Clinical Trials Register

Summary
EudraCT Number:	2014-002340-40
Sponsor's Protocol Code Number:	A9111004
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-08-22
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

2014-002340-40

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled 2-Way Crossover Study to Evaluate the Efficacy, Safety and Tolerability of PF-03715455 Administered Twice Daily By Inhalation for 4 Weeks in Subjects with Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

A.3.1

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

A Study to Evaluate how Safe and the Body's ability to Tolerate PF-03715455 when Given Twice Daily for 4 Weeks to Subjects with Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

A.4.1

Sponsor's protocol code number

A9111004

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1156-7217

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	Pfizer Limited
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	Pfizer Inc., 235 East 42nd Street, New York, NY 10017
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	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1800718 1021
B.5.5	Fax number	+1303739 1119
B.5.6	E-mail	clinicaltrials.govCallCenter@pfizer.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	PF-03715455
D.3.4	Pharmaceutical form	Capsule
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	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	PF-03715455
D.3.9.3	Other descriptive name	N-[3-tert-Butyl-1-(3-chloro-4-hydroxyphenyl)-1Hpyrazol- 5-yl]-N'-{2-[(3-{2-[(2- hydroxyethyl)sulfanyl]phenyl}[1,2,4]triazolo[4,3- a]pyridin-6-yl)sulfanyl]benzyl}urea
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	680
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	Capsule
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)

E.1.1.1

Medical condition in easily understood language

Chronic Obstructive Pulmonary Disease (COPD)

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10010952
E.1.2	Term	COPD
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the effect, at week 4, of orally inhaled PF-03715455 680 micrograms BID on trough FEV1 in subjects with moderate to severe COPD on a stable regimen of short or long acting bronchodilators.

E.2.2

Secondary objectives of the trial

- To determine the effect of orally inhaled PF-03715455 680 micrograms BID administered for 4 weeks, in sputum cell counts in a sub-study of subjects with moderate to severe COPD.
- To determine the effect, averaged over 4 weeks, of orally inhaled PF-03715455 680 micrograms BID on trough FEV1 and forced vital capacity (FVC) in subjects with moderate to severe COPD on a stable regimen of short or long acting bronchodilators.
- To explore the pharmacokinetics of PF-03715455 680 micrograms BID administered for 4 weeks in subjects with moderate to severe COPD.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Sputum sub-study; sputum induction is the only additional procedure involved in the sputum sub-study.

E.3

Principal inclusion criteria

1. Female subjects of non-childbearing potential and male subjects between the ages of 40 and 80 years, inclusive.
Female subjects of non-childbearing potential must meet at least one of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal women.
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
c. Have medically confirmed ovarian failure.
All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian failure) will be considered to be of childbearing potential.
2. Subjects with a diagnosis, for at least 6 months, of moderate to severe COPD (GOLD1) and who meet the criteria for Stage II-III disease:
- Subjects must have a post-bronchodilator FEV1/FVC ratio <0.7 and a postbronchodilator FEV1 of 30-80% (inclusive) of the predicted value for age, height, race and sex using European Community for Coal and Steel (ECCS) standards. To qualify for randomization these criteria must be met at both screening and the run-in viisit.
3. Subjects must have a smoking history of ≥10 pack-years* and meet one of the following criteria:
- They are current smokers, or
- They are ex-smokers who have abstained from smoking for at least 6 months.
*Formula for pack-years:
For cigarettes = (average number of cigarettes/day ÷ 20) x years of smoking,
For tobacco = ounces per week x 2/7 x years of smoking.
4. Subjects must have had stable COPD (for at least 3 months prior to screening. During the screening and run-in phase subjects must be able to manage disease symptoms adequately on bronchodilators alone without the need for other therapies.
5. Subjects must have an mMRC score at screening which is ≥1.
6. Subjects must be able to complete spirometry assessments according to American Thoracic Society/ European Respiratory Society (ATS/ERS) guidelines.
7. Body Mass Index (BMI) of <35 kg/m2; and a total body weight >40 kg.
8. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
9. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Additional Inclusion Criteria for Sputum Sub-Study:
1. Subjects must be able to produce a sputum sample, at screening and randomization, which is sufficient to provide a differential count (<20% squamous cells) and a minimum of 0.1 g in sputum weight after induction with inhaled hypertonic saline.
2. Subjects must have a sputum sample which has >50% neutrophils at screening.
In the event that a subject meets all other Screening criteria but does not provide an evaluable sputum sample they may still be entered into the non-sputum study providing recruitment is still open.

