Chelation Therapy of Iron Overload With Pyridoxal Isonicotinoyl Hydrazone

September 16, 2022 updated by: Case Western Reserve University

Chelation Therapy of Iron Overload With Oral Pyridoxal Isonicotinoyl Hydrazone

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

120

Phase

  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Chronic therapy of PIH according to medical condition

Half of overall participants will get one of the following doses according to their medical condition:

  1. 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);
  2. 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);
  3. 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).
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 Names:
  • Chronic therapy of Pyridoxal Isonicotinoyl Hydrazone
Other: Placebo
Placebo given at same time points as the Intervetnion for each clinical condition.
Other Names:
  • Control
Placebo Comparator: Placebo

Half of the participants will receive a Placebo:

  1. Non-transfusion-dependent patients
  2. Transfusion-dependent patients
  3. Iron-loaded, transfusion-dependent patients
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 Names:
  • Chronic therapy of Pyridoxal Isonicotinoyl Hydrazone
Other: Placebo
Placebo given at same time points as the Intervetnion for each clinical condition.
Other Names:
  • Control

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Case Western Reserve University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Gary Brittenham, Case Western Reserve University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 5, 1989

Primary Completion (Actual)

March 31, 1993

Study Completion (Actual)

March 31, 1995

Study Registration Dates

First Submitted

October 27, 1999

First Submitted That Met QC Criteria

October 27, 1999

First Posted (Estimate)

October 28, 1999

Study Record Updates

Last Update Posted (Actual)

September 21, 2022

Last Update Submitted That Met QC Criteria

September 16, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 308
  • R01HL042814 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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