Clinical Trials Register

Summary
EudraCT Number:	2006-001464-23
Sponsor's Protocol Code Number:	A1481243
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-05-05
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

Germany - BfArM

A.2

EudraCT number

2006-001464-23

A.3

Full title of the trial

A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg TID or placebo when added to Bosentan in the treatement of subjects , aged 18 years and above, with pulmonary arterial hypertension (PAH)

A.3.1

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

A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg three times daily or placebo when added to bosentan in the treatment of adult subjects, with
pulmonary arterial hypertension.

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

A1481243

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 Ltd, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
B.1.3.4	Country	Germany
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 Ltd
B.4.2	Country	Germany
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 Centre
B.5.3	Address:
B.5.3.1	Street Address	235 E 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	+18007181021
B.5.5	Fax number	+13037391119
B.5.6	E-mail	ClinicalTrials.gov_Inquiries@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	Yes
D.2.1.1.1	Trade name	Revatio
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/03/178
D.3 Description of the IMP
D.3.1	Product name	Revatio®
D.3.2	Product code	UK-92,480
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sildenafil
D.3.9.1	CAS number	n/a
D.3.9.2	Current sponsor code	n/a
D.3.9.3	Other descriptive name	n/a
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pulmonary Arterial Hypertension

E.1.1.1

Medical condition in easily understood language

Pulmonary arterial hypertension (PAH) is characterized by a progressive
increase in pulmonary vascular resistance, leading to right ventricular
failure and premature death.

E.1.1.2

Therapeutic area

Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10064911
E.1.2	Term	Pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the effect on exercise capacity (as measured by the 6 Minute Walk Distance) after 12 weeks of treatment of sildenafil (20mg TID) or placebo when added to subjects with PAH who are stabilized on bosentan therapy

E.2.2

Secondary objectives of the trial

1. To assess the safety and tolerability of sildenafil (20mg TID) or placebo, when added to subjects with PAH who are currently treated with bosentan, after 12 weeks of treatment.
2. To assess the safety and tolerability of the open label treatment of sildenafil (20mg TID) and bosentan therapy in subjects with PAH after 12 months of treatment.
3. To assess the effect on other clinical outcome measures (clinical worsening, Borg dyspnoea score and PAH functional class) after 12 weeks of treatment of sildenafil (20mg TID) or placebo when added to bosentan therapy in subjects with PAH.
4. To determine the population pharmacokinetic parameters of sildenafil and bosentan and to investigate potential pharmacokinetic interactions between the two compounds in the target patient population.
5. To investigate the PK/PD relationship between sildenafil and bosentan exposure on the 6-Minute Walk Test

Tertiary Objective
To investigate the effects on BNP and N-terminal pro-BNP

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects aged 18 and above at the time of the screening visit who have any of the following types of pulmonary arterial hypertension and functional class, and for which bosentan therapy is indicated according to EU Marketing Authorisation:
· Idiopathic ‘Primary’ Pulmonary Arterial Hypertension (PAH)
. Pulmonary Hypertension secondary to Scleroderma.
· Subjects with WHO functional class III prior to initiation of bosentan therapy.
2. Subjects must have been treated continually with a stable dose of bosentan (62.5mg bid or 125mg bid) for a minimum of three months prior to randomization.
3. Subject with a mean pulmonary artery pressure ≥25 mmHg and a pulmonary capillary wedge pressure of < 15 mmHg at rest, via right heart catheterization within 3 years prior to randomization.
4. Subjects whose baseline 6-Minute Walk Test distrance is ≥100m and ≤450m.
5. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
7. All women of childbearing potential must have a negative screening serum pregnancy test and:
 Must agree to use a highly effective method of contraception (ie, hormonal in conjunction with intrauterine device or barrier methods with spermicide) throughout the study and for the duration of their bosentan therapy or
 Must be celibate or
 Their partner must have had vasectomy.
8. Women who are not of childbearing potential may be enrolled and do not need to use birth control, provided they meet at least one of the following criteria:
 Have undergone hysterectomy or bilateral oopherectomy or
 Have medically confirmed ovarian failure or
 Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause.

