Imatinib and Carvedilol for High Blood Pressure in the Lungs in Adults With Sickle Cell Disease
- About one-tenth of adults with sickle cell disease have pulmonary hypertension (high blood pressure in the lungs). This condition can cause shortness of breath, pain crisis, and congestive heart failure. It may even lead to death. Researchers want to test the drugs imatinib and carvedilol to see if they can treat high blood pressure in the lungs. Both drugs have been used to treat other types of heart problems, but they have not been tested as a treatment for high blood pressure related to sickle cell disease.
- To see if imatinib and carvedilol are safe and effective treatments for high blood pressure in the lungs in adults with sickle cell disease.
- Adults at least 18 years of age who have sickle cell disease and have or may have high blood pressure in the lungs.
- Participants will be screened with a physical exam and medical history. They will also have different tests of heart and lung function, including a walking test and imaging studies. Blood and urine samples will also be collected.
- Participants who meet specific criteria will take one of two possible study drugs. Those who receive imatinib will take it daily. Those who receive carvedilol will take it twice a day.
- Participants will have weekly study visits for blood tests and other exams. The study drug dose will be adjusted at each weekly visit. It will be increased slowly to reach a target dose(based on the participant s weight) or to find a stable effective dose.
- Participants may continue to take their study drug for up to 24 weeks, with weekly study visits. Regular blood samples and heart and lung function tests will be performed.
- After 24 weeks, qualified participants may continue to take their study drug for up to 6 more months. They will have regular study visits to monitor the treatment.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Study of Treatment of Adults With Sickle Cell Disease Associated Pulmonary Hypertension Based on Hemodynamic Stratification: Safety and Tolerability Study of Imatinib and Carvedilol|
- An open-label non-controlled pilot study, to determine the safety and tolerability of 24-weeks of oral imatinib in SCD associated PAH and of oral carvedilol therapy in SCD associated PVH.
- Assess the efficacy and impact of imatinib and carvedilol on maximum exercise capacity as measured by peak oxygen consumption during a maximal CPET in SCD-PH subjects.
- Assess toxicity associated with concurrent use of study drugs and hydroxyurea.
- To determine appropriate monitoring, visit frequency and intensity, and to select a subject population and develop projections of statistical power for clinical efficacy endpoints.
|Study Start Date:||March 2012|
|Study Completion Date:||December 2012|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
Sickle Cell Disease related pulmonary hypertension is a heterogeneous condition that results in a high mortality and for which no therapy has been documented to be beneficial. We propose to perform a safety and tolerability study of treatments based on right heart catheterization derived hemodynamic profiles associated with higher mortality in our cohort. These same hemodynamic profiles have previously been described and confirmed in other large cohorts as well. We propose treatment of sickle cell subjects with pulmonary arterial hypertension (PAH), defined hemodynamically by pulmonary arterial mean pressures (mPAP) of 25 mmHg or greater, with low estimated left ventricular filling pressures (low pulmonary capillary wedge pressures, or PCWP), and high pulmonary vascular resistance (PVR), with imatinib, a tyrosine kinase inhibitor that modifies the Platelet Derived Growth Factor (PDGF) pathway. PDGF is involved in Sickle Cell related PAH and there is now evidence that imatinib is effective in the treatment of idiopathic PAH. The hemodynamic profile of elevated mPAP with elevated left ventricular filling pressures is also associated with higher mortality rates, and we propose to treat this subgroup with carvedilol, a unique beta-adrenergic receptor antagonist that has been demonstrated to attenuate the adrenergic response and improve right and left heart function. The third subgroup with elevated mPAP is the hyperdynamic group, which by definition has low PVR and the absence of elevated left ventricular filling pressures. This group is also at higher risk but over a longer period of time and for less evident reasons. We will continue with aggressive sickle cell management in the hyperdynamic group according to the expertise offered by the Sickle Cell Group at the Clinical Center while systematically following them and intervening with optimal care. Those who do not quality for any of the three subgroups described above will go into a fourth subgroup and be followed for mortality and data sharing. Our primary endpoint is the safety and tolerability of these interventions and our secondary endpoints will be the clinical efficacy of these treatments.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01568645
|Principal Investigator:||Gregory J Kato, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|