A 7-Day Cross-over Study of QD (Once Daily) and BID (Twice Daily) TD-4208 in Chronic Obstructive Pulmonary Disease (COPD)

• Sponsor: Mylan Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02109172
• Collaborator: Theravance Biopharma (Industry)
• Enrollment: 64
• Location: 1
• Arms: 3
• Duration (Months): 6
• Patients Per Site Per Month: 10.6

Study Details

Study Description

Brief Summary

This study evaluated the safety and efficacy of once and twice daily TD-4208 and placebo when administered using a jet nebulizer for 7 days in a cross-over design to patients with moderate to severe chronic obstructive pulmonary disease.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Cross-Over Study of QD and BID Nebulized TD-4208 in Subjects With Chronic Obstructive Pulmonary Disease
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TD-4208 44 mcg twice daily TD-4208 inhalation solution 44 mcg twice daily for 7 days	Drug: TD-4208; Other Names: Revefenacin
Placebo Comparator: Placebo Placebo inhalation solution twice daily for 7 days	Drug: Placebo
Experimental: TD-4208 175 mcg once daily TD-4208 inhalation solution 175 mcg once daily, placebo once daily	Drug: TD-4208; Other Names: Revefenacin ; Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Weighted Mean (0-24hr) Change From Baseline FEV1 (Forced Expiratory Volume in 1 Second) [Following the Day 7 AM dose -12 hours post-dose and 24 hours post-dose]

   Weighted mean (0-24hr) Change from baseline FEV1 (forced expiratory volume in 1 second). Measurement is change from baseline.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subject must have a negative pregnancy test, and must be prepared to use effective contraception if of child-bearing potential

• Subject is capable of performing reproducible spirometry maneuvers

• Subject has post-bronchodilator FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) ratio <0.7

• Subject has moderate-to-severe stable COPD (Stage 2 or 3 according to the Global Initiative for the Treatment of Obstructive Lung Disease (GOLD) Guidelines)

• Subject has a post-bronchodilator FEV1 greater than or equal to 30% and less than 80% of predicted normal

• Subject demonstrates a post-ipratropium FEV1 response ≥ 12% and ≥ 200 mL of pre-ipratropium FEV1 response

• Subject has a current or past smoking history of at least 10 pack-years.

Exclusion Criteria:

• Subject has a significant respiratory disease or disorder other than COPD that would affect the interpretation of data from this study

• Subject has a history of reactions or hypersensitivity to inhaled anticholinergic or beta-agonist agents

• Subject suffers from any medical condition that would preclude the use of inhaled anticholinergic agents

• Subject has been hospitalized for COPD or pneumonia within 12 weeks.

• Subject requires long-term oxygen therapy (>15 hours a day)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	American Health Research	Charlotte	North Carolina	United States	28207

Sponsors and Collaborators

• Mylan Inc.
• Theravance Biopharma

Investigators

• Study Director: Medical Monitor, Theravance Biopharma, US, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mylan Inc.
• ClinicalTrials.gov Identifier: NCT02109172
• Other Study ID Numbers: 0116
• First Posted: Apr 9, 2014
• 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.: 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	Placebo First, Then 44mcg, Then 175mcg	Placebo First, Then 175mcg, Then 44mcg	44mcg First, Then 175mcg, Then Placebo	44mcg First, Then Placebo, Then 175mcg	175mcg First, Then 44mcg, Then Placebo	175mcg First, Then Placebo, Then 44mcg
Arm/Group Description	Placebo twice daily for 7 days then 44mcg twice daily for 7 days then 175mcg once daily for 7 days	Placebo twice daily for 7 days then 175mcg once daily for 7 days then 44mcg twice daily for 7 days	44mcg twice daily for 7 days then 175mcg once daily for 7 days then placebo twice daily for 7 days	44mcg twice daily for 7 days then placebo twice daily for 7 days then 175mcg once daily for 7 days	175mcg once daily for 7 days then 44mcg twice daily for 7 days then placebo twice daily for 7 days	175mcg once daily for 7 days then placebo twice daily for 7 days then 44mcg twice daily for 7 days
Period Title: Overall Study
STARTED	11	11	10	11	10	11
COMPLETED	10	11	9	10	9	10
NOT COMPLETED	1	0	1	1	1	1

