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Study Using Deferiprone Alone or in Combination With Desferrioxamine in Iron Overloaded Transfusion-dependent Patients

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ClinicalTrials.gov Identifier: NCT00349453
Recruitment Status : Completed
First Posted : July 7, 2006
Last Update Posted : December 12, 2011
Information provided by (Responsible Party):

Brief Summary:
Systematical (retro- and prospective) investigation of the long-term safety (toxicity assessment according to CTCAE v3.0) and efficacy of deferiprone either given alone or in combination with desferrioxamine

Condition or disease Intervention/treatment Phase
Hemochromatosis Drug: Deferiprone (L1) Drug: Desferrioxamine Phase 2

Detailed Description:

Patients with refractory anemias requiring regular blood transfusions accumulate iron at the rate of approximately 0.5 mg/kg/day, which may lead to serious organ toxicity, e.g. to the heart, liver and endocrine organs. The human body has no active mechanism for the excretion of excess iron. Therefore multiply transfused patients will develop a secondary hemosiderosis, if excess iron is not excreted by a chelating agent. Symptoms of iron-overload occur when body iron stores reach 10-20 g. At higher levels severe, even fatal complications, particularly cardiac failure, may develop.

Desferrioxamine (DFO, Desferal) is the established and commonly used iron-chelating drug, but is expensive and must be given by slow subcutaneous or intravenous infusion for 8-12 hours a day during 5-7 days weekly at a dosage of 40-50 mg/kg body weight/day. This often leads to failure of compliance of the patient and therefore to inefficient iron chelation. Further, some patients are hypersensitive to desferrioxamine and others suffer from toxicity, e.g. to the ears or eyes.

Deferiprone (L1; CP20; 1,2 dimethyl-3-hydroxypyrid-4-one) is an orally active iron chelator investigated in various clinical trials since 1987. Dosages of 75 - 100 mg/kg body weight/day of L1 have been considered effective to maintain stable iron balance (urinary iron excretion of 0.5 mg/kg/day) and to reduce serum ferritin levels between 6% and 25% within one year of treatment in iron-overloaded thalassemic patients. There exists long-term experience with patients who have received deferiprone continuously for more than 10 years so far. The main side effects encountered during a deferiprone therapy are arthropathy, gastrointestinal symptoms, headache, and mild zinc deficiency. These adverse reactions are usually reversed on reducing the dose or discontinuing the drug. Except for severe joint symptoms in few patients, most of the subjects in different clinical trials have been able to continue with L1 therapy for a long term. The most severe, but rare complication following administration of deferiprone is agranulocytosis or neutropenia.

A new treatment regimen combining deferiprone with desferrioxamine is currently being investigated in many countries. Preliminary data have demonstrated that the combined use of both drugs is highly active showing an additive or even synergistic effect (significant decrease of serum ferritin and hepatic iron content, increase of urinary iron excretion). This synergism could be explained by the different mode of action of the two drugs. It could be demonstrated that patients who were not sufficiently chelated with desferrioxamine or deferiprone, could achieve a negative iron balance with the combination treatment of both drugs. The combined regimen was generally well tolerated. It has been speculated that the individual toxicity profile of both drugs can be positively influenced by the simultaneous administration of L1 and DFO. The daily treatment with L1 tablets combined with at least twice a week administration of parenteral desferrioxamine is more patient-convenient and therefore may enhance the patient's compliance.

The primary aim of this study is to systematically investigate the long-term safety (toxicity assessment according to CTCAE v3.0) of deferiprone either given alone or in combination with desferrioxamine. Further, in patients agreeing to perform annual SQUID analysis of the liver, the annual change of liver iron concentration (LIC) will be examined for four years.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Retrospective and Prospective Multicenter Study Using Deferiprone (L1) Alone or in Combination With Desferrioxamine for the Treatment of Iron Overload in Transfusion-dependent Patients
Study Start Date : March 2005
Actual Primary Completion Date : May 2011
Actual Study Completion Date : May 2011

Arm Intervention/treatment
Experimental: Deferiprone (L1) monotherapy
Deferiprone (L1) monotherapy
Drug: Deferiprone (L1)
50-100 mg/kg body weight daily

Experimental: Combination therapy
Deferiprone (L1) and desferrioxamine combination treatment
Drug: Deferiprone (L1)
75 mg/kg body weight daily

Drug: Desferrioxamine
35-50 mg/kg body weight on 2 or more days per week

Primary Outcome Measures :
  1. Liver Iron Concentration (LIC) by SQUID [ Time Frame: Yearly ]
  2. Long-term safety profile [ Time Frame: Long-term ]

Secondary Outcome Measures :
  1. Serum ferritin [ Time Frame: At quarterly control visits ]
  2. Urinary Iron Excretion (UIE) [ Time Frame: At six-monthly control visits ]
  3. Heart iron content (optional) by MRI T2* and MRI SIR [ Time Frame: Yearly ]

Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Iron overloaded male or female patients with primary or secondary hemochromatosis
  • Age: 4 years and older
  • Patients with desferrioxamine toxicity or allergy (e.g. visual or hearing defects, bone abnormalities, reactions at injection site)
  • Patients unable or unwilling to comply satisfactorily with regular desferrioxamine administration on 5-7 days/week
  • Combination treatment: patients not sufficiently chelated with desferrioxamine or deferiprone monotherapy
  • Patients must be willing to undergo routine screening including medical history, physical examination and hematology, biochemistry and other laboratory tests
  • Written informed consent

Exclusion Criteria:

  • Children under 4 years of age
  • Female and male of reproductive age, sexually active but not taking adequate contraceptive precaution
  • Woman who are pregnant or breast-feeding
  • Patients with HIV
  • Patients with active hepatitis requiring treatment
  • Patients with severe hepatic failure, cirrhosis
  • Patients with neutropenia (neutrophils less than 1.5 exp9/l, MDS: less than 0.5 exp9/l)
  • Patients with thrombocytopenia (platelets less than 100 exp9/l, MDS: less than 20 exp9/l)
  • Patients with decompensated heart failure (LVEF less than 40% or patients under continuous cardiac medication)
  • Patients with severe renal failure

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): NCT00349453

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Cantonal Hospital, Children's Clinic
Aarau, Aargau, Switzerland, 5001
Cantonal Hospital
Aarau, Aargau, Switzerland, 5001
Cantonal Hospital Graubünden
Chur, Graubünden, Switzerland, 7000
Private practice
Arzo, Ticino, Switzerland, 6864
Private practice
Lugano, Ticino, Switzerland, 6900
Regional Hospital
Lugano, Ticino, Switzerland, 6900
Private practice
Riva San Vitale, Ticino, Switzerland, 6826
Private children's practice
Brig, Wallis, Switzerland, 3900
Private practice
Oerlikon, Zurich, Switzerland, 8050
Private children's practice
Bern, Switzerland, 3014
Children's Hospital of Eastern Switzerland
St. Gallen, Switzerland, 9006
University Children's Hospital
Zurich, Switzerland, 8032
University Hospital
Zurich, Switzerland, 8091
Sponsors and Collaborators
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Principal Investigator: Petrign FG Töndury, MD
Principal Investigator: Markus Schmugge Liner, MD University Children's Hospital, Zurich
Publications of Results:
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Responsible Party: Lipomed
ClinicalTrials.gov Identifier: NCT00349453    
Other Study ID Numbers: DF-2/CH
First Posted: July 7, 2006    Key Record Dates
Last Update Posted: December 12, 2011
Last Verified: December 2011
Keywords provided by Lipomed:
Iron overload
Additional relevant MeSH terms:
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Iron Overload
Iron Metabolism Disorders
Metabolic Diseases
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action