7 Days of TD-4208 in Subjects With Chronic Obstructive Pulmonary Disease

• Sponsor: Mylan Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01704404
• Collaborator: Theravance Biopharma (Industry)
• Enrollment: 62
• Location: 1
• Arms: 7
• Duration (Months): 12
• Patients Per Site Per Month: 5.2

Study Details

Study Description

Brief Summary

This study will characterize the dose response of TD-4208 after 7 days of dosing in subjects with Chronic Obstructive Pulmonary Disease (COPD).

Condition or Disease	Intervention/Treatment	Phase
COPD	Drug: TD-4208; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of the Pharmacodynamics, Safety and Tolerability, and Pharmacokinetics of Multiple Doses of TD-4208 for 7 Days in Subjects Diagnosed With Chronic Obstructive Pulmonary Disease
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Nov 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose 1 TD-4208 22 µg	Drug: TD-4208; Other Names: revefenacin
Experimental: Dose 2 TD-4208 44 µg	Drug: TD-4208; Other Names: revefenacin
Experimental: Dose 3 TD-4208 88 µg	Drug: TD-4208; Other Names: revefenacin
Experimental: Dose 4 TD-4208 175 µg	Drug: TD-4208; Other Names: revefenacin
Experimental: Dose 5 TD-4208 350 µg	Drug: TD-4208; Other Names: revefenacin
Experimental: Dose 6 TD-4208 700 µg	Drug: TD-4208; Other Names: revefenacin
Placebo Comparator: Placebo Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) [From baseline to day 7]

Other Outcome Measures

1. Cmax [From baseline to day 7]

   Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.

2. Tmax [From baseline to day 7]

   Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.

3. Plasma Half-life [From baseline to day 7]

   Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject is a male or female between the ages of 40 and 75 years (inclusive, at randomization).

2. Subject:

• Has an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) <0.7 at screening; and

• Has a post-bronchodilator FEV1 at screening of between 30% and 80% (inclusive) of the predicted normal value.

1. Subject demonstrates at screening at least a 120 mL increase in FEV1 within 1 hour of receiving 500 µg of ipratropium bromide from a PARI LC Sprint® nebulizer.

2. Females of non-childbearing potential. All male subjects must agree to use a highly effective method of birth control with partners of childbearing potential during the study and for 1 month after completion of study dosing.

3. Subject (or care giver) is able to properly prepare and administer study medication.

4. Subject is willing and able to give written informed consent to participate.

Exclusion Criteria:

1. Subject has had a COPD exacerbation or lung infection within 6 weeks before randomization.

2. Subject has had an initiation of treatment, or a change in dose, of an inhaled or oral corticosteroid, or long-acting beta2 agonist (LABA), or long-acting muscarinic antagonist (LAMA) within 4 weeks before the qualifying ipratropium bromide response test.

3. Subject is taking daily maintenance inhaled/systemic corticosteroids (>1000 μg of fluticasone propionate equivalent or ≥10 mg prednisone).

4. Subject has an uncontrolled hematologic, immunologic, renal, neurologic, hepatic, endocrine, or other disease or condition based on information gathered from the medical history, physical examination, or laboratory findings that might place the subject at undue risk or potentially compromise the results or interpretation of the study.

5. Subject has a history of significant cerebrovascular disease, coronary artery disease, or cardiac arrhythmias. Subject has a history (or family history) of congenital prolonged QTc (corrected QT interval) syndrome or has an abnormal clinically significant electrocardiogram (ECG) at screening, including QTcB (QT interval corrected for heart rate using Bazett's formula) value >450 msec (males) or >470 msec (females); or shows evidence of clinically significant rhythm abnormality.

6. Subject has a known hypersensitivity to TD-4208 or similar drug class.

7. Subject has a history of alcoholism or drug abuse within 2 years prior to screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	P3 Research Ltd	Wellington		New Zealand

