Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612001235897
Ethics application status
Approved
Date submitted
10/11/2012
Date registered
22/11/2012
Date last updated
12/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2, Randomized, Double-Blind, Multiple-Dose, Five-Period, Incomplete-Block, Crossover Study to Examine the Pharmacodynamics, Safety and Tolerability, and Pharmacokinetics of Multiple Doses of TD-4208 for 7 Days in Subjects Diagnosed With Chronic Obstructive Pulmonary Disease
Scientific title
Effects of Multiple Doses of TD-4208 for 7 Days on Forced Expiratory Volume in one second (FEV1) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Secondary ID [1] 281431 0
ClinicalTrials.gov Identifier: NCT01704404
Secondary ID [2] 290900 0
0091
Secondary ID [3] 290901 0
EUDRACT # 2012-004949-32
Universal Trial Number (UTN)
U1111-1135-4436
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Obstructive Pulmonary Disease (COPD) 287684 0
Condition category
Condition code
Respiratory 288025 288025 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will evaluate the bronchodilatory effect, tolerability, and pharmacokinetics of multiple doses of TD-4208 for 7 days in subjects with a clinical diagnosis of COPD.

Each subject will receive four of six possible doses of TD-4208 (22 micro g, 44 micro g, 88 micro g, 175 micro g, 350 micro g, or 700 micro g) and placebo once per day via a nebulizer over five 7-day study periods in an incomplete crossover study design. Each period of treatment will be separated a washout period of 10 days up to a maximum of 16 days dependent on logistic considerations for the next dosing period.

A final safety follow-up assessment will be completed for all subjects 7 to 14 days after their last study treatment dose.
Intervention code [1] 285932 0
Treatment: Drugs
Comparator / control treatment
The placebo solution is made of citric acid monohydrate, sodium citrate and normal saline.
Control group
Active

Outcomes
Primary outcome [1] 288233 0
Trough FEV1 is the mean of the 23 and 24 hour FEV1 measured by a maximal exhalation into a spirometer after the seventh dose of each treatment period. This assesses the effectiveness and duration of the bronchial dilatation.
Timepoint [1] 288233 0
24 hour post-dose after seventh dose of each treatment period.
Secondary outcome [1] 299664 0
Heart rate which will be measured by palpation of the radial artery or by an automated heart rate recorder.
Timepoint [1] 299664 0
Baseline to Day 7 in each treatment period.
Secondary outcome [2] 299665 0
Blood Pressure will be recorded using a sphygmomanometer or an automated blood pressure recorder.
Timepoint [2] 299665 0
Baseline to Day 7 in each treatment period.
Secondary outcome [3] 299666 0
QTcF which is a standardized ECG interval will be measured using an ECG machine.
Timepoint [3] 299666 0
Baseline to Day 7 in each treatment period.
Secondary outcome [4] 299667 0
Cmax is the maximum plasma level of TD-4208 the study drug measured from a blood sample.
Timepoint [4] 299667 0
Day 1 and Day 7 in each treatment period.
Secondary outcome [5] 299668 0
Tmax is the time taken to reach the maximum plasma level of TD-4208 the study drug and is measured from the timed blood sample draws.
Timepoint [5] 299668 0
Day 1 and Day 7 in each treatment period.
Secondary outcome [6] 299669 0
Plasma half life is a calculation of the time taken for the plasma level of TD-4208 the study drug measured from a blood sample to be eliminated from the body.
Timepoint [6] 299669 0
Day 7 in each treatment period.

