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

Pulmonary Hypertension Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00310830
• Other study ID #: AC-052-368
• Secondary ID: ASSET-1
• Status: Terminated
• Phase: Phase 3
• First received: April 3, 2006
• Last updated: February 11, 2010
• Start date: March 2006
• Est. completion date: August 2007

Study information

• Verified date: February 2010
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Other known NCT identifiers

• NCT00307359

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 14
• Est. completion date: August 2007
• Est. primary completion date: August 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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/ß0 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 Design

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

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Bosentan
Oral, Initial dose: 62.5 mg b.i.d. for 4 weeks, maintenance dose: 125 mg b.i.d.

Locations

Country	Name	City	State
France	Hopital Antoine Beclere	Clamart
France	CHU Henri Mondor	Creteil
France	CHU de Fort de France	Fort de France	La Martinique
Netherlands	Amsterdam Medical Center, Department of Hematology	Amsterdam
United Kingdom	Royal Free Hospital, Rheumatology Department	London
United Kingdom	Royal Hallamshire Hospital, Pulmonary Vascular Medicine	Sheffield
United States	Alta Bates Medical Center	Berkeley	California
United States	National Institutes of Health	Bethesda	Maryland
United States	University of Alabama	Birmingham	Alabama
United States	Boston Medical Center/Boston University School of Medicine	Boston	Massachusetts
United States	UNC Comprehensive Sickle Cell Program	Chapel Hill	North Carolina
United States	University of Illinois Medical Center	Chicago	Illinois
United States	University Hospitals of Ohio	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	University of Colorado Health Sciences Center	Denver	Colorado
United States	Harper University Hospital/Wayne State University	Detroit	Michigan
United States	Henry Ford Hospital; Dept. of Pulmonology	Detroit	Michigan
United States	Duke University Medical Center; Duke University Health Systems	Durham	North Carolina
United States	The Methodist Hospital/Baylor College of Medicine; Pulmonary and Critical Care Medicine	Houston	Texas
United States	University of Texas Medical School; Division of Pulmonary and Critical Care Medicine	Houston	Texas
United States	University of Tennessee Health Science Center	Memphis	Tennessee
United States	Columbia University Medical Center; Pediatric Cardiology	New York	New York
United States	Temple University Lung Center	Philadelphia	Pennsylvania
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	SoLUtions/Saint Louis University	St. Louis	Missouri
United States	Harbor -UCLA Medical Center	Torrance	California
United States	Howard University Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  France,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Time to clinical worsening from Baseline to EOS.		16 weeks	No

External Links

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