5-Azacytidine and Phenylbutyrate to Treat Severe Thalassemia

NCT00005934 | Completed Phase 2

• 2 other identifiers: 00016600-DK-0166
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the safety and effectiveness of 5-azacytidine and phenylbutyrate for treating thalassemia major. Patients with this disease have abnormal production of hemoglobin (the oxygen-carrying protein in red blood cells), which leads to red blood cell destruction. As a result, patients require frequent red cell transfusions over many years. Because of these transfusions, however, excess iron is deposited in various body organs-such as the heart, liver, thyroid gland and, in men, the testes-impairing their function. Fetal hemoglobin-a type of hemoglobin that is produced during fetal and infant life-can substitute for adult hemoglobin and increase the levels of red cells in the body. After infancy, however, this type of hemoglobin is no longer produced in large quantities. 5-azacytidine can increase fetal hemoglobin levels, but this drug can damage DNA, which in turn can increase the risk of cancer. This study will try to lessen the harmful effects of 5-azacytidine by using only one or two doses of it, followed by long-term therapy with phenylbutyrate, a drug that may be as effective as 5-azacytidine with less harmful side effects. Patients 18 years of age and older with severe thalassemia major may be eligible for this study. Before beginning treatment, candidates will have a medical history and physical examination, blood tests, chest X-ray, electrocardiogram (EKG), bone marrow biopsy (removal of a small sample of bone marrow from the hip for microscopic examination) and whole-body magnetic resonance imaging (MRI). For the biopsy, the area of the hip is anesthetized and a special needle is inserted to draw bone marrow from the hipbone. For the MRI scan, a strong magnetic field is used to produce images that will identify sites where the body is making red blood cells. During this procedure, the patient lies on a table in a narrow cylinder containing a magnetic field. Earplugs are placed in the ears to muffle the loud thumping sounds the machine makes when the magnetic fields are being switched. An intravenous (IV) catheter (flexible tube inserted into a vein) is placed in a large vein of the patient's neck, chest or arm for infusion of 5-azacytidine at a constant rate over 4 days. Patients who do not respond to this first dose of 5-azacytidine will be given the drug again after about 50 days. If they do not respond to the second dose, alternate treatments will have to be considered. Patients who respond to 5-azacytidine will begin taking phenylbutyrate on the 14th day after 5-azacytidine was started. They will take about 10 large pills 3 times a day, continuing for as long as the treatment is beneficial. All patients will be hospitalized for at least 6 days starting with the beginning of 5-azacytidine therapy. Those who are well enough may then be discharged and continue treatment as an outpatient. Patients will be monitored with blood tests daily for 2 weeks and then will be seen weekly for about another 5 weeks. Bone marrow biopsies will be repeated 6 days after treatment begins and again at 2 weeks and 7 weeks. MRI will be repeated 7 weeks after treatment begins. After 7 weeks, patients will be seen at 3-month intervals. Bone marrow biopsies will be done every 6 months for the first 3 years after treatment. Patients will have red cell transfusions as needed and chelation therapy to remove excess iron.

Conditions

Beta Thalassemia

Keywords

Fetal Hemoglobin; 5-Azacytidine; Phenylbutyrate; Thalassemia; Hemoglobin; Anemia; Blood; Thalassemia Major; Beta Thalassemia

Interventions

5-Azacytidine DRUG

Eligibility Criteria

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

You may qualify if:

• Thalassemia major with progressive disease or complications of iron overload despite traditional transfusion and iron chelation therapy
• Thalassemia major in which standard transfusion therapy or iron chelation therapy is contraindicated
• ECOG performance status must be less than or equal to 2
• NYHA less than or equal to class II status
• Progressive disease is defined as 1) an increasing transfusion requirement or difficulty in maintenance of hemoglobin levels greater than 7g/dl as a consequence of autologous or allogeneic antibodies or 2) increasing extramedullary hematopoiesis causing compression phenomena.
• Complications of iron overload despite iron chelation therapy is defined as difficulty in achieving negative iron balance when complications of iron overload exist. Complications of iron overload include heart failure, or decreased cardiac ejection fraction, endocrinopathy and evidence of progressive liver dysfunction.

You may not qualify if:

• Severe sepsis or septic shock
• Current pregnancy or breast feeding
• Not able to give informed consent
• Altered mental status or seizure disorder
• AST or ALT greater than 3X upper limit of normal
• Bilirubin greater than1.5X upper limit of normal, unless the abnormal bilirubin can be accounted for by indirect hyperbilirubinemia due to hemolysis or Gilbert's Disease
• Serum albumin less than 3g/dl
• Creatinine greater than 2mg/dl and creatinine clearance less than 60ml/min
• Patients who are moribund or patients with concurrent hepatic, renal, cardiac, metabolic, or any disease of such severity that death within 7-10 days is likely
• Concurrent myelodysplastic syndrome or leukemia
• NYHA class III/IV status
• ECOG performance status greater than 2
• Age less than 18 years

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Thomas ED, Buckner CD, Sanders JE, Papayannopoulou T, Borgna-Pignatti C, De Stefano P, Sullivan KM, Clift RA, Storb R. Marrow transplantation for thalassaemia. Lancet. 1982 Jul 31;2(8292):227-9. doi: 10.1016/s0140-6736(82)90319-1. No abstract available.

  PMID: 6124668 BACKGROUND

• Wolfe L, Olivieri N, Sallan D, Colan S, Rose V, Propper R, Freedman MH, Nathan DG. Prevention of cardiac disease by subcutaneous deferoxamine in patients with thalassemia major. N Engl J Med. 1985 Jun 20;312(25):1600-3. doi: 10.1056/NEJM198506203122503.

  PMID: 4000198 BACKGROUND

• Modell B, Petrou M. Management of thalassaemia major. Arch Dis Child. 1983 Dec;58(12):1026-30. doi: 10.1136/adc.58.12.1026. No abstract available.

  PMID: 6660889 BACKGROUND

MeSH Terms

Conditions

beta-Thalassemia; Thalassemia; Anemia

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Design

• Study Type: interventional
• Phase: phase 2
• Purpose: TREATMENT
• Sponsor Type: NIH

Study Record Dates

• First Submitted: July 6, 2000
• First Posted: July 7, 2000
• Study Start: June 1, 2000
• Study Completion: June 1, 2003
• Last Updated: March 4, 2008

Record last verified: 2003-06

Locations

US (1)