Sildenafil to Improve Exercise Capacity in People With Thalassemia and Pulmonary Hypertension

Pilot of Oral Sildenafil for the Treatment of Pulmonary Hypertension in Thalassemia With Comparison to Controls

Thalassemia is an inherited blood disorder that can result in mild to severe anemia. Many people with thalassemia also have pulmonary hypertension, which is high blood pressure in the arteries in the lungs. This study will evaluate the safety and effectiveness of the medication sildenafil at reducing blood pressure in the lungs of people with thalassemia and pulmonary hypertension.

Thalassemia is an inherited blood disorder in which the body makes an abnormal form of hemoglobin-the protein in red blood cells that carries oxygen. A potential complication of thalassemia is pulmonary hypertension, which is a condition characterized by abnormally high blood pressure in the arteries of the lungs. People with thalassemia who have pulmonary hypertension tend to experience more health complications, including shortness of breath and a reduced exercise capacity, than people with thalassemia who do not have pulmonary hypertension. Sildenafil is a medication that is used to treat pulmonary hypertension; however, it has not yet been studied in people with thalassemia. The purpose of this study is to evaluate the safety and effectiveness of sildenafil at reducing blood pressure in the lungs of people who have thalassemia and pulmonary hypertension. Study researchers will also further compare the differences between people with thalassemia who have pulmonary hypertension and those who do not have pulmonary hypertension. This study will enroll people with thalassemia who have pulmonary hypertension and a control group of people with thalassemia who do not have pulmonary hypertension. People with thalassemia and pulmonary hypertension will attend a baseline study visit at which time they will undergo the following procedures: medical history and medical record review; physical exam; a 6-minute walk test, which will measure how far participants can walk in 6 minutes; an echocardiogram to obtain images of the heart; blood collection; and for females, a urine collection. Participants will then begin taking sildenafil three times a day for 12 weeks. At study visits at Weeks 2, 4, and 8, participants will undergo repeat baseline testing, and some participants will take part in an exhaled nitric oxide test. At Week 12, participants will also undergo lung function testing and a chest magnetic resonance imaging (MRI) procedure. Participants in the control group will attend one to three study visits at baseline, which will include the same baseline study procedures listed above, plus lung function testing, a chest MRI, a chest computed tomography (CAT) scan, and exhaled nitric oxide testing. They will not receive any medication or have any further study visits.

Participants with thalassemia who do not have pulmonary hypertension will be part of a control group and will only be undergoing screening/baseline assessments.

Participants will receive sildenafil for 12 weeks with the following therapy: 50 mg of oral sildenafil three times a day (TID) increased to 100 mg TID as tolerated in adults and children greater than 50 kg; 1 mg/kg sildenafil TID without dose escalation in children less than 50 kg

Change in six-minute walk test (6MWT) distance was calculated as 6MWT at week 12 minus 6MWT at baseline.

Change in tricuspid regurgitant jet velocity (TRV) was calculated as TRV at week 12 minus TRV at baseline. The TRV provides an estimate of pulmonary artery pressure.

Change in Echo Left Ventricular End Systolic Volume (LVESV) From Baseline to Week 12 Among Sildenafil Group

Change in echo left ventricular end systolic volume (LVESV) was calculated as LVESV at week 12 minus LVESV at baseline.

Change in Echo Left Ventricular End Diastolic Volume (LVEDV) From Baseline to Week 12 Among Sildenafil Group

Change in echo left ventricular end diastolic volume (LVEDV) was calculated as LVEDV at week 12 minus LVEDV at baseline.

Change in Plasma Arginine was calculated as Plasma Arginine at week 12 minus Plasma Arginine at baseline.

Change in Red Blood Cell (RBC) Arginine was calculated as Red Blood Cell (RBC) Arginine at week 12 minus Red Blood Cell (RBC) Arginine at baseline.

Change in Soluble platelet selectin (sP-SELECTIN) was calculated as sP-SELECTIN at week 12 minus sP-SELECTIN at baseline.

Change in Cell Free Hemoglobin was calculated as Cell Free Hemoglobin at week 12 minus Cell Free Hemoglobin at baseline.

Change in Arginase concentration was calculated as Arginase concentration at week 12 minus Arginase concentration at baseline.

Change in Arginase activity was calculated as Arginase activity at week 12 minus Arginase activity at baseline.

Inclusion Criteria for All Participants: Alpha, beta, or E-beta thalassemia confirmed by hemoglobin (Hb)-electrophoresis or molecular diagnosis Inclusion Criteria for Participants with Pulmonary Hypertension: Pulmonary hypertension, defined as a tricuspid regurgitant jet (TRjet) velocity by Doppler echocardiography greater than 2.5 m/s Inclusion Criteria for Participants without Pulmonary Hypertension: Lack of pulmonary hypertension, defined as TRjet velocity by Doppler echocardiography less than 2.5 m/s Exclusion Criteria: Pregnant or breastfeeding Hypersensitivity to arginine or sildenafil, based on prior use Any of the following medical conditions: Severe kidney insufficiency, defined as use of hemodialysis or serum creatinine at levels greater than 2.5 mg/dL at the time of screening Cardiac disease with adjustment of cardiac medications in the 60 days before study entry Symptomatic coronary artery disease, as indicated by a history of chest pain, angina, claudication, or surgery to treat coronary artery disease in the 1 year before study entry Stroke, defined as a new focal neurological deficit lasting more than 24 hours in the 45 days before study entry New diagnosis of pulmonary embolism by ventilation-perfusion scan, angiography, or any other technique in the 90 days before study entry History of retinal detachment or retinal hemorrhage in the 180 days before study entry Use of nitrate-based vasodilators, prostacyclin (inhaled, subcutaneous, or intravenous), endothelin antagonists, or any other medication for pulmonary hypertension Acute asthma exacerbation requiring use of prednisone in the 60 days before study entry Initiation or dosage increase of calcium channel blockers in the 30 days before study entry Initiation of any other cardiac or pulmonary medication in the 90 days before study entry Presence of any other condition, which in the opinion of the investigator, would make the person unsuitable for enrollment or could interfere with compliance in the study, including but not limited to alcohol or drug abuse No measurable TRjet on Doppler echocardiography (i.e., presence of pulmonary hypertension cannot be confirmed or ruled out)

Morris CR, Kim HY, Wood J, Porter JB, Klings ES, Trachtenberg FL, Sweeters N, Olivieri NF, Kwiatkowski JL, Virzi L, Singer ST, Taher A, Neufeld EJ, Thompson AA, Sachdev V, Larkin S, Suh JH, Kuypers FA, Vichinsky EP; Thalassemia Clinical Research Network. Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension. Haematologica. 2013 Sep;98(9):1359-67. doi: 10.3324/haematol.2012.082065. Epub 2013 Apr 12.