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Pharmacokinetics, Safety and Tolerability of Twice-Daily Aclidinium Bromide/Formoterol Fumarate Fixed Dose Combination in Chinese Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease

A Phase IIa, Open-Label, Repeat-Dose Clinical Trial to Evaluate the Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Fixed Dose Combination Administered Twice-Daily by Inhalation in Chinese Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT03276078
Enrollment
20
Registered
2017-09-08
Start date
2017-11-23
Completion date
2018-06-12
Last updated
2019-07-22

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

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

COPD

Brief summary

A Phase IIa, open-label, repeat-dose trial to investigate the pharmacokinetics (PK), safety and tolerability of single and multiple twice daily doses of inhaled Aclidinium Bromide/Formoterol Fumarate 400/12 μg in 20 Chinese male and female patients with stable moderate to severe COPD.

Detailed description

Screening will be performed within 21 days of dosing on Day 1 at visit 2. Eligible participants will be admitted to the trial center the day preceding the first dosing (day -1). Participants will receive Aclidinium Bromide/Formoterol Fumarate 400/12 μg twice-daily (morning and evening) on Days 1 to 4. On Day 5 patients will receive the morning dose only. PK and safety assessments will be conducted at specific timepoints on Day 1 to Day 7. Participants will be discharged 48 h after the last administration of investigational product and completion of the 48-h PK sample collection and safety assessments on Day 7. A follow-up visit will be performed within 5 days of the last PK sample collection on Day 7.

Interventions

DRUGAclidinium Bromide/Formoterol Fumarate 400/12μg BID

Aclidinium bromide/formoterol fumarate 400/12μg administered by inhalation via the Genuair® multidose dry powder inhaler, twice daily (morning and evening) for 5 days

Sponsors

AstraZeneca
Lead SponsorINDUSTRY

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
40 Years to 130 Years
Healthy volunteers
No

Inclusion criteria

* Ability to communicate with medical team and staff, willing to participate in the trial, willing to give written informed consent, and comply with the trial procedures and restrictions. * Chinese men or non-pregnant, non-lactating women, aged ≥40 years old at Visit 1 (Screening). * Patients with a diagnosis of COPD (GOLD guidelines) for a period of at least 6 months prior to Visit 1 (screening). * Current or former smokers with a smoking history of ≥10 pack-years. * Patients with moderate to severe stable COPD (Stage II or Stage III, according to GOLD Guidelines) at Visit 1: post-bronchodilator FEV1 ≥30% and \<80% and post-bronchodilator FEV1/FVC \<70%. * Must be able to perform repeatable pulmonary function testing for FEV1 according to ATS/ERS 2005 criteria at Visit 1 (Screening).

Exclusion criteria

* Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff) or patients employed by or relatives of the employees of the site or sponsor. * Previous enrolment or randomisation in the present study. * History or current diagnosis of asthma. * Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening or during the run-in period. * Patients hospitalized for COPD exacerbation (an emergency room visit for longer than 24 hours will be considered a hospitalization) within 3 months prior to screening and during the run-in period. * Use of long-term oxygen therapy ≥15 hours per day. * Patient with a history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, inhaled medication, or any component thereof. * Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic nonstable prostatic hypertrophy. * Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypothyroidism or hyperthyroidism, hypokalaemia, hyperadrenergic state, or uncontrolled or untreated hypertension. * Clinically significant cardiovascular conditions. * Patient with resting systolic blood pressure ≥160 mmHg, a resting diastolic blood pressure ≥100 mmHg, or a resting heart rate ≤50 bpm or ≥100 bpm at Visit 1 (Screening) or/and at Visit 2 (Day -1 to Day 7). * Have a body mass index (BMI) ≥40 kg/m2 * Electrocardiogram (ECG) at Screening or Day -1 showing corrected QT interval (QTc) using Fridericia's correction (QTcF) \>470 msec. * Patients with clinically relevant abnormalities in the results of the laboratory tests, ECG parameters (other than QTcF), or in the physical examination at Visit 1, except those related to COPD. * Positive results for drugs of abuse in the urine at Visit 1 (Screening). * Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody and/or human immunodeficiency virus (HIV) I antibodies at Visit 1 (Screening). * History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer. * Any other serious or uncontrolled physical or mental condition/disease. * Patient with a history (within 2 years prior to Visit 1 \[Screening\]) of drug and/or alcohol abuse that may prevent trial compliance based on investigator judgment. * Taken any medication within 14 days before the first dose of IP, or hormonal drug products and traditional Chinese medicines within 30 days before the first dose of IP, with the exception of allowed medications listed in the study protocol. * Participation in any other clinical investigation using an experimental drug requiring repeated blood or plasma drawn within 60 days of Day 1 at Visit 2. * Have participated in a blood/plasma donation or blood loss greater than 400 mL within 90 days or greater than 200 mL within 30 days prior to Visit 1 (Screening). * Have any clinical condition that might affect the absorption, distribution, biotransformation, or excretion of Aclidinium Bromide/Formoterol Fumarate. * Have consumed caffeine or any grapefruit-containing products within 48 hours or alcohol within 72 hours before Day -1 at Visit 2. * Inability to be venipunctured or tolerate venous access as determined by the investigator or designee. * Inability to use a multidose DPI. * Subjects unable to give their consent, or subjects of consenting age but under guardianship, or vulnerable subjects. * In the opinion of the PI, subjects who are unlikely to comply with the protocol requirements, instructions, and trial-related restrictions. * Previously taken Aclidinium or previously participated in an investigational study of Aclidinium within 6 months of Day 1

