Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00000588
Other study ID # 308
Secondary ID R01HL042814
Status Completed
Phase Phase 2
First received
Last updated
Start date June 5, 1989
Est. completion date March 31, 1995

Study information

Verified date September 2022
Source Case Western Reserve University
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

To demonstrate the safety and effectiveness of orally-administered pyridoxal isonicotinoyl hydrazone (PIH) for the chronic treatment of iron overload.


Description:

BACKGROUND: Iron overload in patients with refractory anemia may be the consequence of repeated blood transfusion, of excessive absorption of dietary iron, or of a combination of both. The body lacks any effective means for the excretion of excess iron and in patients with refractory anemia, an inexorable accumulation of iron contained in transfused red cells or absorbed from the diet eventually exceeds the body's capacity for safe storage. Without treatment, widespread iron-induced damage to the liver, heart, pancreas, and other organs is followed by an early death, most often the result of cardiac failure. Treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body is the most widely-used therapeutic approach. Desferrioxamine was first introduced 30 years ago and is the only iron-chelating agent now in clinical use. A number of recent studies have shown that regular chelation therapy with desferrioxamine can prevent organ damage and improve survival in transfusion-dependent patients with thalassemia major and other disorders. However, desferrioxamine given orally is poorly absorbed and to be effective must be given by subcutaneous or intravenous infusion using a small portable syringe pump, ideally for 12 hours each day. Compliance with this regimen is frequently poor, particularly in adolescents with thalassemia major who may be at greatest risk for the lethal complications of iron overload. With modern transfusion programs, one of the main threats to life in patients with transfusion-dependent anemias is non-compliance with iron-chelation therapy. Moreover, the cost of desferrioxamine therapy in transfusion-dependent therapy exceeds $10,000 per year, in part because the drug must be isolated from bacterial cultures. Despite the limitations, trials of desferrioxamine have validated iron chelation as a therapeutic approach to iron overload. PIH was first recognized as an effective iron chelator in vitro in 1979. It is easily produced by the Schiff base condensation of two widely used, inexpensive drugs, vitamin B-6 (pyridoxal) and the antituberculous agent isoniazid. The recent Phase I studies of low-dose PIH in healthy controls and volunteers with iron overload have found no evidence of toxicity while producing an amount of iron excretion that would be clinically useful in the treatment of non-transfusion-dependent patients with iron-loading anemias. The trial should provide evidence that orally-administered PIH can be substituted for chronic subcutaneous infusions of desferrioxamine in the management of iron overload in refractory anemia. The trial was part of an Institute-initiated study on Iron Overload: Cooley's Anemia and Other Disorders. DESIGN NARRATIVE: There were three studies in the Phase II trial. Study 1 demonstrated the safety and effectiveness of oral PIH in reducing the body iron burden to near-normal levels in non-transfusion-dependent patients with iron-loading anemias. Study 2 demonstrated the safety and effectiveness of oral PIH in maintaining near-normal body iron stores in transfusion-dependent patients who had previously been well-chelated with chronic subcutaneous or intravenous desferrioxamine. Study 3 demonstrated safety and effectiveness of oral PIH in reducing the body iron burden to near normal levels in iron-loaded transfusion-dependent patients. Studies 1 and 2 were carried out concurrently. Study 3 began after the methods used in the first two studies documented a sufficient level of iron excretion to permit the iron-loaded transfusion patients to keep pace with ongoing transfusional loading and excrete previous accumulations of iron. After an initial 21 day balance study to demonstrate that a selected dose of PIH produced sufficient iron excretion, patients were begun on chronic therapy. PIH or placebo were given on days 4 to 9 and days 13 to 18 in a randomized, double-blind, cross-over design. Study 4 demonstrated the effectiveness in 21 patients of oral deferiprone in inducing sustained decreases in body iron concentrations compatible with the avoidance of complications from iron overload. Repeat balance studies were carried out at three months, six months, and thereafter at least annually with hematological and biochemical parameters monitored at weekly intervals for the first month, at biweekly intervals for the next two months, and at least monthly thereafter. Studies were conducted at the Cleveland Metropolitan General Hospital and at Siriraj Hospital in Bangkok, Thailand.


