Asthma
Conditions
Brief summary
This is a study to establish the equivalence of OT329 Solis and Advair Diskus when administered by inhalation in patients with asthma.
Interventions
DRUGOT329 (combination of fluticasone propionate and salmeterol xinafoate)
Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered by Solis dry powder inhaler
DRUGAdvair Diskus (combination of fluticasone propionate and salmeterol xinafoate)
Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered by Diskus dry powder inhaler
DRUGPlacebo
Placebo (lactose) administered via the Solis dry powder inhaler
Sponsors
Oriel Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females ≥ 18 years old of non-child bearing potential or of child bearing potential committing to consistent and correct use of an acceptable method of birth control 2. Subjects with a reliable clinical history of asthma documented at least 12 weeks prior to screening 3. Subjects with a pre-bronchodilator FEV1 of \> 40% and \<85% of the predicted value during the screening visit and on the first day of treatment 4. Subjects who are currently non-smoking and have not used tobacco products (i.e., cigarettes, cigars, pipe tobacco) within the past year, and had \< 10 pack-years of historical use 5. Subjects with \> 15% reversibility of FEV1 within 30 minutes following 360 mcg of albuterol inhalation (pMDI). Note: This test may be repeated on a different day if the patient fails the first attempt; and if the patient achieves at least 10% reversibility and the Investigator thinks that a second attempt is appropriate 6. Subjects who are able to discontinue their asthma medications (inhaled corticosteroids and long-acting beta agonists) during the run-in period and for the remainder of the study 7. Subjects who are able to replace current short-acting beta agonists (SABAs) with salbutamol/albuterol inhaler for use as needed for the duration of the study (subjects should be able to withhold all inhaled SABAs for at least 6 hours prior to lung function assessments on study visits) 8. Subjects who are able to continue the following medications without a significant adjustment of dosage, formulation, or dosing interval for the duration of the study, and judged able by the investigator to withhold them for the specified minimum time intervals prior to each clinic visit: short-acting forms of theophylline for 12 hours, twice-a-day controlled release forms of theophylline for 24 hours, once-a-day controlled-release forms of theophylline for 36 hours 9. Subjects who are able to discontinue the following medications for the specified minimum time intervals prior to the run-in period and for the remainder of the study: oral and parenteral corticosteroids for 1 month and oral short-acting beta agonists for 12 hours 10. Subjects who are able and willing to give their written informed consent to participate in the study. \*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*
Exclusion criteria
11. Female Subjects who are pregnant or breastfeeding 12. Subjects who have life-threatening asthma in the last 10 years, as defined as a history of asthma episode(s) requiring intubation, and/or associated with hypercapnoea; respiratory arrest or hypoxic seizures, asthma-related syncopal episodes(s), or hospitalizations within the past year or during the run-in period 13. Subjects with evidence or history of clinically significant disease or abnormality including congestive heart failure, uncontrolled hypertension, uncontrolled coronary artery disease, myocardial infarction, or cardiac dysrhythmia. In addition, historical or current evidence of significant hematologic, hepatic, neurologic, psychiatric, renal, or other diseases that in the opinion of the investigator, would put the patient at risk through study participation, or would affect the study analyses if the disease exacerbated during the study 14. Subjects with a hypersensitivity to any sympathomimetic drug (e.g. Salmeterol or salbutamol/albuterol) or any inhaled, intranasal or systemic corticosteroid therapy 15. Subjects who are on other medications with the potential to affect the course of asthma or to interact with sympathomimetic amines (e.g. beta blockers, oral decongestants, benzodiazepines, digitalis, phenothiazines, polycyclic antidepressants, monoamine oxidase inhibitors) 16. Subjects with a viral or bacterial upper or lower respiratory tract infection or sinus or middle ear infection within 4 weeks prior to the screening visit or during the run-in period 17. Subjects with any factors (e.g. infirmity, disability, or geographic location) that the investigator feel would likely limit the patient's compliance with the study protocol or scheduled clinic visits 18. Subjects who have used any investigational drug in any clinical trial within 1 month of receiving the first dose of OT329 Solis™ study medication 19. Subjects who cannot communicate reliably or who are unlikely to co-operate with the requirements of the study, in the opinion of the Investigator 20. Subjects with a milk protein allergy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serial FEV1-time Curve (AUC 0-12h) | 0-12 hours after dosing on Day 1 | Bioequivalence comparison of lung function (FEV1) for 12 hours after the first dose on Day 1 following OT329 Solis and Advair Diskus treatment. Serial lung function measurements were made pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose. |
| FEV1 Trough | Post-4 weeks of treatment | Bioequivalence comparison of trough lung function (FEV1) after 4 weeks of treatment with OT329 SOLIS or ADVAIR DISKUS. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With Adverse Events | From Screen (Day -28) until 1 week post last treatment |
Countries
United States
Participant flow
Recruitment details
