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Chelation Therapy of Iron Overload With Pyridoxal Isonicotinoyl Hydrazone

Primary Purpose

Anemia (Iron-Loading), Beta-Thalassemia, Hematologic Diseases

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Chelation therapy
Placebo
Sponsored by
Case Western Reserve University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anemia (Iron-Loading)

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Chronic therapy of PIH according to medical condition

    Placebo

    Arm Description

    Half of overall participants will get one of the following doses according to their medical condition: Reducing the body iron burden to near-normal levels in non- transfusion-dependent patients with iron-loading anemias (requires chelate- induced iron excretion of at least 0.10 to 0.20 mg Fe/kg/day); Maintaining near-normal body iron stores in transfusion-dependent patients who have previously been well-chelated with chronic subcutaneous or intravenous desferrioxamine (requires chelate-induced iron excretion of at least 0.25 to 0.40 mg Fe/kg/day); Reducing the body iron burden to near-normal levels in iron-loaded, transfusion-dependent patients (requires chelate-induced iron excretion greater than 0.40 mg Fe/kg/day).

    Half of the participants will receive a Placebo: Non-transfusion-dependent patients Transfusion-dependent patients Iron-loaded, transfusion-dependent patients

    Outcomes

    Primary Outcome Measures

    Secondary Outcome Measures

    Full Information

    First Posted
    October 27, 1999
    Last Updated
    September 16, 2022
    Sponsor
    Case Western Reserve University
    Collaborators
    National Heart, Lung, and Blood Institute (NHLBI)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00000588
    Brief Title
    Chelation Therapy of Iron Overload With Pyridoxal Isonicotinoyl Hydrazone
    Official Title
    Chelation Therapy of Iron Overload With Oral Pyridoxal Isonicotinoyl Hydrazone
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2022
    Overall Recruitment Status
    Completed
    Study Start Date
    June 5, 1989 (Actual)
    Primary Completion Date
    March 31, 1993 (Actual)
    Study Completion Date
    March 31, 1995 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Case Western Reserve University
    Collaborators
    National Heart, Lung, and Blood Institute (NHLBI)

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Anemia (Iron-Loading), Beta-Thalassemia, Hematologic Diseases, Hemoglobinopathies, Thalassemia, Iron Overload

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Crossover Assignment
    Model Description
    Chronic dose according to condition: Reducing the body iron burden to near-normal levels in non- transfusion-dependent patients with iron-loading anemias (requires chelate- induced iron excretion of at least 0.10 to 0.20 mg Fe/kg/day); Maintaining near-normal body iron stores in transfusion-dependent patients who have previously been well-chelated with chronic subcutaneous or intravenous desferrioxamine (requires chelate-induced iron excretion of at least 0.25 to 0.40 mg Fe/kg/day); Reducing the body iron burden to near-normal levels in iron-loaded, transfusion-dependent patients (requires chelate-induced iron excretion greater than 0.40 mg Fe/kg/day).
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    120 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Chronic therapy of PIH according to medical condition
    Arm Type
    Experimental
    Arm Description
    Half of overall participants will get one of the following doses according to their medical condition: Reducing the body iron burden to near-normal levels in non- transfusion-dependent patients with iron-loading anemias (requires chelate- induced iron excretion of at least 0.10 to 0.20 mg Fe/kg/day); Maintaining near-normal body iron stores in transfusion-dependent patients who have previously been well-chelated with chronic subcutaneous or intravenous desferrioxamine (requires chelate-induced iron excretion of at least 0.25 to 0.40 mg Fe/kg/day); Reducing the body iron burden to near-normal levels in iron-loaded, transfusion-dependent patients (requires chelate-induced iron excretion greater than 0.40 mg Fe/kg/day).
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Half of the participants will receive a Placebo: Non-transfusion-dependent patients Transfusion-dependent patients Iron-loaded, transfusion-dependent patients
    Intervention Type
    Drug
    Intervention Name(s)
    Chelation therapy
    Other Intervention Name(s)
    Chronic therapy of Pyridoxal Isonicotinoyl Hydrazone
    Intervention Description
    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.
    Intervention Type
    Other
    Intervention Name(s)
    Placebo
    Other Intervention Name(s)
    Control
    Intervention Description
    Placebo given at same time points as the Intervetnion for each clinical condition.

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Gary Brittenham
    Organizational Affiliation
    Case Western Reserve University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    2291560
    Citation
    Brittenham GM. Pyridoxal isonicotinoyl hydrazone. Effective iron chelation after oral administration. Ann N Y Acad Sci. 1990;612:315-26. doi: 10.1111/j.1749-6632.1990.tb24319.x. No abstract available.
    Results Reference
    background
    PubMed Identifier
    2190317
    Citation
    Brittenham GM. Pyridoxal isonicotinoyl hydrazone: an effective iron-chelator after oral administration. Semin Hematol. 1990 Apr;27(2):112-6. No abstract available.
    Results Reference
    background
    PubMed Identifier
    7877655
    Citation
    Nathan DG. An orally active iron chelator. N Engl J Med. 1995 Apr 6;332(14):953-4. doi: 10.1056/NEJM199504063321411. No abstract available. Erratum In: N Engl J Med 1995 May 11;332(19):1315.
    Results Reference
    background
    PubMed Identifier
    7877649
    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. doi: 10.1056/NEJM199504063321404.
    Results Reference
    background

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    Chelation Therapy of Iron Overload With Pyridoxal Isonicotinoyl Hydrazone

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