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Efficacy and Safety of Bosentan in Sickle Cell Disease (SCD) Patients With Pulmonary Arterial Hypertension (PAH)

Primary Purpose

Pulmonary Hypertension

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Bosentan
Sponsored by
Actelion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Hypertension focused on measuring Pulmonary Arterial Hypertension, Pulmonary hypertension, Sickle Cell Disease, Sickle cell anemia, ASSET, ASSET-1

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Screening Criteria: Males or females ≥ 12 years of age with a documented history of SCD Patients with symptomatic PAH associated with shortness of breath Patients with tricuspid regurgitation jet (TRJ) velocity of > 2.9 m/sec based on echo/Doppler conducted within 6 months prior to randomization and not during SCD crisis Signed written informed consent is obtained from the patient or patient's parent/legal representative prior to initiation of any study related procedure Inclusion Criteria: Patients with hemoglobin (Hb) SS or Hb S/β0 genotype and with Hb A ≤ 10% Six-minute walk test (6MWT) distance ≥ 150 m and ≤ 450 m PAH confirmed by right heart catheterization (RHC) performed at the study site within 3 months of the randomization visit and defined as: Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg measured by RHC or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg measured by left heart catheterization, if PCWP measurement is not reliable Pulmonary vascular resistance (PVR) at rest ≥ 160 dyn.sec/cm5 Women of childbearing potential must have a negative result on their serum pregnancy test and use reliable methods of contraception during study treatment and for 3 months after study treatment termination Exclusion Criteria: Left ventricular ejection fraction < 40% (echo/Doppler) Systolic blood pressure < 85 mmHg Uncontrolled hypertension with systolic blood pressure >160 mmHg and/or diastolic blood pressure > 100 mmHg Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC) < 0.5 Total lung capacity (TLC) < 50% of normal predicted value Significant cardiac disease: ischemic, valvular, constrictive Hemoglobin concentration < 6.0 g/dL at the time of randomization Acute liver disease Evidence of cirrhosis or portal hypertension on a liver ultrasound or biopsy ALT ≥ 2 times upper limit of normal (ULN) and/or albumin < 2.8 g/dL Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication, symptomatic hip osteonecrosis Vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) within 2 weeks of randomization or more than 12 VOC and/or ACS within the last 12 months Blood transfusion within 4 weeks prior to randomization Illness with a life expectancy shorter than 6 months HIV with opportunistic infection Psychotic, addictive, or other disorder limiting the ability to provide informed consent or to comply with study requirements Pregnant or lactating women Recently started (< 8 weeks prior to randomization) or planned, exercise-based cardio-pulmonary rehabilitation program Bone marrow transplantation Treatment or planned treatment with another investigational drug within 3 months prior to randomization Treatment for pulmonary hypertension with an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization or with L-arginine within 1 week prior to randomization Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, amiodarone, miconazole and glibenclamide (glyburide) within 1 week prior to randomization Known hypersensitivity to bosentan or any of its excipients

Sites / Locations

  • University of Alabama
  • Alta Bates Medical Center
  • Harbor -UCLA Medical Center
  • University of Colorado Health Sciences Center
  • Howard University Hospital
  • University of Illinois Medical Center
  • National Institutes of Health
  • Boston Medical Center/Boston University School of Medicine
  • Harper University Hospital/Wayne State University
  • Henry Ford Hospital; Dept. of Pulmonology
  • SoLUtions/Saint Louis University
  • Columbia University Medical Center; Pediatric Cardiology
  • UNC Comprehensive Sickle Cell Program
  • Duke University Medical Center; Duke University Health Systems
  • University Hospitals of Ohio
  • Ohio State University
  • Temple University Lung Center
  • University of Tennessee Health Science Center
  • The Methodist Hospital/Baylor College of Medicine; Pulmonary and Critical Care Medicine
  • University of Texas Medical School; Division of Pulmonary and Critical Care Medicine
  • Virginia Commonwealth University Medical Center
  • CHU de Fort de France
  • Hopital Antoine Beclere
  • CHU Henri Mondor
  • Amsterdam Medical Center, Department of Hematology
  • Royal Free Hospital, Rheumatology Department
  • Royal Hallamshire Hospital, Pulmonary Vascular Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

1

2

Arm Description

Outcomes

Primary Outcome Measures

Change from Baseline to End of Study in 6MWT distance. A mean difference from placebo of at least 35 m is considered clinically relevant.