E.4

Principal exclusion criteria

1. Current evidence or history within the previous 6 months of any clinically 1. significant disease (other than COPD) or abnormality in the opinion of the Investigator that would put the subject at risk or which would compromise the quality of the study data
2. Subjects who have clinically significant (as deemed by investigator) abnormalities on physical examination, 12-lead ECG and vital signs (blood pressure and pulse) that would increase the risk to the patient or interfere with the interpretation of the safety or efficacy results.
3. A COPD exacerbation requiring treatment with oral steroids or hospitalization for the treatment of COPD within 3 months of Screening.
4. History of a lower respiratory tract infection or significant COPD disease instability during the 3 months preceding screening or during the time between screening and randomization.
5. History of an upper respiratory tract infection in the 4 weeks preceding screening or during the time between screening and randomization.
6. Use of inhaled corticosteroids within 3 months of Screening.
7. History or presence of respiratory failure, cor pulmonale or right ventricular failure.
8. Subjects with home oxygen therapy or long-term oxygen therapy.
9. Known history of adult asthma or other chronic respiratory disorders (eg, tuberculosis, bronchiectasis, pulmonary fibrosis, pneumoconiosis).
10. History of cancer (other than basal cell carcinoma or treated cervical carcinoma in situ) within the previous 5 years.
11. Symptoms, signs or laboratory findings (screening only) suggestive of an ongoing infective illness.
12. Participation in any clinical study with any investigational drug or marketed investigational biologic in the 4 months or 5 half-lives prior to the screening visit, whichever is longer.
13. ECG abnormalities at screening or randomisation including those listed below:
a. Subjects with pre-randomization evidence of QTcF prolongation (defined as >450 ms for males and >470 ms for females) are not eligible for randomization. This assessment is based on a confirmed mean of the triplicate ECG recordings.
b. Predominant heart rhythm other than normal sinus rhythm eg, atrial fibrillation, atrial flutter, supraventricular tachycardia.
c. Atrioventricular (AV) block greater than first degree.
d. Resting heart rate >100 or <40 bpm.
e. Evidence of previous myocardial infarction in the absence of clinical history associated with these findings.
f. Evidence of acute ischemia.
14. Known previous diagnosis of Hepatitis B or C or human immunodeficiency virus (HIV) infection.
15. Subjects with ANY of the following abnormalities in clinical laboratory tests at screening:
• Aspartate transaminase (AST)/ serum glutamic oxaloacetic transminase (SGOT) or alanine transaminase (ALT)/ serum glutamic pyruvic transminase (SGPT) >1.5 x upper limit of normal (ULN).
• Total bilirubin >1.5 x ULN.
• Albumin <3.5 g/dL due to known liver disease.
• Serum creatinine >1.5 x ULN.
• Hgb <10 g/dL, Hct <32%.
• Absolute white blood count (WBC) count <3.0 x 109/L (<3000/mm3).
• Neutrophil count <1.2 x 109/L (<1200/mm3).
• Platelet count <120 x 109/L (<120,000/mm3).
16. Male subjects with partners who are currently pregnant; male subjects of child bearing potential (who are at risk for pregnancy with their female partners) and unwilling or unable to use a highly effective method of contraception.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in trough FEV1 at Week 4

E.5.1.1

Timepoint(s) of evaluation of this end point

Weeks 1, 3 and 4

E.5.2

Secondary end point(s)

- Change from baseline in sputum cell counts [Total neutrophil count and differential (%), total cell count, total macrophage count and differential (%)] over 4 weeks.
- Change from baseline in trough FEV1 and FVC averaged over 4 weeks and at individual study visits.
- Summary Pharmacokinetic data for PF-03715455.

Safety Endpoints
- 12 lead ECG, BP/pulse rate, safety laboratory tests and adverse events.

Exploratory Endpoints
- Change from baseline in sputum inflammatory markers may include but will not be limited to IL-6, IL-8, Neutrophil Elastase, eosinophil cationic protein (ECP), α2 macroglobulin, MCP-1, MIP-1β and myeloperoxidase (MPO).
- Change from baseline in sputum markers of pharmacology: Phospho p38 and phospho HSP27.
- Change from baseline in high sensitivity C - reactive protein (hsCRP).

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 4

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

Yes

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

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LSLV

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.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None specified

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-03-27

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