Efficacy and Safety of Bosentan in Sickle Cell Disease (SCD) Patients Diagnosed With Pulmonary Hypertension (PH) - Full Text View

Sponsor:	Actelion
Information provided by:	Actelion
ClinicalTrials.gov Identifier:	NCT00313196

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 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 some of the patients will be asked to repeat the right heart catheterization. All patients will repeat an 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 III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: 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 Hypertension Associated With Sickle Cell Disease

Resource links provided by NLM:

Genetics Home Reference related topics: sickle cell disease

MedlinePlus related topics: Anemia High Blood Pressure Pulmonary Hypertension Sickle Cell Anemia

Drug Information available for: Bosentan

U.S. FDA Resources

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

Enrollment:	12
Study Start Date:	April 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 for all patients, maintenance dose: 125 mg

Eligibility

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

Criteria

Inclusion Criteria: Screening Criteria:

Males or females > or = 12 years of age with a documented history of SCD
Patients with symptomatic PH 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 < or = 10%
Six-minute walk test (6MWT) distance > or = 150 m and < or = 450 m
Pulmonary hypertension 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) > or - 25 mmHg
- Pulmonary capillary wedge pressure (PCWP) measured by right heart catheterization or left ventricular end diastolic pressure (LVEDP) measured by left heart catheterization, if PCWP measurement is not reliable. Two subsets of patients will be considered for this study:
- PCWP < or = 15 mm Hg, if PVR at rest < 160 dyn.sec/cm5
- PCWP of 16-25 mm Hg with any PVR value
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 (SBP) < 85 mmHg
Uncontrolled hypertension with SBP > 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
cirrhosis or portal hypertension
ALT > or = 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00313196

Show 27 Study Locations

Sponsors and Collaborators

Actelion

Investigators

Study Director:

Irina M Kline, MD

Actelion

More Information

No publications provided by Actelion

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. Epub 2010 Feb 17.

Responsible Party:	Sebastien Roux, MD, Actelion
ClinicalTrials.gov Identifier:	NCT00313196 History of Changes
Obsolete Identifiers:	NCT00307372
Other Study ID Numbers:	AC-052-369, ASSET-2
Study First Received:	April 10, 2006
Last Updated:	January 11, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Actelion:

Pulmonary Hypertension
Sickle Cell Disease
Sickle cell anemia

bosentan
ASSET
ASSET-2

Additional relevant MeSH terms:

Anemia, Sickle Cell
Hypertension
Hypertension, Pulmonary
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn

Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Bosentan
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 12, 2012