Secondary Outcome Measures

Time to clinical worsening from Baseline to EOS.

Full Information

First Posted
April 3, 2006
Last Updated
February 11, 2010
Sponsor
Actelion
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1. Study Identification

Unique Protocol Identification Number
NCT00310830
Brief Title
Efficacy and Safety of Bosentan in Sickle Cell Disease (SCD) Patients With Pulmonary Arterial Hypertension (PAH)
Official Title
Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Bosentan in Patients With Symptomatic Pulmonary Arterial Hypertension Associated With Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
February 2010
Overall Recruitment Status
Terminated
Why Stopped
Slow enrollment
Study Start Date
March 2006 (undefined)
Primary Completion Date
August 2007 (Actual)
Study Completion Date
August 2007 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Actelion

4. Oversight

5. Study Description

Brief Summary
The study will assess the effect of bosentan on pulmonary vascular resistance and exercise capacity in sickle cell disease (SCD) patients diagnosed with pulmonary arterial hypertension. It consists of 3 phases: Screening, Treatment and Follow-up. During the Screening visit, the study doctor will decide if patients meet the study requirements. All potential patients will have a diagnosis of increased pulmonary artery pressures that is shown by right heart catheterization conducted shortly prior to start of study treatment. Patients will be asked to perform exercise capacity test (walking as far as possible for 6 minutes). Following the Baseline visit, the treatment phase consists of 4 additional clinic visits during which the good and bad effects of the drug are reviewed and exercise capacity test will be repeated. Patients will be treated for 16 weeks. Blood samples will be collected every month, or more often, if needed. At the end of the study, patients will be asked to repeat the right heart catheterization and exercise capacity test. After completion of the study, patients will have the option of enrolling in a long-term follow-up study where all patients will receive active drug. Patients electing not to participate in the extension study will be followed up for safety assessments for about 28 days after the end of the study treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Hypertension
Keywords
Pulmonary Arterial Hypertension, Pulmonary hypertension, Sickle Cell Disease, Sickle cell anemia, ASSET, ASSET-1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
No Intervention
Arm Title
2
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Bosentan
Intervention Description
Oral, Initial dose: 62.5 mg b.i.d. for 4 weeks, maintenance dose: 125 mg b.i.d.
Primary Outcome Measure Information:
Title
Change from Baseline to End of Study in 6MWT distance. A mean difference from placebo of at least 35 m is considered clinically relevant.
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
Time to clinical worsening from Baseline to EOS.
Time Frame
16 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Screening Criteria: Males or females ≥ 12 years of age with a documented history of SCD Patients with symptomatic PAH associated with shortness of breath Patients with tricuspid regurgitation jet (TRJ) velocity of > 2.9 m/sec based on echo/Doppler conducted within 6 months prior to randomization and not during SCD crisis Signed written informed consent is obtained from the patient or patient's parent/legal representative prior to initiation of any study related procedure Inclusion Criteria: Patients with hemoglobin (Hb) SS or Hb S/β0 genotype and with Hb A ≤ 10% Six-minute walk test (6MWT) distance ≥ 150 m and ≤ 450 m PAH confirmed by right heart catheterization (RHC) performed at the study site within 3 months of the randomization visit and defined as: Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg measured by RHC or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg measured by left heart catheterization, if PCWP measurement is not reliable Pulmonary vascular resistance (PVR) at rest ≥ 160 dyn.sec/cm5 Women of childbearing potential must have a negative result on their serum pregnancy test and use reliable methods of contraception during study treatment and for 3 months after study treatment termination Exclusion Criteria: Left ventricular ejection fraction < 40% (echo/Doppler) Systolic blood pressure < 85 mmHg Uncontrolled hypertension with systolic blood pressure >160 mmHg and/or diastolic blood pressure > 100 mmHg Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC) < 0.5 Total lung capacity (TLC) < 50% of normal predicted value Significant cardiac disease: ischemic, valvular, constrictive Hemoglobin concentration < 6.0 g/dL at the time of randomization Acute liver