Hypertension, Pulmonary, Thalassemia
Conditions
Keywords
Pulmonary Hypertension
Brief summary
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.
Detailed description
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.
Interventions
DRUGSildenafil
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
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Carelon Research
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
No
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: 1. Severe kidney insufficiency, defined as use of hemodialysis or serum creatinine at levels greater than 2.5 mg/dL at the time of screening 2. Cardiac disease with adjustment of cardiac medications in the 60 days before study entry 3. 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 4. Stroke, defined as a new focal neurological deficit lasting more than 24 hours in the 45 days before study entry 5. New diagnosis of pulmonary embolism by ventilation-perfusion scan, angiography, or any other technique in the 90 days before study entry 6. History of retinal detachment or retinal hemorrhage in the 180 days before study entry 7. Use of nitrate-based vasodilators, prostacyclin (inhaled, subcutaneous, or intravenous), endothelin antagonists, or any other medication for pulmonary hypertension 8. Acute asthma exacerbation requiring use of prednisone in the 60 days before study entry 9. Initiation or dosage increase of calcium channel blockers in the 30 days before study entry 10. 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Six-minute Walk Test (6MWT) Distance From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | Change in six-minute walk test (6MWT) distance was calculated as 6MWT at week 12 minus 6MWT at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Echo Left Ventricular End Systolic Volume (LVESV) From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | 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 | Baseline and Week 12 | Change in echo left ventricular end diastolic volume (LVEDV) was calculated as LVEDV at week 12 minus LVEDV at baseline. |
| Change in Plasma Arginine From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | Change in Plasma Arginine was calculated as Plasma Arginine at week 12 minus Plasma Arginine at baseline. |
| Change in Red Blood Cell (RBC) Arginine From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | 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 Tricuspid Regurgitant Jet Velocity (TRV) From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | 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 Lactate Dehydrogenase (LDH) From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | Change in Lactate dehydrogenase (LDH) was calculated as LDH at week 12 minus LDH at baseline. |
| Change in Cell Free Hemoglobin From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | Change in Cell Free Hemoglobin was calculated as Cell Free Hemoglobin at week 12 minus Cell Free Hemoglobin at baseline. |
| Change in Arginase Concentration From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | Change in Arginase concentration was calculated as Arginase concentration at week 12 minus Arginase concentration at baseline. |
| Change in Arginase Activity From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | Change in Arginase activity was calculated as Arginase activity at week 12 minus Arginase activity at baseline. |
| Change in Soluble Platelet Selectin (sP-SELECTIN) From Baseline to Week 12 Among Sildenafil Group | Baseline and Week 12 | Change in Soluble platelet selectin (sP-SELECTIN) was calculated as sP-SELECTIN at week 12 minus sP-SELECTIN at baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Participants with thalassemia who have pulmonary hypertension received sildenafil for 12 weeks.
Sildenafil : Participants received 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 | 14 |
| Control Participants with thalassemia who do not have pulmonary hypertension were part of a control group and were only undergoing screening/baseline assessments. | 13 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Control | Total | Sildenafil |
|---|---|---|---|
| Age, Continuous | 33.7 years STANDARD_DEVIATION 12.6 | 34.7 years STANDARD_DEVIATION 11.7 | 35.6 years STANDARD_DEVIATION 11.3 |
| Region of Enrollment Canada | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Lebanon | 0 participants | 2 participants | 2 participants |
| Region of Enrollment United Kingdom | 5 participants | 11 participants | 6 participants |
| Region of Enrollment United States | 6 participants | 10 participants | 4 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 19 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 14 | 0 / 0 |
| serious Total, serious adverse events | 2 / 14 | 0 / 0 |
Outcome results
Primary
Change in Six-minute Walk Test (6MWT) Distance From Baseline to Week 12 Among Sildenafil Group
Change in six-minute walk test (6MWT) distance was calculated as 6MWT at week 12 minus 6MWT at baseline.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and 2 patients who had no 6MWT at 12 weeks were excluded. Patients in control group were only assessed at baseline. Therefore, 8 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Six-minute Walk Test (6MWT) Distance From Baseline to Week 12 Among Sildenafil Group | -1.38 meters | Standard Error 16.01 |
Comparison: This study had 80% power at level alpha=0.05 to detect a 60 m change in 6MWT among N=10 participants, assuming a 60 m standard deviation for 12-week change.p-value: 0.97Mixed Models Analysis
Secondary
Change in Arginase Activity From Baseline to Week 12 Among Sildenafil Group
Change in Arginase activity was calculated as Arginase activity at week 12 minus Arginase activity at baseline.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Arginase Activity From Baseline to Week 12 Among Sildenafil Group | 0.33 U/L | Standard Error 2.88 |
p-value: 0.96Mixed Models Analysis
Secondary
Change in Arginase Concentration From Baseline to Week 12 Among Sildenafil Group
Change in Arginase concentration was calculated as Arginase concentration at week 12 minus Arginase concentration at baseline.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Arginase Concentration From Baseline to Week 12 Among Sildenafil Group | -17.06 ng/ml | Standard Error 16.25 |
p-value: 0.97Mixed Models Analysis
Secondary
Change in Cell Free Hemoglobin From Baseline to Week 12 Among Sildenafil Group
Change in Cell Free Hemoglobin was calculated as Cell Free Hemoglobin at week 12 minus Cell Free Hemoglobin at baseline.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Cell Free Hemoglobin From Baseline to Week 12 Among Sildenafil Group | -67.60 ug/ml | Standard Error 48.03 |
p-value: 0.18Mixed Models Analysis
Secondary
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.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Echo Left Ventricular End Diastolic Volume (LVEDV) From Baseline to Week 12 Among Sildenafil Group | -7.89 ml | Standard Error 2.71 |
p-value: 0.02Mixed Models Analysis
Secondary
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.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Echo Left Ventricular End Systolic Volume (LVESV) From Baseline to Week 12 Among Sildenafil Group | -3.82 ml | Standard Error 0.98 |
p-value: 0.005Mixed Models Analysis
Secondary
Change in Lactate Dehydrogenase (LDH) From Baseline to Week 12 Among Sildenafil Group
Change in Lactate dehydrogenase (LDH) was calculated as LDH at week 12 minus LDH at baseline.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and 2 patients who had no LDH at 12 weeks were excluded. Patients in control group were only assessed at baseline. Therefore, 8 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Lactate Dehydrogenase (LDH) From Baseline to Week 12 Among Sildenafil Group | 23.37 U/L | Standard Error 35.98 |
p-value: 0.33Mixed Models Analysis
Secondary
Change in Plasma Arginine From Baseline to Week 12 Among Sildenafil Group
Change in Plasma Arginine was calculated as Plasma Arginine at week 12 minus Plasma Arginine at baseline.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Plasma Arginine From Baseline to Week 12 Among Sildenafil Group | 31.77 µM | Standard Error 15.81 |
p-value: 0.05Mixed Models Analysis
Secondary
Change in Red Blood Cell (RBC) Arginine From Baseline to Week 12 Among Sildenafil Group
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.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Red Blood Cell (RBC) Arginine From Baseline to Week 12 Among Sildenafil Group | 3.67 µM | Standard Error 1.45 |
p-value: 0.02Mixed Models Analysis
Secondary
Change in Soluble Platelet Selectin (sP-SELECTIN) From Baseline to Week 12 Among Sildenafil Group
Change in Soluble platelet selectin (sP-SELECTIN) was calculated as sP-SELECTIN at week 12 minus sP-SELECTIN at baseline.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Soluble Platelet Selectin (sP-SELECTIN) From Baseline to Week 12 Among Sildenafil Group | 121.13 ng/ml | Standard Error 57.56 |
p-value: 0.04Mixed Models Analysis
Secondary
Change in Tricuspid Regurgitant Jet Velocity (TRV) From Baseline to Week 12 Among Sildenafil Group
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.
Time frame: Baseline and Week 12
Population: Of 14 patients in the Sildenafil arm, 4 patients with discrepant Tricuspid Regurgitant Jet Velocity (TRV) measurements between the local site, core lab and NHLBI readings and one patient who withdrew from the study were excluded. Patients in control group were only assessed at baseline. Therefore, 9 Sildenafil and 0 control patients were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Tricuspid Regurgitant Jet Velocity (TRV) From Baseline to Week 12 Among Sildenafil Group | -0.45 m/s | Standard Error 0.18 |
p-value: 0.04Mixed Models Analysis