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5-Azacytidine and Phenylbutyrate to Treat Severe Thalassemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00005934
Recruitment Status : Completed
First Posted : July 7, 2000
Last Update Posted : March 4, 2008
Information provided by:
National Institutes of Health Clinical Center (CC)

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.

Condition or disease Intervention/treatment Phase
Beta Thalassemia Drug: 5-Azacytidine Phase 2

Detailed Description:
Individuals with homozygous beta-thalassemia are either severely anemic or dependent on blood transfusion to sustain life. Deficient synthesis of the beta chain leads to imbalanced chain synthesis with an excess of alpha globin. This alpha globin precipitates, causing ineffective erythropoiesis and shortened red cell survival. In patients with homozygous beta-thalassemia, enhanced gamma globin synthesis could partially compensate for the deficient synthesis of beta globin rendering chain synthesis more balanced and reducing the relative excess of alpha chains. The purpose of this protocol is to test the hypothesis that induction therapy with 5-azacytidine, followed by maintenance treatment with oral phenylbutyrate will enhance gamma globin synthesis, increase red cell production and partially or substantially correct the anemia in patients with homozygous beta-thalassemia.

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Study Type : Interventional  (Clinical Trial)
Enrollment : 24 participants
Primary Purpose: Treatment
Official Title: A Pilot Study of 5-Azacytidine and Oral Sodium Phenylbutyrate in Severe Thalassemia
Study Start Date : June 2000
Study Completion Date : June 2003

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Thalassemia
Drug Information available for: Azacitidine

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


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.


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00005934

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United States, Maryland
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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ClinicalTrials.gov Identifier: NCT00005934    
Obsolete Identifiers: NCT00007072
Other Study ID Numbers: 000166
First Posted: July 7, 2000    Key Record Dates
Last Update Posted: March 4, 2008
Last Verified: June 2003
Keywords provided by National Institutes of Health Clinical Center (CC):
Fetal Hemoglobin
Thalassemia Major
Beta Thalassemia
Additional relevant MeSH terms:
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Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors