Clinical Endpoint Bioequivalence Study of Test and Reference Inhalation Products in Patients With COPD With Device Robustness

• Sponsor: Lupin, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03137992
• Collaborator: (none)
• Enrollment: 377
• Locations: 34
• Arms: 3
• Actual Duration (Months): 5.3
• Patients Per Site: 11.1
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

The purpose of this study is to show bioequivalence of test product to reference product based on baseline-adjusted forced expiratory volume in one second (FEV1).

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Placebo; Drug: Test Product (tiotropium bromide inhalation powder); Drug: Reference Product (Spiriva®)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 377 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Double-blind, double-dummy, placebo controlledDouble-blind, double-dummy, placebo controlled
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: Double-blind
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Crossover, Multicenter Clinical Study to Assess the Efficacy and Safety of Once Daily Administration of Lupin Tiotropium Bromide Inhalation Powder Compared to SPIRIVA® HANDIHALER® and Placebo in Patients With COPD Including a 12-Week Open Label Extension to Assess Inhaler Robustness
• Actual Study Start Date: Nov 21, 2017
• Actual Primary Completion Date: Jan 31, 2018
• Actual Study Completion Date: Apr 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Test Product (tiotropium bromide inhalation powder) Once daily administration of test product (tiotropium bromide inhalation powder), 18 mcg for open-label extension (device robustness).	Drug: Test Product (tiotropium bromide inhalation powder); Double-Blind: Single dose of test product 18 mcg of test product Open-Label: once daily administration of test product (tiotropium bromide inhalation powder) 18 mcg administered by test dry powder inhaler.
Active Comparator: Reference Product (Spiriva®) Single dose of reference product (Spiriva®) 18 mcg	Drug: Reference Product (Spiriva®); Reference product (Spiriva®) 18 mcg.
Placebo Comparator: Placebo Single dose of placebo inhalation powder	Drug: Placebo; Single dose of placebo inhalation powder administered by test and reference dry powder inhalers.

Outcome Measures

Primary Outcome Measures

1. Baseline Adjusted Mean Change in FEV1 AUC0-24h Post Dose [0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks]

   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.

2. Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo [0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and non-pregnant female subjects (40 years of age and older).

• Patients with diagnosis of COPD according to the GOLD guidelines.

• Post-bronchodilator FEV1 <80% of the predicted value at the screening visit.

• Post-bronchodilator FEV1/FVC ratio ≤0.70 at the screening visit.

• Current or former smokers (e.g., with history of = 10 pack-years).

• Written informed consent.

Exclusion Criteria:

• Known respiratory disorder other than COPD including, but not limited to the following: alpha-1 antitrypsin deficiency, cystic fibrosis, significant asthma, active bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, pulmonary edema, or interstitial lung disease.

• History of allergy or hypersensitivity to anticholinergic/muscarinic receptor antagonist agents, beta-2 adrenergic agonists, lactose/milk proteins, or known hypersensitivity to any of the proposed ingredients or components of the delivery system.

• Hospitalization for COPD or pneumonia within 12 weeks prior to the screening visit.

• Treatment for COPD exacerbation within 12 weeks prior to the screening visit.

• Viral or bacterial upper or lower respiratory tract infection, sinusitis, sinus infection, rhinitis, pharyngitis, middle ear infection, urinary tract infection, or illness within 6 weeks prior to the screening visit.

• Abnormal and significant ECG finding prior to the screening, during the run-in and treatment periods.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Research Center Site #1017	Andalusia	Alabama	United States	36420
2	Investigational Research Center Site #1003	Jasper	Alabama	United States	35501
3	Investigational Research Center Site #1008	Glendale	Arizona	United States	85306
4	Investigational Research Center Site #1034	Los Angeles	California	United States	90025
5	Investigational Research Center Site #1028	Riverside	California	United States	92506
6	Investigational Research Center Site #1010	Westminster	California	United States	92683
7	Investigational Research Center Site #1016	Colorado Springs	Colorado	United States	80907
8	Investigational Research Center Site #1026	Clearwater	Florida	United States	33756
9	Investigational Research Center Site #1019	Clearwater	Florida	United States	33765
10	Investigational Research Center Site #1035	Clearwater	Florida	United States	33765
11	Investigational Research Center Site #1036	Orlando	Florida	United States	32825
12	Investigational Research Center Site #1001	North Dartmouth	Massachusetts	United States	02747
13	Investigational Research Center Site #1011	Fridley	Minnesota	United States	55432
14	Investigational Research Center Site #1029	Saint Louis	Missouri	United States	63141
15	Investigational Research Center Site #1007	Las Vegas	Nevada	United States	89119
16	Investigational Research Center Site #1032	Raleigh	North Carolina	United States	27607
17	Investigational Research Center Site #1037	Columbus	Ohio	United States	43215
18	Investigational Research Center Site #1018	Edmond	Oklahoma	United States	73034
19	Investigational Research Center Site #1009	Oklahoma City	Oklahoma	United States	73103
20	Investigational Research Center Site #1033	Tulsa	Oklahoma	United States	74136
21	Investigational Research Center Site #1005	Medford	Oregon	United States	97504
22	Investigational Research Center Site #1006	Portland	Oregon	United States	97202
23	Investigational Research Center Site #1015	Easley	South Carolina	United States	29640
24	Investigational Research Center Site #1012	Gaffney	South Carolina	United States	29340
25	Investigational Research Center Site #1023	Rock Hill	South Carolina	United States	29732
26	Investigational Research Center Site #1024	Seneca	South Carolina	United States	29678
27	Investigational Research Center Site #1020	Spartanburg	South Carolina	United States	29303
28	Investigational Research Center Site #1025	Spartanburg	South Carolina	United States	29303
29	Investigational Research Center Site #1027	Union	South Carolina	United States	29379
30	Investigational Research Center Site #1004	Knoxville	Tennessee	United States	37909
31	Investigational Research Center Site #1013	El Paso	Texas	United States	79903
32	Investigational Research Center Site #1002	McKinney	Texas	United States	75069
33	Investigational Research Center Site #1030	New Braunfels	Texas	United States	78130
34	Investigational Research Center Site #1031	Newport News	Virginia	United States	23606

