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

NCT00943748 | Completed Phase 2 DMC

• 3 other identifiers: 2008-006842-252008_19/0838A90113-62
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Parkinson's Disease

Outcome Measures

Primary Outcomes (1)

• Decrease the iron overload (as measured by the T2* MRI sequence) in the substantia nigra in patients with Parkinson's disease (PD) after 6 months of deferiprone treatment, relative to the placebo group.

  6 months and 12 months

Secondary Outcomes (7)

• Other radiological criteria: Modification of T2* in MRI of the caudal nucleus head, putamen and pallidum

  6 and 12 months

• Parkinsonian syndrome: UPDRS III

  6 and 12 months

• Cognitive and behavioral functions: function, attention (simple and choice reaction times), drowsiness and sleep (Epworth scale, Parkinson Disease Sleep Scale), depression (MADRS).

  6 months and 12 months

• The Clinical Global Impression scored by the examiner and the patient

  6 months and 12 months

• Specific biochemistry screen: heavy metal profile, oxidative stress and dopamine metabolism

  6 and 12 months

Study Arms (2)

deferiprone

ACTIVE COMPARATOR

deferiprone 30 mg/kg/day

Drug: deferiprone

placebo

PLACEBO COMPARATOR

placebo : 30 mg/kg/day, in 2 liquid doses

Drug: placebo

Interventions

deferiprone DRUG

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 30 mg/kg/day in 2 doses

Also known as: FERRIPROX

deferiprone

placebo DRUG

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 30 mg/kg/day in 2 doses

placebo

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Lille: lead

Study Sites (1)

Service de Neurologie, Clinique Neurologique, EA 2683, IFR 114

Lille, 59037, France

Location

Related Publications (2)

• Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, Jonneaux A, Ryckewaert G, Garcon G, Rouaix N, Duhamel A, Jissendi P, Dujardin K, Auger F, Ravasi L, Hopes L, Grolez G, Firdaus W, Sablonniere B, Strubi-Vuillaume I, Zahr N, Destee A, Corvol JC, Poltl D, Leist M, Rose C, Defebvre L, Marchetti P, Cabantchik ZI, Bordet R. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid Redox Signal. 2014 Jul 10;21(2):195-210. doi: 10.1089/ars.2013.5593. Epub 2014 Feb 6.

  PMID: 24251381 RESULT

• Grolez G, Moreau C, Sablonniere B, Garcon G, Devedjian JC, Meguig S, Gele P, Delmaire C, Bordet R, Defebvre L, Cabantchik IZ, Devos D. Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease. BMC Neurol. 2015 May 6;15:74. doi: 10.1186/s12883-015-0331-3.

  PMID: 25943368 DERIVED

MeSH Terms

Conditions

Parkinson Disease

Interventions

Deferiprone

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Pyridones; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• David Devos, MD, PhD

  Service de Neurologie, Clinique Neurologique, EA 2683, IFR 114, IMPRT

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2009
• First Posted: July 22, 2009
• Study Start: October 1, 2009
• Primary Completion: August 1, 2011
• Study Completion: October 1, 2011
• Last Updated: May 14, 2026

Record last verified: 2009-07

Locations

FR (1)