Design outcomes

Primary

MeasureTime frameDescription
Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1. Additional parameters may be determined where appropriate.
CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Apparent plasma clearance for parent drug estimated as dose divided by AUCss
Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz.
Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12
%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Fluctuation index during a dosing interval estimated as 100\*(Cmax-Cmin)/Cav (%).
Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1
Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1
Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).
Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose).
Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible.
AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration.
AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1Area under the plasma concentration curve during the first dosing interval, tau (first dose).
Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Observed maximum concentration, taken directly from the individual concentration-time curve at steady state.
Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5.
Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state.
λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Terminal rate constant, estimated by log-linear least square regression of the terminal part of the concentration-time curve.
t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Terminal half-life (h), estimated as (ln2)/λz.
AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5Area under the plasma concentration curve during the dosing interval, tau at steady state.

Secondary

MeasureTime frameDescription
Treatment-emergent AEs Related to Blood PressureScreening (Day -21) to Follow-up visit (Days 8-12)Assessment of the safety in terms of notable changes from baseline in blood pressure after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.
Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)Screening (Day -21) to Follow-up visit (Days 8-12)Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.
Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)Screening (Day -21) to Follow-up visit (Days 8-12)Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.
Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)Screening (Day -21) to Follow-up visit (Days 8-12)Assessment of the safety in terms of serum biochemistry parameters (Alanine aminotransferase \[ALT\], Aspartate aminotransferase \[AST\], alkaline phosphatase \[ALP\], Gamma-glutamyl transferase \[GGT\], bilirubin, creatine kinase, lactate dehydrogenase, urea nitrogen, creatinine, urate, cholesterol, glucose, sodium, potassium, calcium, chloride, phosphate, protein, and albumin) after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.
Treatment-emergent AEs Related to 12-lead ECG ParametersScreening (Day -21) to Follow-up visit (Days 8-12)Assessment of the safety in terms of the 12-lead ECG parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.
Adverse Events (AEs)/Serious AEs (SAEs)Screening (Day -21) to Follow-up visit (Days 8-12)Assessment of the safety in terms of the incidences of AEs/SAEs after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Countries

China

Participant flow

Recruitment details

This study was conducted at a single centre in China. The first participant was enrolled in December 2017 and the last participant visit was in June 2018.

Pre-assignment details

A total of 97 participants were screened. Of these, 20 were enrolled and received treatment.

Participants by arm

ArmCount
AB/FF 400/12 BID
Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
20
Total20

Withdrawals & dropouts

PeriodReasonFG000
Overall StudyAdverse Event1

Baseline characteristics

CharacteristicAB/FF 400/12 BID
Age, Continuous59.2 Years
STANDARD_DEVIATION 6.8
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
Race (NIH/OMB)
Asian
20 Participants
Race (NIH/OMB)
Black or African American
0 Participants
Race (NIH/OMB)
More than one race
0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
Race (NIH/OMB)
White
0 Participants
Sex: Female, Male
Female
5 Participants
Sex: Female, Male
Male
15 Participants

Adverse events

Event typeEG000
affected / at risk
deaths
Total, all-cause mortality
0 / 20
other
Total, other adverse events
3 / 20
serious
Total, serious adverse events
1 / 20

Outcome results

Primary

AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).

Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDAUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Aclidinium Bromide78.61 pg*hour/mLGeometric Coefficient of Variation 90.69
AB/FF 400/12 BIDAUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS3485020280 pg*hour/mLGeometric Coefficient of Variation 54.28
AB/FF 400/12 BIDAUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS34823201.1 pg*hour/mLGeometric Coefficient of Variation 106.3
AB/FF 400/12 BIDAUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Formoterol Fumarate20.04 pg*hour/mLGeometric Coefficient of Variation 64.22
Primary

AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Area under the plasma concentration curve during the dosing interval, tau at steady state.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDAUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide168.8 pg*hour/mLGeometric Coefficient of Variation 82.15
AB/FF 400/12 BIDAUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS3485027300 pg*hour/mLGeometric Coefficient of Variation 52.29
AB/FF 400/12 BIDAUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS34823540.9 pg*hour/mLGeometric Coefficient of Variation 54.97
AB/FF 400/12 BIDAUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate31.98 pg*hour/mLGeometric Coefficient of Variation 51.6
Primary

AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).

