Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease

• Status: Completed
• Trial end date: 2011-10-01
• Target enrollment: 0
• Participant gender: All

Summary

Few available drugs can slow the progression of neurodegenerative pathologies such as Parkinson's disease (PD). One of the recent hypotheses concerning the reduction of oxidative stress and neuron death features a harmful effect of iron, which may reach abnormally high levels in the substantia nigra (SN) pars compacta (iron overload has been seen in the substantia nigra in parkinsonian patients and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD). Iron overload is harmful because it reacts with hydrogen peroxide (H2O2) produced during the oxidative deamination of dopamine, generating hydroxyl radicals which then damage proteins, DNA and phospholipid membranes and may be responsible for neuron death. The use of an iron chelator (clioquinol) produces a reduction in neuron death in the MPTP mouse model. In humans, a special, partially refocused interleaved multiple echo (PRIME) MR sequence has been used to study the relaxation time (T2*) and quantify iron overload in the SN of PD patients and the nucleus dentatus of patients with Friedreich's ataxia. T2* sequences have revealed a decrease in iron overload following treatment with the chelator deferiprone, in parallel with a clinical improvement in these patients. Furthermore, the very recent open label use of deferiprone in rare serious, systemic, neurological iron overload diseases (Neurodegeneration with Brain Iron Accumulation (NBIA)) has revealed a clinical improvement after 6 months, with 2 case reports from our group and another from an Italian group (Forni et al., 2008). The safety of the low dosages of deferiprone (20 to 30 mg/kg/day) used in neurology appears to be much greater than for the high dosages (75 to 100 mg/kg/day in 3 doses) used in hematology to decrease post-transfusion iron overloads in thalassemia major.

Hence, the investigators wish to evaluate the effect of treatment with an oral iron chelator which is capable of crossing the blood-brain barrier (deferiprone) on iron overload in the SN(as assessed by the T2* sequence) with respect to the progression of clinical sign in PD. It is expected a 6-month course of deferiprone able to produce a moderate reduction in iron overload of the SN, associated with a drop in the motor handicap score. Depending on the risk/benefit balance determined in this initial pilot study, a larger, multicenter neuroprotection study could be envisaged.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University Hospital, Lille
• Treatments: Chelating Agents; Deferiprone

Criteria

Inclusion Criteria:

• Patients with typical Parkinson's disease according to the Gibb criteria and the Parkinson's Disease Society criteria (Daniel and Lees, 1993).

• Ideally less than 2 to 3 years since disease onset and never more than 4 years.

• Patients on dopaminergic drugs and/or L-Dopa.

• Non-fluctuating disease because otherwise the degenerative process would be well advanced, the clinical score would vary from one day to another and the imaging evaluation would be complicated by dyskinesia.

Exclusion Criteria:

• Subjects over the age of 80

• Demented subjects: MMSE score ≤ 24, Mattis score of < 130 and DSM IV criteria

• Subjects with radiological anomalies on MRI, whether incidental or suggestive of vascular involvement or significant cortical or subcortical atrophy

• Subjects for whom MRI is contra-indicated (metal objects in the body, severe claustrophobia, pacemaker, etc.)

• Subjects undergoing brain stimulation

• Very severe rest tremor, which could induce MRI artifacts

• Subjects that have not stabilized in terms of the therapeutic regimen and who are likely to require changes in their dopamine therapy in the coming 6 months

• Hoehn and Yahr stage ≥ 3 in the "Off" state, indicating the need for walking assistance in the absence of treatment.

• Hypersensitivity to iron chelator drugs

• Patients at risk of or having experienced agranulocytosis

• Patients on a drug that can potentially induce agranulocytosis (clozapine, Closaril®/Leponex®)

• Patients with anemia (regardless of the latter's etiology) or a history of other hematological diseases - even an iron deficiency

• Ferritin blood level < 100 ng/ml (100 µg/l)

• A history of hemochromatosis or known iron metabolism disorders.

• Pregnant or breastfeeding women or women not taking effective contraception

• Kidney or liver failure

• Blood coagulation disorders, antiplatelet drugs or anticoagulants

• Concomitant treatment with aluminum-based antacids (interaction)

• Concomitant treatment with vitamin C (interaction)

• Presence of other serious diseases

• Inability to provide informed consent