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

• Sponsor: HealthCore-NERI (Other)
• Overall Status: Completed
• CT.gov ID: NCT00872170
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 27
• Location: 1
• Arms: 2
• Duration (Months): 20
• Patients Per Site Per Month: 1.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Thalassemia; Hypertension, Pulmonary	Drug: Sildenafil	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot of Oral Sildenafil for the Treatment of Pulmonary Hypertension in Thalassemia With Comparison to Controls
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Intervention Participants with thalassemia who have pulmonary hypertension will receive sildenafil for 12 weeks.	Drug: Sildenafil; 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; Other Names: Revatio Viagra
No Intervention: Control Participants with thalassemia who do not have pulmonary hypertension will be part of a control group and will only be undergoing screening/baseline assessments.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital and Research Institute Oakland	Oakland	California	United States	94609

Sponsors and Collaborators

• HealthCore-NERI
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Ellis Neufeld, MD, PhD, Boston Children's Hospital
• Study Chair: Claudia Morris, MD, Children's Hospital and Research Institute Oakland
• Principal Investigator: Charles Quinn, MD, University of Texas, Southwestern Medical Center at Dallas
• Principal Investigator: Patricia Giardina, MD, Weill Medical College of Cornell
• Principal Investigator: Janet Kwiatkowski, MD, Children's Hospital of Philadelphia
• Principal Investigator: Nancy Olivieri, MD, Toronto General Hospital
• Principal Investigator: John Porter, MD, University College, London
• Principal Investigator: Ali Taher, MD, American University of Beirut Medical Center- Lebannon

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT00872170
• Other Study ID Numbers: 638; U01HL065238
• First Posted: Mar 31, 2009
• Last Update Posted: Feb 21, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by HealthCore-NERI: Pulmonary Hypertension
• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Thalassemia; Sildenafil Citrate

Study Results

Participant Flow

Arm/Group Title	Sildenafil	Control
Arm/Group Description	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	Participants with thalassemia who do not have pulmonary hypertension were part of a control group and were only undergoing screening/baseline assessments.
Period Title: Overall Study
STARTED	14	13
COMPLETED	13	13
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Sildenafil	Control	Total
Arm/Group Description	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	Participants with thalassemia who do not have pulmonary hypertension were part of a control group and were only undergoing screening/baseline assessments.	Total of all reporting groups
Overall Participants	14	13	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.6 (11.3)	33.7 (12.6)	34.7 (11.7)
Sex: Female, Male (Count of Participants)
Female	2 14.3%	6 46.2%	8 29.6%
Male	12 85.7%	7 53.8%	19 70.4%
Region of Enrollment (participants) [Number]
United States	4 28.6%	6 46.2%	10 37%
Canada	2 14.3%	2 15.4%	4 14.8%
United Kingdom	6 42.9%	5 38.5%	11 40.7%
Lebanon	2 14.3%	0 0%	2 7.4%

Outcome Measures

1. Primary Outcome

Title	Change in Six-minute Walk Test (6MWT) Distance From Baseline to Week 12 Among Sildenafil Group
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	8
Mean (Standard Error) [meters]	-1.38 (16.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

2. Secondary Outcome

Title	Change in Tricuspid Regurgitant Jet Velocity (TRV) From Baseline to Week 12 Among Sildenafil Group
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [m/s]	-0.45 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [ml]	-3.82 (0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [ml]	-7.89 (2.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

5. Secondary Outcome

Title	Change in Plasma Arginine From Baseline to Week 12 Among Sildenafil Group
Description	Change in Plasma Arginine was calculated as Plasma Arginine at week 12 minus Plasma Arginine at baseline.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [µM]	31.77 (15.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

6. Secondary Outcome

Title	Change in Red Blood Cell (RBC) Arginine From Baseline to Week 12 Among Sildenafil Group
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [µM]	3.67 (1.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

7. Secondary Outcome

Title	Change in Soluble Platelet Selectin (sP-SELECTIN) From Baseline to Week 12 Among Sildenafil Group
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [ng/ml]	121.13 (57.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

8. Secondary Outcome

Title	Change in Lactate Dehydrogenase (LDH) From Baseline to Week 12 Among Sildenafil Group
Description	Change in Lactate dehydrogenase (LDH) was calculated as LDH at week 12 minus LDH at baseline.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	8
Mean (Standard Error) [U/L]	23.37 (35.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

9. Secondary Outcome

Title	Change in Cell Free Hemoglobin From Baseline to Week 12 Among Sildenafil Group
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [ug/ml]	-67.60 (48.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

10. Secondary Outcome

Title	Change in Arginase Concentration From Baseline to Week 12 Among Sildenafil Group
Description	Change in Arginase concentration was calculated as Arginase concentration at week 12 minus Arginase concentration at baseline.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [ng/ml]	-17.06 (16.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

11. Secondary Outcome

Title	Change in Arginase Activity From Baseline to Week 12 Among Sildenafil Group
Description	Change in Arginase activity was calculated as Arginase activity at week 12 minus Arginase activity at baseline.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil
Arm/Group Description	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
Measure Participants	9
Mean (Standard Error) [U/L]	0.33 (2.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed models with participant-specific intercepts and slopes controlled for time effects were used.

Adverse Events

Time Frame	up to Week 12
Adverse Event Reporting Description	At each follow-up visit, Sildenafil patients were interviewed for medical conditions, medical changes, and symptoms that have occurred since the last visit. An Adverse Event (AE) form was completed if any AE was reported. A Serious Adverse Event form was completed for all AEs rated as serious. No AEs were collected for the control group.
Arm/Group Title	Sildenafil		Control
Arm/Group Description	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		Participants with thalassemia who do not have pulmonary hypertension were part of a control group and were only undergoing screening/baseline assessments.
All Cause Mortality
	Sildenafil		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sildenafil		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/14 (14.3%)		0/0 (NaN)
Eye disorders
Vision/color disturbance	1/14 (7.1%)	1	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/14 (7.1%)	1	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Sildenafil		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/14 (78.6%)		0/0 (NaN)
Blood and lymphatic system disorders
Hemoglobin decreased	1/14 (7.1%)	1	0/0 (NaN)	0
Eye disorders
Photophobia	1/14 (7.1%)	1	0/0 (NaN)	0
Vision/color disturbance	2/14 (14.3%)	3	0/0 (NaN)	0
Vision blurred	1/14 (7.1%)	1	0/0 (NaN)	0
Ocular/visual - other (shining outline on objects)	1/14 (7.1%)	1	0/0 (NaN)	0
General disorders
Fatigue	1/14 (7.1%)	1	0/0 (NaN)	0
Edema limbs	2/14 (14.3%)	2	0/0 (NaN)	0
Dizziness	1/14 (7.1%)	1	0/0 (NaN)	0
Hepatobiliary disorders
INR increased	1/14 (7.1%)	1	0/0 (NaN)	0
Injury, poisoning and procedural complications
Phlebitis	1/14 (7.1%)	1	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
Back pain	1/14 (7.1%)	1	0/0 (NaN)	0
Pain-other: sciatic pain of left leg with associated back pain	1/14 (7.1%)	1	0/0 (NaN)	0
Nervous system disorders
Headache	5/14 (35.7%)	6	0/0 (NaN)	0
Reproductive system and breast disorders
Prolonged erection (priapism)	1/14 (7.1%)	2	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/14 (14.3%)	2	0/0 (NaN)	0

Limitations/Caveats

Of 14 patients in the Sildenafil arm, 4 patients with discrepant TRVs between the local site, core lab and NHLBI readings were excluded for the main analyses.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.