Trial Outcomes & Findings for Clinical Endpoint Bioequivalence Study of Test and Reference Inhalation Products in Patients With COPD With Device Robustness (NCT NCT03137992)
NCT ID: NCT03137992
Last Updated: 2021-04-05
Results Overview
To show clinical bioequivalence in the efficacy of the test product as a single dose versus reference product based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
377 participants
Primary outcome timeframe
0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks
Results posted on
2021-04-05
Participant Flow
Of the 377 participants randomized to treatment groups, three subjects did not receive treatment.
Participant milestones
| Measure |
Sequence A (T-R-P)
Participants received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 1 (2 inhalations from one capsule), followed by Spiriva Handihaler 18 mcg in Period 2 (2 inhalations from one capsule), followed by Placebo in period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence B (R-P-T)
Participants received SPIRIVA Handihaler 18 mcg in Period 1 (2 inhalations from one capsule), followed by placebo in Period 2 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence C (P-T-R)
Participants received Placebo in Period 1 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 2 (2 inhalations from one capsule), followed by SPIRIVA Handihaler 18 mcg in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence D (P-R-T)
Participants received Placebo in Period 1 (2 inhalations from one capsule), followed by SPIRIVA Handihaler 18 mcg in Period 2 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence E (T-P-R)
Participants received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 1 (2 inhalations from one capsule), followed by Placebo in Period 2 (2 inhalations from one capsule), followed by SPIRIVA Handihaler 18 mcg in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence F (R-T-P)
Participants received SPIRIVA Handihaler 18 mcg in Period 1 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 2 (2 inhalations from one capsule), followed by Placebo in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
|---|---|---|---|---|---|---|
|
Period 1 (Visit 2)
STARTED
|
62
|
63
|
63
|
63
|
62
|
61
|
|
Period 1 (Visit 2)
COMPLETED
|
62
|
63
|
63
|
63
|
62
|
61
|
|
Period 1 (Visit 2)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Washout Period 1
STARTED
|
62
|
63
|
63
|
63
|
62
|
61
|
|
Washout Period 1
COMPLETED
|
59
|
59
|
61
|
63
|
60
|
59
|
|
Washout Period 1
NOT COMPLETED
|
3
|
4
|
2
|
0
|
2
|
2
|
|
Period 2 (Visit 3)
STARTED
|
59
|
59
|
61
|
63
|
60
|
59
|
|
Period 2 (Visit 3)
COMPLETED
|
56
|
52
|
58
|
58
|
56
|
51
|
|
Period 2 (Visit 3)
NOT COMPLETED
|
3
|
7
|
3
|
5
|
4
|
8
|
|
Washout Period 2
STARTED
|
56
|
52
|
58
|
58
|
56
|
51
|
|
Washout Period 2
COMPLETED
|
54
|
50
|
58
|
57
|
53
|
50
|
|
Washout Period 2
NOT COMPLETED
|
2
|
2
|
0
|
1
|
3
|
1
|
|
Period 3 (Visit 04)
STARTED
|
54
|
50
|
58
|
57
|
53
|
50
|
|
Period 3 (Visit 04)
COMPLETED
|
48
|
48
|
55
|
57
|
50
|
47
|
|
Period 3 (Visit 04)
NOT COMPLETED
|
6
|
2
|
3
|
0
|
3
|
3
|
|
Part 2 (Open-label Extension)
STARTED
|
22
|
17
|
21
|
25
|
18
|
22
|
|
Part 2 (Open-label Extension)
COMPLETED
|
20
|
17
|
20
|
24
|
18
|
21
|
|
Part 2 (Open-label Extension)
NOT COMPLETED
|
2
|
0
|
1
|
1
|
0
|
1
|
Reasons for withdrawal
| Measure |
Sequence A (T-R-P)
Participants received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 1 (2 inhalations from one capsule), followed by Spiriva Handihaler 18 mcg in Period 2 (2 inhalations from one capsule), followed by Placebo in period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence B (R-P-T)
Participants received SPIRIVA Handihaler 18 mcg in Period 1 (2 inhalations from one capsule), followed by placebo in Period 2 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence C (P-T-R)
Participants received Placebo in Period 1 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 2 (2 inhalations from one capsule), followed by SPIRIVA Handihaler 18 mcg in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence D (P-R-T)
Participants received Placebo in Period 1 (2 inhalations from one capsule), followed by SPIRIVA Handihaler 18 mcg in Period 2 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence E (T-P-R)
Participants received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 1 (2 inhalations from one capsule), followed by Placebo in Period 2 (2 inhalations from one capsule), followed by SPIRIVA Handihaler 18 mcg in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
Sequence F (R-T-P)
Participants received SPIRIVA Handihaler 18 mcg in Period 1 (2 inhalations from one capsule), followed by Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER in Period 2 (2 inhalations from one capsule), followed by Placebo in Period 3 (2 inhalations from one capsule). Select participants who completed Part 1 of the study participated in Part 2 (open-label extension). Subjects received Lupin Tiotropium Bromide Inhalation Powder 18 mcg via LUPINHALER once daily (2 inhalations from one capsule) for 72 days
|
|---|---|---|---|---|---|---|
|
Washout Period 1
Adverse Event
|
1
|
1
|
0
|
0
|
0
|
1
|
|
Washout Period 1
Withdrawal by Subject
|
0
|
1
|
1
|
0
|
0
|
0
|
|
Washout Period 1
Principal Investigator Discretion
|
0
|
1
|
0
|
0
|
0
|
0
|
|
Washout Period 1
COPD Exacerbation
|
1
|
1
|
1
|
0
|
1
|
1
|
|
Washout Period 1
Subject Noncompliance
|
1
|
0
|
0
|
0
|
1
|