Sponsors and Collaborators

• Lupin, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Feb 8, 2018
• Study Protocol - May 11, 2017

More Information

Publications

None provided.

• Responsible Party: Lupin, Inc.
• ClinicalTrials.gov Identifier: NCT03137992
• Other Study ID Numbers: TB-DPI-301
• First Posted: May 3, 2017
• Last Update Posted: Apr 5, 2021
• Last Verified: Mar 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Lupin, Inc.: COPD
• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Bromides; Tiotropium Bromide

Study Results

Participant Flow

Pre-assignment Detail	Of the 377 participants randomized to treatment groups, three subjects did not receive treatment.

Arm/Group Title	Sequence A (T-R-P)	Sequence B (R-P-T)	Sequence C (P-T-R)	Sequence D (P-R-T)	Sequence E (T-P-R)	Sequence F (R-T-P)
Arm/Group Description	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	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	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	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	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	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 Title: Period 1 (Visit 2)
STARTED	62	63	63	63	62	61
COMPLETED	62	63	63	63	62	61
NOT COMPLETED	0	0	0	0	0	0
Period Title: Period 1 (Visit 2)
STARTED	62	63	63	63	62	61
COMPLETED	59	59	61	63	60	59
NOT COMPLETED	3	4	2	0	2	2
Period Title: Period 1 (Visit 2)
STARTED	59	59	61	63	60	59
COMPLETED	56	52	58	58	56	51
NOT COMPLETED	3	7	3	5	4	8
Period Title: Period 1 (Visit 2)
STARTED	56	52	58	58	56	51
COMPLETED	54	50	58	57	53	50
NOT COMPLETED	2	2	0	1	3	1
Period Title: Period 1 (Visit 2)
STARTED	54	50	58	57	53	50
COMPLETED	48	48	55	57	50	47
NOT COMPLETED	6	2	3	0	3	3
Period Title: Period 1 (Visit 2)
STARTED	22	17	21	25	18	22
COMPLETED	20	17	20	24	18	21
NOT COMPLETED	2	0	1	1	0	1

Baseline Characteristics

Arm/Group Title	Safety Population
Arm/Group Description	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).
Overall Participants	374
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	210 56.1%
>=65 years	164 43.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.5 (8.47)
Sex: Female, Male (Count of Participants)
Female	195 52.1%
Male	179 47.9%
Race/Ethnicity, Customized (Count of Participants)
White	350 93.6%
Black/African American	19 5.1%
Asian	3 0.8%
American Indian/Alaska Native	2 0.5%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	7 1.9%
Not Hispanic or Latino	367 98.1%
Region of Enrollment (Count of Participants)
United States	374 100%
Baseline Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	82.710 (25.452)
Baseline Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	168.72 (9.927)

Outcome Measures

1. Primary Outcome

Title	Baseline Adjusted Mean Change in FEV1 AUC0-24h Post Dose
Description	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.
Time Frame	0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks

