Pulmonary hypertension associated with sickle cell disease
Conditions
Interventions
Trade Name: Revatio
Product Name: Sildenafil
Pharmaceutical Form: Tablet
INN or Proposed INN: SILDENAFIL CITRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Sponsors
Imperial College London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Males or females, greater than or equal to 12 years of age and less than or equal to 70 years of age 2. For female subjects, on a reliable method of birth control or not physically able to bear children 3. Electrophoretic documentation of sickle cell disease (including, but not limited to SS, SC, SD, or Sß°/+ thalassemia) 4. At least mild pulmonary hypertension with TRV = 2.7 m/s by echocardiogram 5. Six minute walk distance of 150-500 m 6. In the opinion of the investigator, ability to complete the protocol scheduled assessments during the 16 week, double-blind phase 7. Provision of informed consent and, where applicable, assent 8. Subjects with systemic hypertension must be on a stable antihypertensive regimen for greater than or equal to 90 days and a stable dose for greater than or equal to 30 days. Are the trial subjects under 18? yes Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Current pregnancy or lactation 2. Any one of the following medical conditions: • Stroke within the last six weeks • New diagnosis of pulmonary embolism within the last three months • History of retinal detachment or retinal hemorrhage in the last 6 months • Non-arteritic anterior ischemic optic neuropathy (NAION) in one or both eyes • History of sustained priapism requiring medical or surgical treatment, unless currently impotent or on transfusion program within the last two years • Any unstable (chronic or acute) condition that in the opinion of the investigator will prevent completion of the study 3. Subjects taking nitrate-based vasodilators (including, but not limited to nicorandil [available in the UK only] ), prostacyclin (inhaled, subcutaneous or intravenous) or endothelin antagonists. Subjects taking calcium channel blockers will be allowed to participate provided they are on a stable dose for = 3 months. 4. Left ventricular ejection fraction < 40% or clinically significant ischemic, valvular or constrictive heart disease: LVEF <40% or SF < 22% 5. Subjects who are in other research studies with investigational drugs, with the exception of hydroxyurea, unless the other trial has been approved by the walk-PHaSST Executive Committee for co-participation 6. 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 7. Tonsillectomies for sleep apnea within 3 months prior to randomization 8. Active therapy for pulmonary hypertension, including prostacyclin analog, endothelin-1 antagonists, or PDE-5 inhibitor 9. Protease inhibitor therapy for the treatment of HIV 10. Subjects taking potent CYP3A4 inhibitor therapy (e.g., itraconazole, ritonavir, ketoconazole) 11. Subjects who are anticoagulated and have proliferative retinopathy (unless they have had ophthalmologist recommended intervention (e.g., phototherapy) or have been otherwise cleared by an ophthalmologist to participate in the study) 12. Subjects with systolic blood pressure greater than or equal to 140 mmHg OR diastolic blood pressure greater than or equal to 90 mmHg. See Section 9.3.3 for qualifying blood pressure assessment instructions.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: In a randomised, double-blind, placebo-controlled phase II/III trial, to determine the efficacy of 16 weeks of sildenafil therapy on exercise capacity (six-minute walk distance).;Secondary Objective: 1.To determine the efficacy of 16 weeks of sildenafil therapy on echocardiographic estimates of right ventricular systolic pressure, and symptoms in patients with sickle cell disease and pulmonary hypertension. 2.In subjects with more severe pulmonary hypertension (TRV greater than or equal to 3.0 m/sec stratum), to evaluate and compare the acute haemodynamic effects of inhaled nitric oxide and of oral sildenafil and to determine the changes in hemodynamics after 16 weeks of sildenafil therapy 3.To determine the safety of 16 weeks of sildenafil therapy via adverse event reports and laboratory assessments 4.To evaluate prospective clinical outcomes in the subjects participating in the Observational Follow-up Study to the extent possible by each participating site 5.To provide subjects with open-label sildenafil for up to one year after completion of the Main Interventional Trial and to evaluate the long term safety of sildenafil in this population ;Primary end point(s): The primary efficacy hypothesis is that 16 weeks of sildenafil therapy provides greater improvement in six-minute walk (6MW) distance than does placebo in patients with sickle cell disease (SCD) and pulmonary hypertension. The primary efficacy analysis is an Analysis of Covariance Analysis (ANCOVA) on 6MW distance change from baseline to Week 16 on the Intent to Treat (ITT) Population. The primary hypothesis test will be based on a test that the average change differs between the two treatment groups, with baseline 6MW distance and TRV stratum used as covariates. This type of model controls for any impact of baseline 6MW on the treatment effect without assumptions about the slope of the relationship between the baseline and Week 16 measures. | — |
Countries
United Kingdom
Outcome results
None listed