0
|
|
Period 2 (Visit 3)
COPD Exacerbation
|
1
|
1
|
0
|
0
|
0
|
1
|
|
Period 2 (Visit 3)
Did not meet continuation criteria
|
2
|
3
|
3
|
4
|
3
|
7
|
|
Period 2 (Visit 3)
Adverse Event
|
0
|
1
|
0
|
0
|
0
|
0
|
|
Period 2 (Visit 3)
Lost to Follow-up
|
0
|
0
|
0
|
1
|
0
|
0
|
|
Period 2 (Visit 3)
Withdrawal by Subject
|
0
|
2
|
0
|
0
|
1
|
0
|
|
Washout Period 2
COPD Exacerbation
|
1
|
1
|
0
|
0
|
1
|
0
|
|
Washout Period 2
Subject Non-compliance
|
0
|
1
|
0
|
0
|
0
|
0
|
|
Washout Period 2
Adverse Event
|
0
|
0
|
0
|
1
|
1
|
0
|
|
Washout Period 2
Withdrawal by Subject
|
1
|
0
|
0
|
0
|
1
|
0
|
|
Washout Period 2
Sponsor Decision
|
0
|
0
|
0
|
0
|
0
|
1
|
|
Period 3 (Visit 04)
Did not meet continuation criteria
|
6
|
0
|
2
|
0
|
2
|
3
|
|
Period 3 (Visit 04)
Withdrawal by Subject
|
0
|
2
|
1
|
0
|
1
|
0
|
|
Part 2 (Open-label Extension)
Withdrawal by Subject
|
1
|
0
|
1
|
0
|
0
|
0
|
|
Part 2 (Open-label Extension)
COPD exacerbation
|
0
|
0
|
0
|
1
|
0
|
0
|
|
Part 2 (Open-label Extension)
Per study team
|
1
|
0
|
0
|
0
|
0
|
0
|
|
Part 2 (Open-label Extension)
Prohibited Medication
|
0
|
0
|
0
|
0
|
0
|
1
|
Baseline Characteristics
Clinical Endpoint Bioequivalence Study of Test and Reference Inhalation Products in Patients With COPD With Device Robustness
Baseline characteristics by cohort
| Measure |
Safety Population
n=374 Participants
The safety analysis population included all patients who received at least one dose of any one of the randomized investigational products and for whom data had been collected after randomization. Patient baseline characteristics are not designated by treatment arms due to the crossover design of the study (treatment groups are not mutually exclusive).
|
|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
210 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
164 Participants
n=5 Participants
|
|
Age, Continuous
|
63.5 years
STANDARD_DEVIATION 8.47 • n=5 Participants
|
|
Sex: Female, Male
Female
|
195 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
179 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Race · White
|
350 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Race · Black/African American
|
19 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Race · Asian
|
3 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Race · American Indian/Alaska Native
|
2 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Ethnicity · Hispanic or Latino
|
7 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Ethnicity · Not Hispanic or Latino
|
367 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
374 Participants
n=5 Participants
|
|
Baseline Weight
|
82.710 kilograms
STANDARD_DEVIATION 25.452 • n=5 Participants
|
|
Baseline Height
|
168.72 centimeters
STANDARD_DEVIATION 9.927 • n=5 Participants
|
PRIMARY outcome
Timeframe: 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeksPopulation: Per-Protocol population
To show clinical bioequivalence in the efficacy of the test product as a single dose versus reference product based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication.
Outcome measures
| Measure |
Test Product (Tiotropium Bromide Inhalation Powder)
n=291 Participants
Single dose 18 mcg of test product (tiotropium bromide inhalation powder), a long acting muscarinic receptor antagonist, for double blind portion.
Once daily administration of test product (tiotropium bromide inhalation powder), 18 mcg for open-label extension (device robustness).
|
Reference Product (Spiriva®)
n=291 Participants
Single dose of reference product (Spiriva®) 18 mcg
Reference Product (Spiriva®): Reference product (Spiriva®) 18 mcg.
|
Placebo
Single dose of placebo inhalation powder
Placebo: Single dose of placebo inhalation powder administered by test and reference dry powder inhalers.
|
|---|---|---|---|
|
Baseline Adjusted Mean Change in FEV1 AUC0-24h Post Dose
|
2.5644 L*hour
Standard Error 0.323
|
2.7370 L*hour
Standard Error 0.322
|
—
|
PRIMARY outcome
Timeframe: 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeksPopulation: Intention-To-Treat population
This measure is to demonstrate that test product as a single dose and reference product are superior to placebo based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication.
Outcome measures
| Measure |
Test Product (Tiotropium Bromide Inhalation Powder)
n=372 Participants
Single dose 18 mcg of test product (tiotropium bromide inhalation powder), a long acting muscarinic receptor antagonist, for double blind portion.
Once daily administration of test product (tiotropium bromide inhalation powder), 18 mcg for open-label extension (device robustness).
|
Reference Product (Spiriva®)
n=372 Participants
Single dose of reference product (Spiriva®) 18 mcg
Reference Product (Spiriva®): Reference product (Spiriva®) 18 mcg.
|
Placebo
n=372 Participants
Single dose of placebo inhalation powder
Placebo: Single dose of placebo inhalation powder administered by test and reference dry powder inhalers.
|
|---|---|---|---|
|
Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo
|
2.90 L*hour
Standard Error 0.197
|
3.03 L*hour
Standard Error 0.196
|
-0.40 L*hour
Standard Error 0.199
|
Adverse Events
Test Product (Lupin Tiotropium Bromide Inhalation Powder)
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Reference Product (Spiriva®)
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Placebo
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place