Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease (FAIR-PARK-I)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University Hospital, Lille
ClinicalTrials.gov Identifier:
NCT00943748
First received: July 20, 2009
Last updated: August 31, 2012
Last verified: July 2009
  Purpose

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.


Condition Intervention Phase
Parkinson's Disease
Drug: deferiprone
Drug: placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of the Iron Chelator Deferiprone on Iron Overload in the Brain in Parkinson's Disease

Resource links provided by NLM:


Further study details as provided by University Hospital, Lille:

Primary Outcome Measures:
  • 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. [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Other radiological criteria: Modification of T2* in MRI of the caudal nucleus head, putamen and pallidum [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
  • Parkinsonian syndrome: UPDRS III [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
  • Cognitive and behavioral functions: function, attention (simple and choice reaction times), drowsiness and sleep (Epworth scale, Parkinson Disease Sleep Scale), depression (MADRS). [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: Yes ]
    MDS-UPDRS I, overall cognitive function (Mattis, MMSE), memory, executive

  • The Clinical Global Impression scored by the examiner and the patient [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]
  • Specific biochemistry screen: heavy metal profile, oxidative stress and dopamine metabolism [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
  • Complete blood count (CBC) with weekly leukocyte counts, standard blood biochemistry profile, blood iron profile, ECG, blood pressure, bodyweight, adverse event reporting. [ Time Frame: 6 and 12 months ] [ Designated as safety issue: Yes ]
  • Ancillary study involving analysis of the cerebrospinal fluid (CSF). [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 40
Study Start Date: October 2009
Study Completion Date: October 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: deferiprone
deferiprone 30 mg/kg/day
Drug: deferiprone
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
Other Name: FERRIPROX
Placebo Comparator: placebo
placebo : 30 mg/kg/day, in 2 liquid doses
Drug: placebo
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
Other Name: placebo

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   30 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00943748

Locations
France
Service de Neurologie, Clinique Neurologique, EA 2683, IFR 114
Lille, France, 59037
Sponsors and Collaborators
University Hospital, Lille
Investigators
Principal Investigator: David Devos, MD, PhD Service de Neurologie, Clinique Neurologique, EA 2683, IFR 114, IMPRT
  More Information

No publications provided

Responsible Party: University Hospital, Lille
ClinicalTrials.gov Identifier: NCT00943748     History of Changes
Other Study ID Numbers: 2008-006842-25, 2008_19/0838, A90113-62
Study First Received: July 20, 2009
Last Updated: August 31, 2012
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Additional relevant MeSH terms:
Brain Diseases
Iron Chelating Agents
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Chelating Agents
Deferiprone
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 20, 2014