1526 Patients with asthma were screened at 48 clinical sites
Pre-assignment details
647 Failed screening (42%) * 239 failed because they did not have 40-85% pred FEV1 * 240 failed because they were not \>15% reversible with albuterol * 168 failed for other inclusion/exclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| OT329 Solis OT329 Solis (twice daily inhalation throughout the study)
OT329 (combination of fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered by Solis dry powder inhaler | 418 |
| Advair Diskus Advair Diskus (twice daily inhalation throughout the study)
Advair Diskus (combination of fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered by Diskus dry powder inhaler | 419 |
| Placebo Placebo (twice daily inhalation throughout the study)
Placebo: Placebo (lactose) administered via the Solis dry powder inhaler | 42 |
| Total | 879 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 1 | 2 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 12 | 9 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 2 |
Baseline characteristics
| Characteristic | OT329 Solis | Advair Diskus | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 43.9 years STANDARD_DEVIATION 14.52 | 43.3 years STANDARD_DEVIATION 14.26 | 43.2 years STANDARD_DEVIATION 15.25 | 43.6 years STANDARD_DEVIATION 14.42 |
| Airways Reversibility with Albuterol | 30.5 % change from pre-albuterol lung functio STANDARD_DEVIATION 19.3 | 29.7 % change from pre-albuterol lung functio STANDARD_DEVIATION 17.5 | 25.9 % change from pre-albuterol lung functio STANDARD_DEVIATION 13.3 | 29.9 % change from pre-albuterol lung functio STANDARD_DEVIATION 18.3 |
| Body Mass Index | 31.49 Kg/m^2 STANDARD_DEVIATION 7.61 | 29.91 Kg/m^2 STANDARD_DEVIATION 7.2 | 29.32 Kg/m^2 STANDARD_DEVIATION 6.3 | 30.63 Kg/m^2 STANDARD_DEVIATION 7.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 122 Participants | 118 Participants | 9 Participants | 249 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 296 Participants | 301 Participants | 33 Participants | 630 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height (cm) | 167.5 cm STANDARD_DEVIATION 9.9 | 169.2 cm STANDARD_DEVIATION 10.7 | 166.3 cm STANDARD_DEVIATION 8.3 | 168.2 cm STANDARD_DEVIATION 10.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 74 Participants | 89 Participants | 10 Participants | 173 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 13 Participants | 2 Participants | 22 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 332 Participants | 308 Participants | 29 Participants | 669 Participants |
| Region of Enrollment United States | 418 participants | 419 participants | 42 participants | 879 participants |
| Sex: Female, Male Female | 274 Participants | 251 Participants | 30 Participants | 555 Participants |
| Sex: Female, Male Male | 144 Participants | 168 Participants | 12 Participants | 324 Participants |
| Weight (kg) | 88.5 Kg STANDARD_DEVIATION 22.9 | 85.9 Kg STANDARD_DEVIATION 23.1 | 81.0 Kg STANDARD_DEVIATION 17.2 | 86.9 Kg STANDARD_DEVIATION 22.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 417 | 1 / 419 | 0 / 43 |
| other Total, other adverse events | 52 / 417 | 47 / 419 | 7 / 43 |
| serious Total, serious adverse events | 0 / 417 | 2 / 419 | 0 / 43 |
Outcome results
Primary
Area Under the Serial FEV1-time Curve (AUC 0-12h)
Bioequivalence comparison of lung function (FEV1) for 12 hours after the first dose on Day 1 following OT329 Solis and Advair Diskus treatment. Serial lung function measurements were made pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose.
Time frame: 0-12 hours after dosing on Day 1
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OT329 Solis | Area Under the Serial FEV1-time Curve (AUC 0-12h) | 29.610 Liters | Standard Deviation 9.044 |
| Advair Diskus | Area Under the Serial FEV1-time Curve (AUC 0-12h) | 30.151 Liters | Standard Deviation 9.107 |
| Placebo | Area Under the Serial FEV1-time Curve (AUC 0-12h) | 27.270 Liters | Standard Deviation 7.71 |
Comparison: Primary analyses were conducted on BL subtracted values (pre-dose - post-dose). The two one-sided tests method of interval analysis is standard for bioequivalence testing and employs 2 sets of one-sided hypotheses as follows, performed at the 5% alpha level:~H01: uT-uR \< -0.20 uR vs. Ha1: -0.20 uR \</= uT- uR (the lower tail) and H02: uT-uR \>0.25 uR vs. Ha2: uT- uR \</=0.25 uR (the upper tail) When uT is the LSM SOLIS, uR is the LSM of ADVAIR DISKUSp-value: <0.0590% CI: [0.8, 1.25]ANCOVA
Primary
FEV1 Trough
Bioequivalence comparison of trough lung function (FEV1) after 4 weeks of treatment with OT329 SOLIS or ADVAIR DISKUS.
Time frame: Post-4 weeks of treatment
Population: Intent-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OT329 Solis | FEV1 Trough | 2.516 Liters | Standard Deviation 0.792 |
| Advair Diskus | FEV1 Trough | 2.579 Liters | Standard Deviation 0.774 |
| Placebo | FEV1 Trough | 2.323 Liters | Standard Deviation 0.736 |
Comparison: Same as the Day 1 analysesp-value: <0.0590% CI: [0.8, 1.25]ANOVA
Secondary
Number of Participants With Adverse Events
Time frame: From Screen (Day -28) until 1 week post last treatment
Population: One subject who was assigned OT329 SOLIS received placebo treatment kit in error. The mistake was discovered on Day 1 and the patient was removed from the study. The patient was included in the OT329 SOLIS group for the intent-to-treat analysis but was put in the Placebo group for the Safety analysis as defined by the Statisical Analysis Plan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OT329 Solis | Number of Participants With Adverse Events | 67 Participants |
| Advair Diskus | Number of Participants With Adverse Events | 66 Participants |
| Placebo | Number of Participants With Adverse Events | 7 Participants |