disease Evidence of cirrhosis or portal hypertension on a liver ultrasound or biopsy ALT ≥ 2 times upper limit of normal (ULN) and/or albumin < 2.8 g/dL Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication, symptomatic hip osteonecrosis Vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) within 2 weeks of randomization or more than 12 VOC and/or ACS within the last 12 months Blood transfusion within 4 weeks prior to randomization Illness with a life expectancy shorter than 6 months HIV with opportunistic infection Psychotic, addictive, or other disorder limiting the ability to provide informed consent or to comply with study requirements Pregnant or lactating women Recently started (< 8 weeks prior to randomization) or planned, exercise-based cardio-pulmonary rehabilitation program Bone marrow transplantation Treatment or planned treatment with another investigational drug within 3 months prior to randomization Treatment for pulmonary hypertension with an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization or with L-arginine within 1 week prior to randomization Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, amiodarone, miconazole and glibenclamide (glyburide) within 1 week prior to randomization Known hypersensitivity to bosentan or any of its excipients
Facility Information:
Facility Name
University of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Alta Bates Medical Center
City
Berkeley
State/Province
California
ZIP/Postal Code
94705
Country
United States
Facility Name
Harbor -UCLA Medical Center
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
University of Colorado Health Sciences Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80262
Country
United States
Facility Name
Howard University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20060
Country
United States
Facility Name
University of Illinois Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
National Institutes of Health
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Boston Medical Center/Boston University School of Medicine
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Harper University Hospital/Wayne State University
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Henry Ford Hospital; Dept. of Pulmonology
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
SoLUtions/Saint Louis University
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
Columbia University Medical Center; Pediatric Cardiology
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
UNC Comprehensive Sickle Cell Program
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Duke University Medical Center; Duke University Health Systems
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University Hospitals of Ohio
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Temple University Lung Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
University of Tennessee Health Science Center
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38163
Country
United States
Facility Name
The Methodist Hospital/Baylor College of Medicine; Pulmonary and Critical Care Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Texas Medical School; Division of Pulmonary and Critical Care Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Virginia Commonwealth University Medical Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298-5028
Country
United States
Facility Name
CHU de Fort de France
City
Fort de France
State/Province
La Martinique
ZIP/Postal Code
97200
Country
France
Facility Name
Hopital Antoine Beclere
City
Clamart
ZIP/Postal Code
92141
Country
France
Facility Name
CHU Henri Mondor
City
Creteil
ZIP/Postal Code
94010
Country
France
Facility Name
Amsterdam Medical Center, Department of Hematology
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Royal Free Hospital, Rheumatology Department
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Facility Name
Royal Hallamshire Hospital, Pulmonary Vascular Medicine
City
Sheffield
ZIP/Postal Code
S10 2JF
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
20175775
Citation
Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, Naeije R, Sood N, Swerdlow PS, Hildesheim M, Gladwin MT; ASSET study group*. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br J Haematol. 2010 May;149(3):426-35. doi: 10.1111/j.1365-2141.2010.08097.x. Epub 2010 Feb 17.
Results Reference
derived
Links:
URL
http://www.sicklecelldisease.org/
Description
A web site with information for patients about the disease and treatment options
URL
http://www.SCInfo.org
Description
A newsletter and information web site

Learn more about this trial

Efficacy and Safety of Bosentan in Sickle Cell Disease (SCD) Patients With Pulmonary Arterial Hypertension (PAH)

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