Area under the plasma concentration curve during the first dosing interval, tau (first dose).

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDAUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Aclidinium Bromide85.45 pg*hour/mLGeometric Coefficient of Variation 79.02
AB/FF 400/12 BIDAUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS3485020330 pg*hour/mLGeometric Coefficient of Variation 54.24
AB/FF 400/12 BIDAUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS34823252.9 pg*hour/mLGeometric Coefficient of Variation 60.63
AB/FF 400/12 BIDAUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Formoterol Fumarate22.78 pg*hour/mLGeometric Coefficient of Variation 43.64
Primary

Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDCav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide14.07 pg/mLGeometric Coefficient of Variation 82.15
AB/FF 400/12 BIDCav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348502275 pg/mLGeometric Coefficient of Variation 52.29
AB/FF 400/12 BIDCav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS3482345.07 pg/mLGeometric Coefficient of Variation 54.97
AB/FF 400/12 BIDCav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate2.665 pg/mLGeometric Coefficient of Variation 51.6
Primary

CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).

Apparent plasma clearance for parent drug estimated as dose divided by AUCss

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (MEAN)Dispersion
AB/FF 400/12 BIDCL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide3140 L/hourStandard Deviation 2868
AB/FF 400/12 BIDCL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate422.2 L/hourStandard Deviation 222.7
Primary

Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).

Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDCmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Aclidinium Bromide45.82 pg/mLGeometric Coefficient of Variation 84.54
AB/FF 400/12 BIDCmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS348503149 pg/mLGeometric Coefficient of Variation 55.56
AB/FF 400/12 BIDCmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS3482338.82 pg/mLGeometric Coefficient of Variation 86.6
AB/FF 400/12 BIDCmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Formoterol Fumarate4.786 pg/mLGeometric Coefficient of Variation 62.78
Primary

Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).

Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDCmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Aclidinium Bromide Not calculable0 pg/mLGeometric Coefficient of Variation 0
AB/FF 400/12 BIDCmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS34850627.7 pg/mLGeometric Coefficient of Variation 52.02
AB/FF 400/12 BIDCmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS34823 Not calculable0 pg/mLGeometric Coefficient of Variation 0
AB/FF 400/12 BIDCmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Formoterol Fumarate Not calculable0 pg/mLGeometric Coefficient of Variation 0
Primary

Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Observed maximum concentration, taken directly from the individual concentration-time curve at steady state.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDCss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide60.86 pg/mLGeometric Coefficient of Variation 150
AB/FF 400/12 BIDCss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348503691 pg/mLGeometric Coefficient of Variation 56.03
AB/FF 400/12 BIDCss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS3482381.02 pg/mLGeometric Coefficient of Variation 69.52
AB/FF 400/12 BIDCss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate6.465 pg/mLGeometric Coefficient of Variation 84.34
Primary

Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDCss,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide4.528 pg/mLGeometric Coefficient of Variation 47.34
AB/FF 400/12 BIDCss,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348501032 pg/mLGeometric Coefficient of Variation 43.05
AB/FF 400/12 BIDCss,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS3482322.88 pg/mLGeometric Coefficient of Variation 47.22
AB/FF 400/12 BIDCss,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate1.281 pg/mLGeometric Coefficient of Variation 36.63
Primary

%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Fluctuation index during a dosing interval estimated as 100\*(Cmax-Cmin)/Cav (%).

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (MEAN)Dispersion
AB/FF 400/12 BID%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide452.5 PercentageStandard Deviation 269.4
AB/FF 400/12 BID%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS34850117.0 PercentageStandard Deviation 24.69
AB/FF 400/12 BID%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS34823132.0 PercentageStandard Deviation 57.81
AB/FF 400/12 BID%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate205.9 PercentageStandard Deviation 90.94
Primary

Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDRac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate1.436 ratioGeometric Coefficient of Variation 56.27
AB/FF 400/12 BIDRac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide1.966 ratioGeometric Coefficient of Variation 108.9
AB/FF 400/12 BIDRac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348501.355 ratioGeometric Coefficient of Variation 76.54
AB/FF 400/12 BIDRac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348232.157 ratioGeometric Coefficient of Variation 82
Primary

Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDRac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide1.297 ratioGeometric Coefficient of Variation 216.6
AB/FF 400/12 BIDRac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348501.185 ratioGeometric Coefficient of Variation 80.29
AB/FF 400/12 BIDRac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348232.070 ratioGeometric Coefficient of Variation 113.5
AB/FF 400/12 BIDRac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate1.384 ratioGeometric Coefficient of Variation 90.21
Primary

Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1. Additional parameters may be determined where appropriate.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (GEOMETRIC_MEAN)Dispersion
AB/FF 400/12 BIDRac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide1.877 ratioGeometric Coefficient of Variation 45.19
AB/FF 400/12 BIDRac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348501.641 ratioGeometric Coefficient of Variation 69.91
AB/FF 400/12 BIDRac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348232.601 ratioGeometric Coefficient of Variation 54.86
AB/FF 400/12 BIDRac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate1.822 ratioGeometric Coefficient of Variation 31.43
Primary

t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Terminal half-life (h), estimated as (ln2)/λz.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (MEAN)Dispersion
AB/FF 400/12 BIDt½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide19.42 hoursStandard Deviation 11.1
AB/FF 400/12 BIDt½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS3485020.95 hoursStandard Deviation 18.78
AB/FF 400/12 BIDt½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS3482317.34 hoursStandard Deviation 8.096
AB/FF 400/12 BIDt½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate14.06 hoursStandard Deviation 4.796
Primary

Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).

Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose).

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (MEDIAN)
AB/FF 400/12 BIDTmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Aclidinium Bromide0.08 hours
AB/FF 400/12 BIDTmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS348503.00 hours
AB/FF 400/12 BIDTmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).LAS348231.75 hours
AB/FF 400/12 BIDTmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose).Formoterol Fumarate1.00 hours
Primary

Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (MEDIAN)
AB/FF 400/12 BIDTss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide0.08 hours
AB/FF 400/12 BIDTss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348503.00 hours
AB/FF 400/12 BIDTss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348230.50 hours
AB/FF 400/12 BIDTss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate0.08 hours
Primary

Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).

Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (MEAN)Dispersion
AB/FF 400/12 BIDVz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide81990 LStandard Deviation 87200
AB/FF 400/12 BIDVz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate8284 LStandard Deviation 5161
Primary

λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).

Terminal rate constant, estimated by log-linear least square regression of the terminal part of the concentration-time curve.

Time frame: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

ArmMeasureGroupValue (MEAN)Dispersion
AB/FF 400/12 BIDλz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Aclidinium Bromide0.053 1/hoursStandard Deviation 0.04
AB/FF 400/12 BIDλz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348500.045 1/hoursStandard Deviation 0.018
AB/FF 400/12 BIDλz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).LAS348230.048 1/hoursStandard Deviation 0.021
AB/FF 400/12 BIDλz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses).Formoterol Fumarate0.057 1/hoursStandard Deviation 0.029
Secondary

Adverse Events (AEs)/Serious AEs (SAEs)

Assessment of the safety in terms of the incidences of AEs/SAEs after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Time frame: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of the investigational product.

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
AB/FF 400/12 BIDAdverse Events (AEs)/Serious AEs (SAEs)Any AE5 Participants
AB/FF 400/12 BIDAdverse Events (AEs)/Serious AEs (SAEs)Any SAE1 Participants
Secondary

Treatment-emergent AEs Related to 12-lead ECG Parameters

Assessment of the safety in terms of the 12-lead ECG parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Time frame: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
AB/FF 400/12 BIDTreatment-emergent AEs Related to 12-lead ECG Parameters0 Participants
Secondary

Treatment-emergent AEs Related to Blood Pressure

Assessment of the safety in terms of notable changes from baseline in blood pressure after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Time frame: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

ArmMeasureCategoryValue (COUNT_OF_PARTICIPANTS)
AB/FF 400/12 BIDTreatment-emergent AEs Related to Blood PressureBlood pressure increased1 Participants
Secondary

Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)

Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Time frame: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
AB/FF 400/12 BIDTreatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)0 Participants
Secondary

Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)

Assessment of the safety in terms of serum biochemistry parameters (Alanine aminotransferase \[ALT\], Aspartate aminotransferase \[AST\], alkaline phosphatase \[ALP\], Gamma-glutamyl transferase \[GGT\], bilirubin, creatine kinase, lactate dehydrogenase, urea nitrogen, creatinine, urate, cholesterol, glucose, sodium, potassium, calcium, chloride, phosphate, protein, and albumin) after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Time frame: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
AB/FF 400/12 BIDTreatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)0 Participants
Secondary

Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)

Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Time frame: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
AB/FF 400/12 BIDTreatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)Urine protein present3 Participants
AB/FF 400/12 BIDTreatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis)Haematuria1 Participants

Source: ClinicalTrials.gov · Data processed: Feb 13, 2026