Sponsors and Collaborators

• Mylan Inc.
• Theravance Biopharma

Investigators

• Study Director: Medical Monitor, Theravance Biopharma

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mylan Inc.
• ClinicalTrials.gov Identifier: NCT01704404
• Other Study ID Numbers: 0091
• First Posted: Oct 11, 2012
• Last Update Posted: Feb 24, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Mylan Inc.: Long acting muscarinic antagonist; Chronic Bronchitis; Emphysema; Chronic Obstructive Pulmonary Disease; COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Arm/Group Title	Treatment 1	Treatment 2	Treatment 3	Treatment 4	Treatment 5	Treatment 6
Arm/Group Description	Placebo, 44 µg, 88 µg, 350 µg, 700 µg	Placebo, 22 µg, 88 µg, 350 µg, 700 µg	Placebo, 22 µg, 88 µg, 175 µg, 700 µg	22 µg, 44 µg, 175 µg, 700 µg	22 µg, 44 µg, 175 µg, 350 µg	Placebo, 44 µg, 88 µg, 175 µg, 350 µg
Period Title: Overall Study
STARTED	11	10	10	11	11	9
COMPLETED	10	9	9	8	10	9
NOT COMPLETED	1	1	1	3	1	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	All subjects received Placebo and 4 of 6 TD-4208 dose levels: TD-4208 - 22 µg TD-4208 - 44 µg TD-4208 - 88 µg TD-4208 - 175 µg TD-4208 - 350 µg TD-4208 - 700 µg
Overall Participants	62
Age (year) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [year]	64.2 (6.80)
Sex: Female, Male (Count of Participants)
Female	27 43.5%
Male	35 56.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second)
Time Frame	From baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose 1 TD-4208	Dose 2 TD-4208	Dose 3 TD-4208	Dose 4 TD-4208	Dose 5 TD-4208	Dose 6 TD-4208	Placebo
Arm/Group Description	22 µg TD-4208	44 µg TD-4208	88 µg TD-4208	175 µg TD-4208	350 µg TD-4208	700 µg TD-4208	Placebo Placebo
Measure Participants	40	39	39	39	39	40	59
Mean (Standard Error) [FEV1 (mL)]	91.2 (19.21)	92.8 (20.25)	113.1 (19.55)	151.9 (19.99)	132.2 (19.02)	119.4 (19.54)	37.8 (16.93)

2. Other Pre-specified Outcome

Title	Cmax
Description	Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.
Time Frame	From baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose 1 TD-4208	Dose 2 TD-4208	Dose 3 TD-4208	Dose 4 TD-4208	Dose 5 TD-4208	Dose 6 TD-4208
Arm/Group Description	22 µg TD-4208	44 µg TD-4208	88 µg TD-4208	175 µg TD-4208	350 µg TD-4208	700 µg TD-4208
Measure Participants	37	36	35	35	40	35
Mean (Standard Deviation) [ng/mL]	.0125 (.00627)	.0224 (.00864)	.0526 (.0214)	.114 (.0488)	.243 (.104)	.577 (.261)

3. Other Pre-specified Outcome

Title	Tmax
Description	Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.
Time Frame	From baseline to day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose 1 TD-4208	Dose 2 TD-4208	Dose 3 TD-4208	Dose 4 TD-4208	Dose 5 TD-4208	Dose 6 TD-4208
Arm/Group Description	22 µg TD-4208	44 µg TD-4208	88 µg TD-4208	175 µg TD-4208	350 µg TD-4208	700 µg TD-4208
Measure Participants	37	36	35	35	40	35
Mean (Standard Deviation) [hours]	.233 (.217)	.233 (0.200)	0.233 (0.200)	0.233 (0.200)	0.233 (0.217)	0.233 (0.200)

4. Other Pre-specified Outcome

Title	Plasma Half-life
Description	Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.
Time Frame	From baseline to day 7

Outcome Measure Data

Analysis Population Description

The number of subjects reported for plasma half lives are based on the actual evaluable PK data.

Arm/Group Title	Dose 1 TD-4208	Dose 2 TD-4208	Dose 3 TD-4208	Dose 4 TD-4208	Dose 5 TD-4208	Dose 6 TD-4208
Arm/Group Description	22 µg TD-4208	44 µg TD-4208	88 µg TD-4208	175 µg TD-4208	350 µg TD-4208	700 µg TD-4208
Measure Participants	0	0	0	0	31	26
Mean (Standard Deviation) [hours]	25.1 (7.89)	23.0 (7.05)

