	370.0 Liters per minute	Standard Error 73.7
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 33, AM, n=1	470.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 33,PM, n=3	370.0 Liters per minute	Standard Error 70.9
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 34, AM, n=1	460.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 34,PM, n=3	390.0 Liters per minute	Standard Error 83.2
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 35, AM, n=1	480.0 Liters per minute	—
FF 25 mcg	PEFR as a Measure of Safety and Tolerability of Placebo in Period 2	Day 35,PM, n=2	345.0 Liters per minute	Standard Error 105

Source: ClinicalTrials.gov · Data processed: Feb 20, 2026

Phase 2a, AMP Challenge, Dose Escalation Study to Assess the Dose Response for Topical Efficacy and Systemic Activity in Asthmatic Subjects

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis

Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis

Theraputic Index of BUD

Theraputic Index of FF

Theraputic Index of FP

Forced Expiratory Volume in 1 Second (FEV 1) in Period 1

Forced Expiratory Volume in 1 Second (FEV 1) in Period 2

Forced Vital Capacity (FVC) in Period 1

Forced Vital Capacity (FVC) in Period 2

Number of Participants With Abnormal Physical Examination

Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)

Number of Participants With Clinically Significant Abnormal Chemistry Parameters

Number of Participants With Clinically Significant Abnormal Hematology Parameters

Number of Participants With Clinically Significant Abnormal Urinalysis Parameters

Number of Participants With Clinically Significant Abnormal Vital Signs: Pulse Rate

Number of Participants With Clinically Significant Abnormal Vital Signs: Respiratory Rate

Number of Participants With Clinically Significant Abnormal Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Number of Participants With Clinically Significant Abnormal Vital Signs: Temperature

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2

Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1

PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1

PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2

PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1

PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2

PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1

PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2

PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1

PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2

PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1

PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2

PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1

PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2

PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1

PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2

PEFR as a Measure of Safety and Tolerability of Placebo in Period 2