Clinical Trials Register

Summary
EudraCT Number:	2005-005068-97
Sponsor's Protocol Code Number:	AC-052-414
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-07-06
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2005-005068-97

A.3

Full title of the trial

Effects of combination of bosentan and sildenafil versus sildenafil monotherapy on morbidity and mortality in symptomatic patients with pulmonary arterial hypertension – A multicenter, double - blind, randomized, placebo - controlled, parallel group, prospective, event driven Phase IV study

A.3.1

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

A clinical trial to investigate the safety and effectiveness of the combination of bosentan and sildenafil to treat patients with symptomatic pulmonary arterial hypertension in comparison to treatment with sildenafil on its own

A.3.2

Name or abbreviated title of the trial where available

COMPASS 2

A.4.1

Sponsor's protocol code number

AC-052-414

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	Actelion Pharmaceuticals Ltd.
B.1.3.4	Country	Switzerland
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	Actelion Pharmaceuticals Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Actelion Pharmaceuticals Ltd
B.5.2	Functional name of contact point	GLOBAL MEDICAL INFORMATION
B.5.3	Address:
B.5.3.1	Street Address	Gewerbestrasse 16
B.5.3.2	Town/ city	Allschwil
B.5.3.3	Post code	4123
B.5.3.4	Country	Switzerland
B.5.6	E-mail	medinfo@actelion.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	Tracleer
D.2.1.1.2	Name of the Marketing Authorisation holder	Actelion Registration 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/3/01/019
D.3 Description of the IMP
D.3.1	Product name	bosentan
D.3.2	Product code	Ro-47-0203
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	BOSENTAN MONOHYDRATE
D.3.9.1	CAS number	157212-55-0
D.3.9.2	Current sponsor code	ACT-050088
D.3.9.3	Other descriptive name	Ro-47-0203/029
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	62.5
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.IMP: 2
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	Tracleer
D.2.1.1.2	Name of the Marketing Authorisation holder	Actelion Registration 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/3/01/019
D.3 Description of the IMP
D.3.1	Product name	Bosentan
D.3.2	Product code	Ro-47-0203
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	BOSENTAN MONOHYDRATE
D.3.9.1	CAS number	157212-55-0
D.3.9.2	Current sponsor code	ACT-050088
D.3.9.3	Other descriptive name	Ro-47-0203/029
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	125
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

Patients to be included must have PAH belonging to WHO Group I, in agreement with the approved indications for sildenafil in PAH by the US FDA:

a.Idiopathic (IPAH)
b.Familial (FPAH)
c.Associated with (APAH):
i.Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%)
ii.Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair
iii.Drugs and toxins

E.1.1.1

Medical condition in easily understood language

Pulmonary arterial hypertension is a disease of the blood circulatory system in the lungs by where narrowing of the blood vessels causes elevation of the blood pressure in the main pulmonary artery

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

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	10064910
E.1.2	Term	Familial (FPAH)
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	10064909
E.1.2	Term	Idiopathic (IPAH)
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	10064908
E.1.2	Term	Associated with (APAH)
E.1.2	System Organ Class	100000004855

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 demonstrate that the combination of bosentan and sildenafil prolongs the time to the first adjudicated morbidity/mortality event compared with sildenafil monotherapy in symptomatic patients with pulmonary arterial hypertension (PAH)

E.2.2

Secondary objectives of the trial

-6MWT
-WHO functional class
-Borg dyspnea
-QoL
-Clinical worsening
-Death
-Safety

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1)Signed informed consent prior to initiation of any study-mandated procedure
2)Males or females >= 18 years of age
•Women of childbearing potential must have a negative pre-treatment pregnancy test and must use reliable methods of contraception.
•Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.
3)Patients with symptomatic PAH
4)Patients with the following types of PAH belonging to WHO Group I:
a.Idiopathic (IPAH)
b.Familial (FPAH)
c.Associated with (APAH):
i.Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%)
ii.Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair
iii.Drugs and toxins
5)PAH diagnosed by right heart catheter showing:
a.Mean pulmonary arterial pressure
(mPAP) >= 25 mmHg
AND
b.Pulmonary capillary wedge pressure
(PCWP) <= 15 mmHg or left ventricular end diastolic pressure (LVEDP) <= 15 mmHg
If both PCWP and LVEDP are available then the LVEDP value is retained for inclusion

6)Treatment with a stable dose of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to randomization (no sildenafil dosage adjustment should occur in this period)
7)150 m <= 6MWT <= 480 m