Adverse Events

Time Frame	13 weeks
Adverse Event Reporting Description	The Participant Flow shows the # of subjs in each of the 6 treatment sequences (each sequence has 4 treatments; 4/6 study drug doses and placebo) as instructed by CTgov for complex crossover designs. The Number of Participants at Risk, instead, shows the # of subjs exposed to each of the 6 doses of study drug and placebo. Also, some subjs did not complete all of the doses in their treatment sequence. The # of subjs in each sequence is not related to the # of subjs in each dose level therefore.
Arm/Group Title	Dose 1 TD-4208		Dose 2 TD-4208		Dose 3 TD-4208		Dose 4 TD-4208		Dose 5 TD-4208		Dose 6 TD-4208		Placebo
Arm/Group Description	22 µg TD-4208		44 µg TD-4208		88 µg TD-4208		175 µg TD-4208		350 µg TD-4208		700 µg TD-4208		Placebo Placebo
All Cause Mortality
	Dose 1 TD-4208		Dose 2 TD-4208		Dose 3 TD-4208		Dose 4 TD-4208		Dose 5 TD-4208		Dose 6 TD-4208		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose 1 TD-4208		Dose 2 TD-4208		Dose 3 TD-4208		Dose 4 TD-4208		Dose 5 TD-4208		Dose 6 TD-4208		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/42 (4.8%)		0/42 (0%)		0/40 (0%)		0/41 (0%)		0/41 (0%)		0/42 (0%)		1/62 (1.6%)
General disorders
Chest Pain	1/42 (2.4%)	1	0/42 (0%)	0	0/40 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	0/42 (0%)	0	0/62 (0%)	0
Infections and infestations
Pneumonia	0/42 (0%)	0	0/42 (0%)	0	0/40 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	0/42 (0%)	0	1/62 (1.6%)	1
Nervous system disorders
Transient Ischaemic Attack	1/42 (2.4%)	1	0/42 (0%)	0	0/40 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	0/42 (0%)	0	0/62 (0%)	0
Other (Not Including Serious) Adverse Events
	Dose 1 TD-4208		Dose 2 TD-4208		Dose 3 TD-4208		Dose 4 TD-4208		Dose 5 TD-4208		Dose 6 TD-4208		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/41 (34.1%)		12/39 (30.8%)		12/40 (30%)		13/37 (35.1%)		8/41 (19.5%)		9/37 (24.3%)		16/61 (26.2%)
Gastrointestinal disorders
Nausea	0/41 (0%)	0	2/39 (5.1%)	2	0/40 (0%)	0	1/37 (2.7%)	1	0/41 (0%)	0	0/37 (0%)	0	1/61 (1.6%)	1
General disorders
Fatigue	2/41 (4.9%)	2	2/39 (5.1%)	2	0/40 (0%)	0	0/37 (0%)	0	0/41 (0%)	0	0/37 (0%)	0	0/61 (0%)	0
Injury, poisoning and procedural complications
Contusion	2/41 (4.9%)	2	1/39 (2.6%)	1	0/40 (0%)	0	0/37 (0%)	0	0/41 (0%)	0	0/37 (0%)	0	0/61 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	2/41 (4.9%)	2	0/39 (0%)	0	1/40 (2.5%)	1	1/37 (2.7%)	1	1/41 (2.4%)	1	0/37 (0%)	0	0/61 (0%)	0
Nervous system disorders
Headache	3/41 (7.3%)	3	2/39 (5.1%)	2	3/40 (7.5%)	3	4/37 (10.8%)	4	3/41 (7.3%)	3	5/37 (13.5%)	5	9/61 (14.8%)	9
Respiratory, thoracic and mediastinal disorders
Cough	2/41 (4.9%)	2	1/39 (2.6%)	1	2/40 (5%)	2	2/37 (5.4%)	2	2/41 (4.9%)	2	2/37 (5.4%)	2	1/61 (1.6%)	1
Dyspnoea	1/41 (2.4%)	1	1/39 (2.6%)	1	1/40 (2.5%)	1	2/37 (5.4%)	2	2/41 (4.9%)	2	1/37 (2.7%)	1	4/61 (6.6%)	4
COPD	1/41 (2.4%)	1	0/39 (0%)	0	3/40 (7.5%)	3	0/37 (0%)	0	0/41 (0%)	0	0/37 (0%)	0	0/61 (0%)	0
Rhinorrhoea	0/41 (0%)	0	2/39 (5.1%)	2	0/40 (0%)	0	1/37 (2.7%)	1	0/41 (0%)	0	0/37 (0%)	0	0/61 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/41 (2.4%)	1	1/39 (2.6%)	1	0/40 (0%)	0	2/37 (5.4%)	2	0/41 (0%)	0	1/37 (2.7%)	1	0/61 (0%)	0
Vascular disorders
Haematoma	0/41 (0%)	0	0/39 (0%)	0	2/40 (5%)	2	0/37 (0%)	0	0/41 (0%)	0	0/37 (0%)	0	1/61 (1.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The PI may communicate the trial results generated by the PI, but only after the first publication or presentation of the combined study results generated by all participating sites. The Sponsor can then review trial results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The Sponsor cannot require changes to the communication and cannot extend the embargo.