E.4

Principal exclusion criteria

1. PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria. 2. With the exception of bosentan therapy, subjects who are currently receiving any forms of chronic treatment for PAH such as any formulations of prostacyclin, PDE-5 inhibitors, other endothelin-receptor antagonists, nitrates or nitric oxide donors (e.g. arginine supplements) including nicorandil in any form or any potent CYP3A4 inhibitors (e.g. Cyclosporin A and Glibenclamide). 3. Subjects with significant (i.e. > 2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation. Subjects with previous surgical replacement of a valve may be eligible for entry into the study after consultation with a Pfizer study clinician provided the following conditions are satisfied:That there was no evidence of PAH secondary to valvular disease prior to surgery; The prosthetic valve is functioning normally on echocardiography; The valve replacement occurred at least one year prior to randomization. 4. Subjects with acutely decompensated heart failure within 30 days prior to randomization. 5. Subjects with LV Ejection Fraction of <45% or LV shortening fraction of <0.2 within three months prior to randomization. 6. Subjects who have had a myocardial infarction within 6 months prior to randomization 7. Subjects who have had a change of dose or class of standard background therapy used for treatment of PAH (i.e. oxygen, calcium channel blockers, digoxin, diuretics) used for the treatment of PAH within 30 days prior to randomization. Note: a change in the dose or oral anticoagulant therapy within this timeframe to maintain the INR within the therapeutic range is acceptable. 8. Subjects with congenital heart disease (unless they fulfill inclusion 1.), pulmonary hypertension due to thromboembolism, HIV or schistosomiasis. 9. Subjects who have undergone atrial septostomy within six months prior to randomization. 10. Subjects with uncontrolled brady- or tachyarrhythmias, placement of pacemakers orimplantable defibrillators <60 days prior to randomization. 11. Subjects whose 6 Minute Walk Test distance may be limited by conditions other than PAH related dyspnoea or fatigue e.g. claudication from vascular insufficiency or arthritis. 12. Pregnant or lactating women. 13. Subjects with a history or pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest CT scan. 14. Subjects with hypotension defined as systolic arterial pressure <90 mm Hg after sitting for 5 minutes at either screening or baseline. 15. Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic ischemic optic neuropathy (NAION). 16. Subjects with history of chronic lung diseases / restrictive lung disease (e.g. COPD or scleroderma) with impairment of lung function as defined by TLC <60% and/or FEV1 ≤80% predicted within 30 days or randomization. 17. Subjects who have previously failed on bosentan or sildenafil therapy (defined as those subjects who had no evidence of clinical improvement whilst on the medicines, and no worsening in symptoms or clinical status, on discontinuation of the medicines). 18. Subjects at screening with impairment of renal function (serum creatinine > 2.5 X Upper Limits of Normal (ULN)). 19. Subjects at screening with severe hepatic impairment (ALT/AST > 3X ULN) or portalpulmonary hypertension. 20. Subjects using chronic arginine supplementation including HeartBar® 21. Subjects who have received any experimental drug within the past four months prior to randomization. An experimental drug is defined as any drug that does not have regulatory approval for the indication that it is being prescribed for.
22. Subjects who have evidence of any drug abuse, including alcohol.
23. Subjects who have donated blood during the previous month or intend to donate blood or blood products during the study or for one month following the completion of the study. 24. In the opinion of the investigator, a subject who is not likely to complete the study forwhatever reason. 25. Subjects who have untreated proliferative diabetic retinopathy.
26. Subjects with a history of multiple clinically significant allergies (including those with known allergies or intolerances to sildenafil).
27. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial.
28. Subjects who are investigational site staff members or relatives of those site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial.

E.5 End points

E.5.1

Primary end point(s)

The change from baseline in the total distance walked during the 6-Minute Walk Test at Week 12 of the study.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline, Week 4, Week 8, Week 12 and Weeks 28, 40, 52 and 64.

E.5.2

Secondary end point(s)

Borg Dyspnoea Score, WHO Functional Capacity and Therapeutic Class, Time to Clinical Worsening.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, Week 4, Week 8, Week 12 and Weeks 28, 40, 52 and 64; Time to Clinical Worsening at weeks 4, 8 and 12.

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Second phase of the study will be open-label

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

Australia

Belgium

Czech Republic

France

Germany

Greece

Israel

Italy

Taiwan

United Kingdom

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

End of trial in all participating countries is defined as 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