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

This study has been terminated.
(Slow enrollment)
Sponsor:
Information provided by:
Actelion
ClinicalTrials.gov Identifier:
NCT00310830
First received: April 3, 2006
Last updated: February 11, 2010
Last verified: February 2010
  Purpose

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.


Condition Intervention Phase
Pulmonary Hypertension
Drug: Bosentan
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Actelion:

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. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to clinical worsening from Baseline to EOS. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Enrollment: 14
Study Start Date: March 2006
Study Completion Date: August 2007
Primary Completion Date: August 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: 1
Experimental: 2 Drug: Bosentan
Oral, Initial dose: 62.5 mg b.i.d. for 4 weeks, maintenance dose: 125 mg b.i.d.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00310830

  Show 27 Study Locations
Sponsors and Collaborators
Actelion
  More Information

Additional Information:
No publications provided by Actelion

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sebastien Roux, MD, Actelion
ClinicalTrials.gov Identifier: NCT00310830     History of Changes
Obsolete Identifiers: NCT00307359
Other Study ID Numbers: AC-052-368, ASSET-1
Study First Received: April 3, 2006
Last Updated: February 11, 2010
Health Authority: United States: Food and Drug Administration

Keywords provided by Actelion:
Pulmonary Arterial Hypertension
Pulmonary hypertension
Sickle Cell Disease
Sickle cell anemia
ASSET
ASSET-1

Additional relevant MeSH terms:
Anemia, Sickle Cell
Hypertension
Hypertension, Pulmonary
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Cardiovascular Diseases
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Bosentan
Antihypertensive Agents
Cardiovascular Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014