E.4

Principal exclusion criteria

1) PAH belonging to WHO group II-V
2) PAH associated with portal hypertension and HIV infection
3) PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
4) PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
5) Persistent pulmonary hypertension of the newborn
6) Significant valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e., patients with tricuspid or pulmonary insufficiency secondary to PAH can be included)
7) Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value
8) Obstructive lung disease: forced expiratory volume/ forced vital capacity (FEV1/FVC) < 0.5
9) Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
10) Known HIV infection
11) Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements or that may interfere with the safety or the evaluation of the study, such as chronic infection, chronic renal failure etc.
12) Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
13) Pregnancy or breast-feeding
14) Condition that prevents compliance with the protocol or adherence to therapy
15) Systolic blood pressure < 85 mmHg
16) Body weight < 40 kg
17) Hemoglobin < 75% of the lower limit of the normal range
18) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges
19) Known hypersensitivity or history of drug-related adverse events with bosentan (e.g., increase in liver function test results [LFTs]), or any of the excipients of its formulation
20) Receipt of an investigational product other than sildenafil within 3 months prior to randomization
21) Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
22) Concomitant systemic treatment within 1 week prior to randomization with
• calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus
• glibenclamide (glyburide)
• inhibitors of both CYP2C9 and CYP3A4 (e.g., fluconazole, amiodarone, voriconazole)
• combination of drugs that inhibit CYP2C9 and CYP3A4
23) Treatment with nitrates and alpha-blockers at time of randomization
24) In the opinion of the investigator – patients in need for treatment with any prostanoid up to Visit 4
25) Significant left ventricular dysfunction

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoint
•Time from baseline to first adjudicated morbidity/mortality event, defined as follows:
a. Death
b. Hospitalization for worsening or complications of PAH or initiation of i.v. prostanoids
c. Atrial septostomy
d. Lung transplantation
e. Worsening PAH defined by fulfillment of both of the following criteria:
1) The recognition that the patient’s symptoms are worse using a 7-item Patient Global Self Assessment Scale:
•If the Patient Global Self Assessment is “moderately worse” or “markedly worse,” confirmatory examinations of worsening PAH may be performed if deemed necessary by the investigator. These examinations include (but are not limited to): right heart catheterization (RHC), 6MWT. However, none of these examinations are mandatory and the investigator can choose the method of evaluation.
•If the Patient Global Self Assessment is “no change” or “mildly worse,” but in the opinion of the investigator the patient’s condition is bad enough to initiate additional therapy (e.g., for patients in denial), then a 6MWT is mandatory to demonstrate either a decrease by more than 20% from the previous evaluation or a decrease by more than 30% from baseline in order to confirm disease progression.
The 6MWT should be performed in the absence of any factor, e.g. pneumonia, that may cause a temporary deterioration in 6MWT
AND
2)The initiation of s.c. or inhaled prostanoids or the “Disease Progression Package”

The observation period for all patients will start with the treatment start of the first patient and end when the overall target number of adjudicated morbidity/mortality events is achieved; the length of the observation period is independent of the duration of treatment. Censoring before EOS will be applied only to patients who are lost to follow-up and is expected to be 5.7%/year.

The risk of a morbidity/mortality event in one group relative to the other is not expected to change with time, and the risk in the placebo group is expected to be 20%/year. The anticipated treatment effect to be detected is a risk reduction of 40% that corresponds to a Hazard Ratio for bosentan/placebo of 0.5729 i.e., 12% in the bosentan group. Patients’ enrollment is expected to be 75 patients per year.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be evaluated at the End of Study, defined as when the target 156 adjudicated morbidity/mortality events has been reached

E.5.2

Secondary end point(s)

(a) To assess the effects of the combination of bosentan and sildenafil compared with sildenafil monotherapy on the 6-minute walk test
(b) To assess the effects of the combination of bosentan and sildenafil compared with sildenafil monotherapy on the modified WHO functional class
(c) To assess the effects of the combination of bosentan and sildenafil compared with sildenafil monotherapy on the time to event for the first occurrence of hospitalization for worsening or complication of PAH or initiation of i.v. prostanoids, atrial septostomy, lung transplantation or death
(d) To assess the effects of the combination of bosentan and sildenafil compared with sildenafil monotherapy on the time to death of all causes

E.5.2.1

Timepoint(s) of evaluation of this end point

(a) After 16 weeks of treatment with double-blind study medication
(b) After 16 weeks of treatment with double-blind study medication
(c) End of Study, i.e., after 156 adjudicated morbidity/mortality events have been reached
(d) End of Study, i.e., after 156 adjudicated morbidity/mortality events have been reached

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

E.6.7

Pharmacodynamic

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

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

Belgium

Brazil

Czech Republic

Denmark

Germany

Greece

Portugal

Saudi Arabia

Slovakia

Spain

Sweden

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LPLV

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero