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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
New England Research Institutes
ClinicalTrials.gov Identifier:
NCT00872170
First received: March 30, 2009
Last updated: January 2, 2014
Last verified: January 2014
  Purpose

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 Intervention Phase
Thalassemia
Hypertension, Pulmonary
Drug: Sildenafil
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot of Oral Sildenafil for the Treatment of Pulmonary Hypertension in Thalassemia With Comparison to Controls

Resource links provided by NLM:


Further study details as provided by New England Research Institutes:

Primary Outcome Measures:
  • Change in Six-minute Walk Test (6MWT) Distance From Baseline to Week 12 Among Sildenafil Group [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    Change in six-minute walk test (6MWT) distance was calculated as 6MWT at week 12 minus 6MWT at baseline.


Secondary Outcome Measures:
  • Change in Tricuspid Regurgitant Jet Velocity (TRV) From Baseline to Week 12 Among Sildenafil Group [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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) From Baseline to Week 12 Among Sildenafil Group [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    Change in Soluble platelet selectin (sP-SELECTIN) was calculated as sP-SELECTIN at week 12 minus sP-SELECTIN at baseline.

  • Change in Lactate Dehydrogenase (LDH) From Baseline to Week 12 Among Sildenafil Group [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: Yes ]
    Change in Arginase activity was calculated as Arginase activity at week 12 minus Arginase activity at baseline.


Enrollment: 27
Study Start Date: March 2009
Study Completion Date: November 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   7 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00872170

Locations
United States, California
Children's Hospital and Research Institute Oakland
Oakland, California, United States, 94609
Sponsors and Collaborators
New England Research Institutes
Investigators
Principal Investigator: Ellis Neufeld, MD, PhD Children's Hospital Boston
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
  More Information

Publications:
Responsible Party: New England Research Institutes
ClinicalTrials.gov Identifier: NCT00872170     History of Changes
Other Study ID Numbers: 638, U01HL065238
Study First Received: March 30, 2009
Results First Received: April 24, 2013
Last Updated: January 2, 2014
Health Authority: United States: Federal Government
Canada: Health Canada
European Union: European Medicines Agency

Keywords provided by New England Research Institutes:
Pulmonary Hypertension

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Thalassemia
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Cardiovascular Diseases
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Sildenafil
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Therapeutic Uses
Urological Agents
Vasodilator Agents

ClinicalTrials.gov processed this record on November 24, 2014