Outcome Measure Data

Analysis Population Description

Per-Protocol population

Arm/Group Title	Test Product (Tiotropium Bromide Inhalation Powder)	Reference Product (Spiriva®)
Arm/Group Description	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).	Single dose of reference product (Spiriva®) 18 mcg Reference Product (Spiriva®): Reference product (Spiriva®) 18 mcg.
Measure Participants	291	291
Least Squares Mean (Standard Error) [L*hour]	2.5644 (0.323)	2.7370 (0.322)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Product (Tiotropium Bromide Inhalation Powder), Reference Product (Spiriva®)
	Comments	A blinded interim analysis was performed after 241 subjects had been randomized with measurable AUC data, which estimated 238 patients would be needed to demonstrate BE with 90% power. Therefore, it was planned that approximately 378 patients would be randomized to allow for a potential 30% loss/withdrawal from the PP population.
	Type of Statistical Test	Equivalence
	Comments	Bioequivalence was declared if the 90% CI was entirely contained within the bioequivalence interval, 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squared Mean Ratio
	Estimated Value	0.9369
	Confidence Interval	(2-Sided) 90%; 0.834 to 1.047
	Parameter Dispersion	Type: Value:
	Estimation Comments	Fieller's formula was applied to calculate the 90% confidence interval (CI) for the Lupin Tiotropium and Spiriva Handihaler LS mean ratio.

2. Primary Outcome

Title	Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo
Description	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.
Time Frame	0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks

Outcome Measure Data

Analysis Population Description

Intention-To-Treat population

Arm/Group Title	Test Product (Tiotropium Bromide Inhalation Powder)	Reference Product (Spiriva®)	Placebo
Arm/Group Description	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).	Single dose of reference product (Spiriva®) 18 mcg Reference Product (Spiriva®): Reference product (Spiriva®) 18 mcg.	Single dose of placebo inhalation powder Placebo: Single dose of placebo inhalation powder administered by test and reference dry powder inhalers.
Measure Participants	372	372	372
Least Squares Mean (Standard Error) [L*hour]	2.90 (0.197)	3.03 (0.196)	-0.40 (0.199)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Product (Tiotropium Bromide Inhalation Powder), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Efficacy of the Test (T) product was demonstrated if the T was shown to be statistically superior to Placebo (p<0.05 [two-tailed]).Outcome variable was Difference in Baseline adjusted FEV1 AUC0-24h.
	Method	Mixed Models Analysis
	Comments	Mixed model repeated measures analysis consisted of effects of treatment, period, and sequence.
Method of Estimation	Estimation Parameter	Least Squared Mean Difference
	Estimated Value	3.29
	Confidence Interval	(2-Sided) 95%; 2.9386 to 3.646
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.180
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reference Product (Spiriva®), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Study sensitivity was demonstrated if the Reference (R) product was shown to be statistically superior to Placebo (P) (p <0.05 [two-tailed]). Outcome variable was Difference in Baseline adjusted FEV1 AUC0-24h.
	Method	Mixed Models Analysis
	Comments	Mixed model repeated measures analysis consisted of effects of treatment, period, and sequence.
Method of Estimation	Estimation Parameter	Least Squared Mean Difference
	Estimated Value	3.43
	Confidence Interval	(2-Sided) 95%; 3.0718 to 3.7797
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.180
	Estimation Comments

Adverse Events

Time Frame	All AEs/SAEs were assessed through study completion, an average of 14 weeks for participants enrolled in only part 1 of the study and 26 weeks for participants enrolled in part 1 and part 2 of the study. AEs were recorded starting after the patient signed the informed consent form and assessed at each visit.
Adverse Event Reporting Description	Adverse events are illnesses or signs/symptoms that appear or worsen during the testing of a drug whether o not considered related to the investigational product (synonyms = medicinal or pharmaceutical product, study medication, clinical trial materials, etc.) including side effects, injury, toxicity, or hypersensitivity reactions. AEs were captured during participant interviews during on-site and telephonic visits.
Arm/Group Title	Test Product (Lupin Tiotropium Bromide Inhalation Powder)		Reference Product (Spiriva®)		Placebo
Arm/Group Description	Single dose 18 mcg of test product (tiotropium bromide inhalation powder) for double blind portion. Once daily administration of test product (tiotropium bromide inhalation powder), 18 mcg for open-label extension (device robustness).		Single dose of reference product (Spiriva®) 18 mcg Reference Product (Spiriva®): Reference product (Spiriva®) 18 mcg.		Single dose of placebo inhalation powder Placebo: Single dose of placebo inhalation powder administered by test and reference dry powder inhalers.
All Cause Mortality
	Test Product (Lupin Tiotropium Bromide Inhalation Powder)		Reference Product (Spiriva®)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/337 (0%)		0/343 (0%)		0/329 (0%)
Serious Adverse Events
	Test Product (Lupin Tiotropium Bromide Inhalation Powder)		Reference Product (Spiriva®)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/337 (0%)		0/343 (0%)		0/329 (0%)
Other (Not Including Serious) Adverse Events
	Test Product (Lupin Tiotropium Bromide Inhalation Powder)		Reference Product (Spiriva®)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/337 (0%)		0/343 (0%)		0/329 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.