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Efficacy and Safety of the Iron Chelator Deferiprone on Iron Overload in the Brain in Parkinson's Disease
This study is currently Recruiting
July 2009 By University Hospital, Lille
First Recieved on July 20, 2009
Last Updated on February 18, 2011
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.
||Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Resources/Links provided by NLM:
|Study Start Date:
|Estimated Primary Completion Date:
deferiprone 30 mg/kg/day
placebo : 25 mg/kg/day, in 2 liquid doses
A standard dose-escalation phase will be initiated, with a 3 ml of the deferiprone oral solution twice a day (breakfast and dinner) increase every 3 days up to a total of a fixed dose of 9 ml of deferiprone oral solution twice a day corresponding to 25 mg/kg/day in 2 doses (about 1750mg/day)
A standard dose-escalation phase will first be initiated, with a 3 ml of the placebo oral solution twice a day (breakfast and dinner) increase every 3 days up to a total of a fixed dose of 9 ml of placebo oral solution twice a day corresponding to 25 mg/kg/day in 2 doses (about 1750mg/day)
|Ages Eligible for Study:||30 Years|
|Genders Eligible for Study:||Both|
|Accepts Healthy Volunteers:||No|
- 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 5 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.
- 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,
- 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 ?g/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
- Investigator: David Devos, MD, PhD - Principal Investigator - Service de Neurologie, Clinique Neurologique, EA 2683, IFR 114, IMPRT
- Service de Neurologie, Clinique Neurologique, EA 2683, IFR 114
Lille, 59037 France