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

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

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.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Bosentan

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Clamart, France, 92141
    • Hôpital Antoine Béclère
  • Creteil, France, 94010
    • CHU Henri Mondor
  • La Martinique
    • Fort de France, La Martinique, France, 97200
      • CHU de Fort de France
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam Medical Center, Department of Hematology
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital, Rheumatology Department
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital, Pulmonary Vascular Medicine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • California
    • Berkeley, California, United States, 94705
      • Alta Bates Medical Center
    • Torrance, California, United States, 90502
      • Harbor -UCLA Medical Center
  • Colorado
    • Denver, Colorado, United States, 80262
      • University of Colorado Health Sciences Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center/Boston University School of Medicine
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Harper University Hospital/Wayne State University
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital; Dept. of Pulmonology
  • Missouri
    • St. Louis, Missouri, United States, 63104
      • SoLUtions/Saint Louis University
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center; Pediatric Cardiology
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Comprehensive Sickle Cell Program
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center; Duke University Health Systems
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Lung Center
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee Health Science Center
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital/Baylor College of Medicine; Pulmonary and Critical Care Medicine
    • Houston, Texas, United States, 77030
      • University of Texas Medical School; Division of Pulmonary and Critical Care Medicine
  • Virginia
    • Richmond, Virginia, United States, 23298-5028
      • Virginia Commonwealth University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: Screening Criteria:

1. Males or females ≥ 12 years of age with a documented history of SCD
2. Patients with symptomatic PAH associated with shortness of breath
3. 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
4. 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:

1. Patients with hemoglobin (Hb) SS or Hb S/β0 genotype and with Hb A ≤ 10%
2. Six-minute walk test (6MWT) distance ≥ 150 m and ≤ 450 m

3. 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
4. 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:

1. Left ventricular ejection fraction < 40% (echo/Doppler)
2. Systolic blood pressure < 85 mmHg
3. Uncontrolled hypertension with systolic blood pressure >160 mmHg and/or diastolic blood pressure > 100 mmHg
4. Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC) < 0.5
5. Total lung capacity (TLC) < 50% of normal predicted value
6. Significant cardiac disease: ischemic, valvular, constrictive
7. Hemoglobin concentration < 6.0 g/dL at the time of randomization
8. Acute liver disease
9. Evidence of cirrhosis or portal hypertension on a liver ultrasound or biopsy
10. ALT ≥ 2 times upper limit of normal (ULN) and/or albumin < 2.8 g/dL
11. 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
12. 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
13. Blood transfusion within 4 weeks prior to randomization
14. Illness with a life expectancy shorter than 6 months
15. HIV with opportunistic infection
16. Psychotic, addictive, or other disorder limiting the ability to provide informed consent or to comply with study requirements
17. Pregnant or lactating women
18. Recently started (< 8 weeks prior to randomization) or planned, exercise-based cardio-pulmonary rehabilitation program
19. Bone marrow transplantation
20. Treatment or planned treatment with another investigational drug within 3 months prior to randomization
21. 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
22. Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, amiodarone, miconazole and glibenclamide (glyburide) within 1 week prior to randomization
23. Known hypersensitivity to bosentan or any of its excipients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 2	Drug: Bosentan; Oral, Initial dose: 62.5 mg b.i.d. for 4 weeks, maintenance dose: 125 mg b.i.d.
No Intervention: 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline to End of Study in 6MWT distance. A mean difference from placebo of at least 35 m is considered clinically relevant.	16 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to clinical worsening from Baseline to EOS.	16 weeks

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• 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.

Helpful Links

• A web site with information for patients about the disease and treatment options
• A newsletter and information web site

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Actual): August 1, 2007
• Study Completion (Actual): August 1, 2007

Study Registration Dates

• First Submitted: April 3, 2006
• First Submitted That Met QC Criteria: April 3, 2006
• First Posted (Estimate): April 5, 2006

Study Record Updates

• Last Update Posted (Estimate): February 15, 2010
• Last Update Submitted That Met QC Criteria: February 11, 2010
• Last Verified: February 1, 2010

More Information

Terms related to this study

• Keywords: Pulmonary hypertension; Sickle Cell Disease; Pulmonary Arterial Hypertension; Sickle cell anemia; ASSET; ASSET-1
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Hypertension; Pulmonary Arterial Hypertension; Anemia, Sickle Cell; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: AC-052-368; ASSET-1