Evaluation of Hydroxyurea Plus L-arginine or Sildenafil to Treat Sickle Cell Anemia

NCT00056433 | Completed Phase 1

• 2 other identifiers: 03012703-CC-0127
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with sickle cell disease have abnormal hemoglobin (the protein in red blood cells that carries oxygen to the body). This abnormality causes red blood cells to take on a sickle shape, producing disease symptoms. Fetal hemoglobin, a type of hemoglobin present in fetuses and babies, can prevent red cells from sickling. The drug hydroxyurea increases fetal hemoglobin production in patients with sickle cell disease by making a molecule called nitric oxide. The drugs L-arginine and Sildenafil (Viagra) increase the amount or the effect of nitric oxide. This study will evaluate:

• The safety of giving L-arginine or Sildenafil together with hydroxyurea in patients with sickle cell disease;
• The effectiveness of L-arginine plus hydroxyurea or Sildenafil plus hydroxyurea in increasing fetal hemoglobin in patients with sickle cell disease; and
• The effectiveness of L-arginine plus hydroxyurea or Sildenafil and hydroxyurea in lowering blood pressure in the lungs of patients with sickle cell disease. (Pulmonary blood pressure is elevated in about one-third of patients with sickle cell disease, and this condition increases the risk of dying from the disease.) Patients with hemoglobin S-only, S-beta-thalassemia, or other sickle cell disease genotype may be eligible for this study. Before starting treatment, patients will have a complete medical history and physical examination. All patients will take hydroxyurea once a day every day by mouth for at least 2 months. They will be admitted to the NIH Clinical Center to take their first dose of hydroxyurea, and will have blood drawn through a catheter (plastic tube placed in a vein) every hour for 6 hours for tests to determine nitric oxide levels. After discharge, they will return to the clinic once every 2 weeks to check for treatment side effects and for blood tests to monitor hemoglobin and fetal hemoglobin levels. After fetal hemoglobin levels have been stable for 2 months, patients will be admitted to the Clinical Center for their first dose of L-arginine (for men) or Sildenafil (for women). Again, blood samples will be collected through a catheter once an hour for 6 hours. If there are no complications, patients will be discharged and will continue taking hydroxyurea once a day and L-arginine or Sildenafil three times a day for at least 3 months until fetal hemoglobin levels have been stable for at least 2 months. Patients will return to the clinic for blood tests every week for 2 weeks and then every 2 weeks to monitor hemoglobin and fetal hemoglobin levels and to check for treatment side effects. Patients will have eye examinations before and during treatment. Some patients with sickle cell disease develop abnormalities in the blood vessels of the eye. Also, Sildenafil can cause temporary changes in color vision. Rarely, more serious eye problems can occur, such as bleeding from the eye blood vessels or damage to the retina a layer of tissue that lines the back of the eye. Patients will also have an echocardiogram (ultrasound of the heart) before beginning treatment, after hydroxyurea treatment, and after 1 and 3 months of combined treatment with hydroxyurea and L-arginine or Sildenafil to help measure blood pressure in the lungs. Patients who develop complications from L-arginine or Sildenafil may continue in the study on hydroxyurea alone. Patients whose fetal hemoglobin levels increase with the combination therapy of hydroxyurea and L-arginine or Sildenafil may continue to take them.

Conditions

Sickle Cell Anemia

Keywords

Fetal Hemoglobin Induction; L-Arginine; Nitric Oxide Therapy; Sickle Cell Disease; Sildenafil (Viagra); Sickle Cell Anemia

Interventions

Hydroxyurea DRUG

L-Arginine DRUG

Sildenafil DRUG

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have documented hemoglobin S-only, S-beta-thalassemia, or other sickle cell disease genotype. Only patients with hemoglobin S-only will be considered in the primary analysis.
• Patients must have relatively well preserved renal and hepatic function (creatinine less than 1.6 mg/dl and normal liver function test less than 5 X normal ALT).
• Evidence of severe sickle cell anemia will include one or more of the following: recurrent pain crisis (greater than or equal to 2 ER visits per year), recurrent acute chest syndrome (a lung problem like pneumonia), hospitalizations, leg ulceration, priapism, aseptic necrosis of the hip, and/or pulmonary hypertension.
• Patients must be able to provide informed consent.

You may not qualify if:

• Patients who have hemoglobin S and A (trait) or hemoglobin A-only (non-sickle cell).
• Patients must not be on a chronic transfusion program, defined as regular transfusions every 2-8 weeks.
• Patients must not be pregnant or breast feeding.
• Patients on chronic nitrates, such as nitroglycerin.

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med. 1990 Apr 12;322(15):1037-45. doi: 10.1056/NEJM199004123221504.

  PMID: 1690857 BACKGROUND

• Goldberg MA, Brugnara C, Dover GJ, Schapira L, Charache S, Bunn HF. Treatment of sickle cell anemia with hydroxyurea and erythropoietin. N Engl J Med. 1990 Aug 9;323(6):366-72. doi: 10.1056/NEJM199008093230602.

  PMID: 1695325 BACKGROUND

• Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, Milner PF, Orringer EP, Phillips G Jr, Platt OS, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992 May 15;79(10):2555-65.

  PMID: 1375104 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Hydroxyurea; Arginine; Sildenafil Citrate

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Sulfonamides; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• John F Tisdale, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2003
• First Posted: March 13, 2003
• Study Start: March 10, 2003
• Primary Completion: December 27, 2006
• Study Completion: December 27, 2006
• Last Updated: November 22, 2019

Record last verified: 2015-12-07

Locations

US (1)