Chelation Therapy of Iron Overload With Pyridoxal Isonicotinoyl Hydrazone
Condition: Anemia (Iron-Loading); Beta-Thalassemia; Hematologic Diseases; Hemoglobinopathies; Thalassemia; Iron Overload
MeSH terms: Thalassemia; Hematologic Diseases; beta-Thalassemia; Hemoglobinopathies; Iron Overload
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Chelation therapy; Placebo
Intervention type(s): Drug; Other
Intervention description(s): 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.; Placebo given at same time points as the Intervetnion for each clinical condition.
Other intervention name(s): Chronic therapy of Pyridoxal Isonicotinoyl Hydrazone; Control
Intervention MeSH terms: Pyridoxal; Pyridoxal isonicotinoyl hydrazone
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention 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)
Primary purpose: Treatment