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	All groups were randomized to receive placebo, TD-4208 44mcg twice daily, and TD-4208 175 mcg once daily
Overall Participants	64
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	39 60.9%
>=65 years	25 39.1%
Sex: Female, Male (Count of Participants)
Female	27 42.2%
Male	37 57.8%

Outcome Measures

1. Primary Outcome

Title	Weighted Mean (0-24hr) Change From Baseline FEV1 (Forced Expiratory Volume in 1 Second)
Description	Weighted mean (0-24hr) Change from baseline FEV1 (forced expiratory volume in 1 second). Measurement is change from baseline.
Time Frame	Following the Day 7 AM dose -12 hours post-dose and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	TD-4208 44 mcg Twice Daily	TD-4208 175 mcg Once Daily
Arm/Group Description	Placebo inhalation solution twice daily for 7 days Placebo	TD-4208 inhalation solution 44 mcg twice daily for 7 days TD-4208	TD-4208 inhalation solution 175 mcg once daily, placebo once daily TD-4208 Placebo
Measure Participants	64	64	64
Least Squares Mean (Standard Error) [mL]	-14.4 (15.29)	90.2 (15.00)	98.5 (15.03)

Adverse Events

Arm/Group Title	Placebo		TD-4208 44mcg Twice Daily		TD-4208 175mcg Once Daily
Arm/Group Description	Placebo inhalation solution twice daily for 7 days		TD-4208 inhalation solution 44 mcg twice daily for 7 days		TD-4208 inhalation solution 175 mcg once daily
All Cause Mortality
	Placebo		TD-4208 44mcg Twice Daily		TD-4208 175mcg Once Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		TD-4208 44mcg Twice Daily		TD-4208 175mcg Once Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/64 (0%)		1/64 (1.6%)
Cardiac disorders
Coronary Artery Insufficiency	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Placebo		TD-4208 44mcg Twice Daily		TD-4208 175mcg Once Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/64 (35.9%)		24/64 (37.5%)		14/64 (21.9%)
Gastrointestinal disorders
Dry Mouth	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Gingival pain	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Inguinal hernia	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Vomiting	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Abdominal pain lower	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
General disorders
Oedema	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Oedema	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Oedema peripheral	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Infections and infestations
Ear Infection	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Urinary tract infection	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Furuncle	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Oral candidiasis	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Upper respiratory tract infection	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/64 (1.6%)	1	2/64 (3.1%)	2	1/64 (1.6%)	1
Eye Swelling	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Eye contusion	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Foot fracture	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Laceration	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Procedural pain	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Investigations
Haemoglobin decreased	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle Spasms	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Musculoskeletal pain	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Neck Pain	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Basal cell carcinoma	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Nervous system disorders
Dizziness	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Headache	1/64 (1.6%)	1	2/64 (3.1%)	2	1/64 (1.6%)	1
Tremor	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Respiratory, thoracic and mediastinal disorders
Breath sounds abnormal	2/64 (3.1%)	2	0/64 (0%)	0	0/64 (0%)	0
Chest Discomfort	0/64 (0%)	0	1/64 (1.6%)	1	1/64 (1.6%)	1
COPD	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Cough	1/64 (1.6%)	1	1/64 (1.6%)	1	0/64 (0%)	0
Dysphonia	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Dyspnoea	3/64 (4.7%)	3	1/64 (1.6%)	1	1/64 (1.6%)	1
Respiratory distress	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Respiratory tract congestion	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Rhonchi	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Sinus congestion	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Wheezing	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Rales	1/64 (1.6%)	1	0/64 (0%)	0	0/64 (0%)	0
Sputum increased	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	0/64 (0%)	0	0/64 (0%)	0	2/64 (3.1%)	2
Rash	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Vascular disorders
Blood Pressure Increased	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Hypotension	0/64 (0%)	0	1/64 (1.6%)	1	0/64 (0%)	0
Coronary artery insufficiency	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1
Hypertension	0/64 (0%)	0	0/64 (0%)	0	1/64 (1.6%)	1

Limitations/Caveats

The study was designed to evaluate whether a lower dose (44) BID would achieve a greater response than a higher dose (175) QD.

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.