Clinical Trials Register

Summary
EudraCT Number:	2012-004949-32
Sponsor's Protocol Code Number:	0091
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-12-27
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2012-004949-32

A.3

Full title of the trial

A Phase 2, Randomised, 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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The effects of multiple doses of TD4208 for 7 days in COPD

A.3.2

Name or abbreviated title of the trial where available

The effects of multiple doses of TD-4208 for 7 days in COPD

A.4.1

Sponsor's protocol code number

0091

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1135-4436

A.5.4

Other Identifiers

Name:

www.clinicaltrials.gov

Number:

NCT01704404

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Theravance, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Theravance, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Theravance, Inc.
B.5.2	Functional name of contact point	Claudia Fuentes
B.5.3	Address:
B.5.3.1	Street Address	901 Gateway Blvd
B.5.3.2	Town/ city	South San Francisco, CA
B.5.3.3	Post code	94080
B.5.3.4	Country	United States
B.5.4	Telephone number	001650-808-6094
B.5.5	Fax number	001650-808-6464
B.5.6	E-mail	CFuentes@theravance.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TD-4208
D.3.2	Product code	TD-4208
D.3.4	Pharmaceutical form	Inhalation vapour, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	THRX-195518
D.3.9.2	Current sponsor code	TD-4208
D.3.9.3	Other descriptive name	TD-4208 diphosphate
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	22 to 700
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Inhalation vapour, solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Obstructive Pulmonary Disease (COPD) - GOLD stage 2 or 3

E.1.1.1

Medical condition in easily understood language

Chronic Obstructive Pulmonary Disease (COPD) - chronic bronchitis and emphysema

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10010952
E.1.2	Term	COPD
E.1.2	System Organ Class	100000004855

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10010953
E.1.2	Term	COPD exacerbation
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To characterise the dose response curve of TD-4208 after 7 days of dosing in subjects with COPD with the intent to identify an effective dose, a minimal-effect dose, and a no-effect dose, measured by spirometry (forced expiratory volume in 1 second [FEV1])

E.2.2

Secondary objectives of the trial

• To evaluate the safety and tolerability profile of nebulized TD-4208 administered once per day for 7 days
• To evaluate the steady-state pharmacokinetics of TD-4208 and its active metabolite in male and female subjects with COPD

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject is a male or female between the ages of 40 and 75 years (inclusive, at randomisation).
2. Subject has a current or past smoking history >10 pack-years.
3. Subject:
• Is capable of performing reproducible spirometry maneuvers as described by current ATS Guidelines;
• Has an FEV1/FVC <0.7 at screening; and
• Has an FEV1 at screening post-ipratropium of between 30% and 80% (inclusive) of the predicted normal value after withholding short acting bronchodilators for at least 6 hours and long acting bronchodilators for at least 24 hours.
4. 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® nebuliser.
5. Women who are of non-childbearing potential. Women are considered to not be of childbearing potential if they have had a hysterectomy or tubal ligation (documentation for either must be provided before enrollment) or are at least 2 years postmenopausal.
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.
6. Subject (or care giver) is able to properly prepare and administer study medication based on a hands-on demonstration in the presence of experienced site staff, at the investigator’s discretion.
7. Subject is willing and able to give written informed consent to participate.

E.4

Principal exclusion criteria

1. Subject has had a COPD exacerbation or lung infection within 6 weeks before randomisation.
2. Subject has a history of cor pulmonale or has any other significant respiratory disease, other than COPD, and/or requires daily long-term oxygen therapy.
3. 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.
4. Subject is taking daily maintenance inhaled/systemic corticosteroids (>1000 μg of fluticasone propionate equivalent or ≥10 mg prednisone).
5. Subject has taken any of the following prior to the first dose or is not willing to abstain from their use for the designated times:
• Salbutamol or similar short-acting beta2 agonists (SABAs) <12 hours before the first and seventh dose administered in each Period , however salbutamol or albuterol will be provided for rescue/maintenance;
• Long-acting QD beta2 agonists (LABA) e.g., indacaterol <5 days before the first dose administered in Period 1 through Period 5;
• Ipratropium bromide <24 hours before the first dose administered in each period (Day 1) through the end of each period (morning of Day 8);
• Long-acting muscarinic antagonists (LAMA), e.g., tiotropium (Spiriva®, Handihaler or Respimat, glycopyrronium bromide, other newly approved LAMAs) <5 days before the first dose administered in Period 1 through Period 5;
• Long-acting, twice-daily bronchodilating products (e.g., fluticasone propionate/salmeterol combination product (Advair®), budesonide/formoterol fumarate dihydrate combination product (Symbicort®), salmeterol, formoterol fumarate, arformoterol tartrate, aclidinium bromide, etc.) <48 hours before the first dose administered in Period 1 through Period 5; and/or
• Oral leukotriene antagonists, other oral bronchodilators (roflumilast (Daxas®)), or theophylline <48 hours before the first dose administered in Period 1 through Period 5;.
6. Subject is taking other antimuscarinic medications (e.g., atropine, cyclopentolate, hyoscine, Toviaz® [fesoterodine fumarate], or Ditropan, Lyrinel XL [oxybutynin], etc.),
7. Subject has symptomatic prostatic hypertrophy or bladder neck obstruction.
8. Subject has a history of narrow angle glaucoma.
9. Subject has an uncontrolled haematologic, 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.
10. 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.
11. Subject has a history of active cancer (excludes basal cell or cancer in remission for more than 5 years).
12. Subject has a known hypersensitivity to TD-4208 or similar drug class.
13. Subject has a history of alcoholism or drug abuse within 2 years prior to screening.
14. Subject has participated in another investigational drug study where they received an investigational drug within 30 days before the screening visit.
15. Subject has a potential for noncompliance or inability to comply with study procedures, or is considered a person of a vulnerable population (e.g., prisoner or military personnel) based on previous history or the judgment of the investigator.

E.5 End points

E.5.1

Primary end point(s)

The primary pharmacodynamic (PD) endpoint is:
• Trough FEV1 after the seventh dose of each treatment period (Trough is the mean of the 23- and 24-hour postdose FEV1 time points.)

E.5.1.1

Timepoint(s) of evaluation of this end point

The mean of the 23 and 24 hour postdose FEV1 time points after the seventh dose of each treatment period.

E.5.2

Secondary end point(s)

The secondary PD endpoints are:
• FEV1: AUC 0-24, AUC 0-12, and AUC 12-24 after the seventh dose of each treatment period (The mean of the observed 23 and 24hour spirometry is used for the 24 hour
postdose time point)
• FEV1: Peak and AUC0-6 on Day 1 and Day 7 of each treatment period.
• FVC: same endpoints as FEV1

The safety endpoints are:
• Adverse events, vital signs, ECG parameters, physical exam results, and clinical laboratory results

The reported pharmacokinetic parameters for TD4208 and its active metabolite are:
• Cmax, Tmax, AUC0-t, and t½ on Days 1 and 7-8
• Metabolite profiling may be conducted with plasma samples and would be reported separately

E.5.2.1

Timepoint(s) of evaluation of this end point

For the safety endpoints, from the first drug administration to the end of trial.
For all other endpoints, see above.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Incomplete-block

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Germany

New Zealand

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last patient last visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1