Recruitment information / eligibility

Status Completed
Enrollment 120
Est. completion date March 31, 1995
Est. primary completion date March 31, 1993
Accepts healthy volunteers No
Gender All
Age group 18 Years to 75 Years
Eligibility Inclusion Criteria: - Patients meeting any of the following health conditions and eligible for Chronic PIH Treatment - Non- transfusion-dependent patients with iron-loading anemias - Transfusion-dependent patients who have previously been well-chelated with chronic subcutaneous or intravenous desferrioxamine - Iron-loaded, transfusion-dependent patients - Ages: 18-75 years old Exclusion Criteria: - People who are not eligible for chronic PIH therapy and not meet the medical conditions listed in the Inclusion criteria - Ages: 17 years old or younger or 76 years old or older

Study Design


Intervention

Drug:
Chelation therapy
After an initial 21 day balance study to demonstrate that a selected dose of PIH produced sufficient iron excretion, patients were begun on chronic therapy. PIH or placebo were given on days 4 to 9 and days 13 to 18 in a randomized, double-blind, cross-over design.
Other:
Placebo
Placebo given at same time points as the Intervetnion for each clinical condition.

Locations

Country Name City State
n/a

Sponsors (2)

Lead Sponsor Collaborator
Case Western Reserve University National Heart, Lung, and Blood Institute (NHLBI)

References & Publications (4)

Brittenham GM. Pyridoxal isonicotinoyl hydrazone. Effective iron chelation after oral administration. Ann N Y Acad Sci. 1990;612:315-26. Review. — View Citation

Brittenham GM. Pyridoxal isonicotinoyl hydrazone: an effective iron-chelator after oral administration. Semin Hematol. 1990 Apr;27(2):112-6. Review. — View Citation

Nathan DG. An orally active iron chelator. N Engl J Med. 1995 Apr 6;332(14):953-4. Erratum in: N Engl J Med 1995 May 11;332(19):1315. — View Citation

Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis LM, Cameron RG, McClelland RA, Liu PP, Templeton DM, Koren G. Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med. 1995 Apr 6;332(14):918-22. — View Citation

See also
  Status Clinical Trial Phase
Recruiting NCT04094844 - Health Information Technology System ("Roadmap 2.0") in the Context of Hematopoietic Cell Transplantation N/A
Completed NCT04474678 - Quality Improvement Project - "My Logbook! - I Know my Way Around!"; ("Mein Logbuch - Ich Kenne Mich Aus!") N/A
Recruiting NCT03918343 - Lipopolysaccharide Metabolism and Identification of Potential Biomarkers Predictive of Graft-versus-host Disease After Allogeneic Stem Cell Transplantation N/A
Completed NCT01445561 - Ultra Low Dose Interleukin-2 in Healthy Volunteers Phase 1
Recruiting NCT06148610 - Evaluation of the Impact of the Use of NewSpringForMe on Transplanted Patients' Quality of Life and Support
Completed NCT04168983 - Impact of Sophrology on the Pain Felt During a Bone Marrow Aspiration and Biopsy N/A
Not yet recruiting NCT05969821 - Clonal Hematopoiesis of Immunological Significance
Withdrawn NCT04282174 - CD34+ Enriched Transplants From HLA-Compatible Patients With Hematologic Malignancies Phase 2
Completed NCT01108159 - Integrated Whole-Genome Analysis of Hematologic Disorders
Completed NCT00800839 - Busulfan and Fludarabine Followed by Post-transplant Cyclophosphamide Phase 2
Completed NCT00213239 - A Dose Finding Study of Remifentanil and Propofol for Lumbar Punctures in Children Phase 1/Phase 2
Terminated NCT00208949 - A Comparison of Dendritic Cell Content and T-Cell Phenotype Between Granulocyte Colony-Stimulating Factor (G-CSF) or G-CSF + Granulocyte Macrophage (GM)-CSF Phase 2
Terminated NCT00176826 - T-Cell Depletion and Stem Cell Transplant for Immune Deficiencies and Histiocytic Disorders Phase 2/Phase 3
Completed NCT00208962 - Allogeneic Cell Therapy for Adults With Hematologic Malignancies Phase 2
Completed NCT00000603 - Cord Blood Stem Cell Transplantation Study (COBLT) Phase 2
Completed NCT00000587 - Erythropoietin for Anemia Due to Zidovudine in Human Immunodeficiency Virus Infection Phase 2
Active, not recruiting NCT03655678 - A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia Phase 2/Phase 3
Recruiting NCT05487794 - Effect of Dose Fractionation of Testosterone Cypionate on Transgender Men With Erythrocytosis N/A
Completed NCT03611257 - Effect of dRAST on Treatment for Bacteremia in Patients With Hematologic Diseases N/A
Completed NCT02827149 - High Resolution Donor Recipient HLA Matching Level in Unrelated HSCT