Eligibility
Key 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 <0.7 at screening; and has a post-bronchodilator FEV1 at screening of between 30% and 80% (inclusive) of the predicted normal value.
3.Subject demonstrates at screening at least a 120 mL increase in FEV1 within 1 hour of receiving 500 microgram of ipratropium bromide from a PARI LC Sprint 'Registered Trademark' Nebulizer.
4.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.
5.Subject (or care giver) is able to properly prepare and administer study medication.
6.Subject is willing and able to give written informed consent to participate.
Minimum age
40 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 microgram of fluticasone propionate equivalent or > 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 syndrome or has an abnormal clinically significant electrocardiogram (ECG) at screening, including QTcB 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Each subject will be randomized immediately before dosing using a central Interactive Web Randomization System (IWRS) to one of 60 unique treatment sequences (six different treatment combinations, each ordered in 10 unique sequences) with placebo and four dose levels of TD-4208. The Investigator and study staff and all sponsor trial staff will be blinded to the treatment allocation. Non-study staff prepared the randomization lists and these reside in the IWRS system and are not available except in the case of an emergency.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A statistical programmer at Theravance Biopharma, Inc. who is not involved in the study was responsible for preparing the randomization schedule using a computer program. The randomization schedule specifies the treatment sequence for each treatment number.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
22/11/2012
Actual
13/12/2012
Date of last participant enrolment
Anticipated
Actual
1/05/2013
Date of last data collection
Anticipated
Actual
23/08/2013
Sample size
Target
60
Accrual to date
Final
62
Recruitment outside Australia
Country [1] 4620 0
New Zealand
State/province [1] 4620 0
Country [2] 4622 0
United Kingdom
State/province [2] 4622 0

Funding & Sponsors
Funding source category [1] 286198 0
Commercial sector/Industry
Name [1] 286198 0
Theravance Biopharma R & D, Inc.
Country [1] 286198 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Theravance Biopharma R & D, Inc.
Address
901 Gateway Boulevard
South San Francisco, CA 94080
Country
United States of America
Secondary sponsor category [1] 285006 0
None
Name [1] 285006 0
Address [1] 285006 0
Country [1] 285006 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288268 0
Health and Disabilities Ethics Committees (HDEC)
Ethics committee address [1] 288268 0
Health and Disability Ethics Committees
Ministry of Health
1 the Terrace
PO Box 5013
Wellington
6011
Ethics committee country [1] 288268 0
New Zealand
Date submitted for ethics approval [1] 288268 0
10/10/2012
Approval date [1] 288268 0
20/11/2012
Ethics approval number [1] 288268 0
12/NTB/44

Summary
Brief summary
There are five (5) periods in the study. Study treatments are to be administered once daily for seven (7) days in each of the five (5) periods. All participants will receive seven (7) daily doses of placebo for one of the five (5) treatment periods.

The duration of the study is up to 134 days:
- participants will receive study medication for up to 35 days (28 days active drug and 7 days placebo)
- the remaining 99 days consist of: the screening period; each washout period between the five (5) dosing periods (i.e., the period when participants are not taking study medication); and the safety follow-up visit.
Trial website
Trial related presentations / publications
Bourdet DL, Barnes C, Yates W, Moran EJ, Nicholls AJ, and Haumann B; Repeated-Dose
Pharmacokinetics of Once-Daily TD-4208, a Long-acting Muscarinic Receptor Antagonist (LAMA), in Subjects with COPD, Abstract European Respiratory Society Congress 2014, print pending.

Nicholls AJ, Barnes C, Yates W, Moran EJ, Singh D; ID 55105 A Randomized, Crossover, 7-Day Study Of Once-Daily TD 4208, A Long-Acting Muscarinic Antagonist, In Subjects With COPD, presented at 2014 American Thoracic Society International Conference, San Diego, California.
Public notes

Contacts
Principal investigator
Name 34866 0
Prof Dave Singh
Address 34866 0
Medicines Evaluation Unit (MEU)
The Langley Building
Southmoor Road
Manchester M23 9QZ
Country 34866 0
United Kingdom
Phone 34866 0
+440 161 946 4073
Fax 34866 0
Email 34866 0
[email protected]
Contact person for public queries
Name 18113 0
Dr. Dean Quinn
Address 18113 0
1st Floor 121 Adelaide Road
Newton
Wellington 6021
Country 18113 0
New Zealand
Phone 18113 0
+64 0 4 801 0002
Fax 18113 0
Email 18113 0
[email protected]
Contact person for scientific queries
Name 9041 0
Glenn Crater, M.D.
Address 9041 0
901 Gateway Boulevard
South San Francisco, CA 94080
Country 9041 0
United States of America
Phone 9041 0
+1 650 808 4078
Fax 9041 0
+1 650 808 6464
Email 9041 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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