Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease - Full Text View

Sponsored by:	University Hospital, Lille
Information provided by:	University Hospital, Lille
ClinicalTrials.gov Identifier:	NCT00943748

Purpose

In general, there are few available drugs for slowing 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 pars compacta. In fact, 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 substantia nigra 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 (Ferriprox®), 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, Ferriprox®) on iron overload in the substantia nigra (as assessed by the T2* sequence) with respect to the progression of clinical sign in PD. The investigators expect a 6-month course of deferiprone to produce a moderate reduction in iron overload of the substantia nigra, associated with a drop in the motor handicap score (relative to the placebo group). 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 II Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study
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:

Genetics Home Reference related topics: familial paroxysmal nonkinesigenic dyskinesia Parkinson disease

MedlinePlus related topics: Parkinson's Disease

Drug Information available for: 1,2-Dimethyl-3-hydroxypyrid-4-one

U.S. FDA Resources

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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Other radiological criteria: Modification of T2* in MRI of the caudal nucleus head, putamen, pallidum and frontal white matter. Spectroscopy (the NAA/creatine peak and the choline peak in the putamen). [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Parkinsonian syndrome: UPDRS I, II, III & IV, stand-walk-sit test, CAPIT finger dexterity test. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Cognitive and behavioral functions: overall cognitive function (Mattis, MMSE), memory, executive function, attention (simple and choice reaction times), drowsiness and sleep (Epworth scale, Parkinson Disease Sleep Scale), depression (MADRS). [ Time Frame: 6 months ] [ Designated as safety issue: No ]
The Clinical Global Impression scored by the examiner and the patient, plus the PDQ 39 quality of life scale. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Specific biochemistry screen: heavy metal profile, change in labile plasma iron (LPI, which reflects the iron's toxicity), oxidative stress and inflammatory, apoptotic & growth factors. [ Time Frame: 6 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 months ] [ Designated as safety issue: Yes ]
Ancillary study involving analysis of the cerebrospinal fluid (CSF). [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	September 2009
Estimated Study Completion Date:	November 2010
Estimated Primary Completion Date:	September 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
deferiprone: Active Comparator 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 25 mg/kg/day in 2 doses (about 1750mg/day)
placebo: Placebo Comparator placebo : 25 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 25 mg/kg/day in 2 doses (about 1750mg/day)

Detailed Description:

Primary objective: 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.

Secondary objectives:

Other radiological criteria: Modification of T2* in MRI of the caudal nucleus head, putamen, pallidum and frontal white matter. Spectroscopy (the NAA/creatine peak and the choline peak in the putamen).
Evaluate the "disease modifier" effect on the clinical symptoms:
- Parkinsonian syndrome: UPDRS I, II, III & IV, stand-walk-sit test, CAPIT finger dexterity test.
- cognitive and behavioral functions: overall cognitive function (Mattis, MMSE), memory, executive function, attention (simple and choice reaction times), drowsiness and sleep (Epworth scale, Parkinson Disease Sleep Scale), depression (MADRS).
- the Clinical Global Impression scored by the examiner and the patient, plus the PDQ 39 quality of life scale.
Specific biochemistry screen: heavy metal profile, change in labile plasma iron (LPI, which reflects the iron's toxicity), oxidative stress and inflammatory, apoptotic & growth factors.
Safety: complete blood count (CBC) with weekly leukocyte counts, standard blood biochemistry profile, blood iron profile, ECG, blood pressure, bodyweight, adverse event reporting. Study center: Service de Neurologie et Pathologie du Mouvement (Head: Prof. Destée, Clinique Neurologique, EA 2683, IFR 114, IMPRT and Service de Neuroradiologie (Head: Prof. Pruvo), IFR 114, IMPRT, Salengro Hospital, Lille University Medical Center, Lille, France. Study characteristics: a randomized, double-blind, placebo-controlled, parallel-group, single-center trial of the effect of a 6-month course of deferiprone on the relaxation time of the substantia nigra during a T2* MRI sequence (reflecting iron overload) with respect to motor and cognitive/behavioral disorders in Parkinson's disease. Active compound: the iron chelator 1,2-dimethyl-3-hydroxy-4-pyridinone (deferiprone, FERRIPROX®), which decreases abnormally high iron and ferritin levels. Its low molecular weight and liposolubility enable it to cross the blood-brain barrier. Posology: the recommended dosage in neurology is a total of 25 mg/kg/day, in 2 doses (1750mg/day).

Study population: 40 adult parkinsonian volunteers, with early-stage PD and free of motor fluctuations or dementia. Overall study duration: 18 months. Planned inclusion period: 12 months. Study duration for individual patients: 7 months (2 weeks between screening and randomization, 6 months of double-blind treatment and then a 2-week wash-out period).

Study procedures and timeline:

A screening visit (Sc).
Two comprehensive examinations (a neurological and neuropsychological check-up) at the randomization visit (V0, at D7-15 ± 1 week after Sc) and the final visit after 6 months (V6, at least 6 months after V0).
Weekly monitoring of the CBC with the leukocyte count, results faxed by the patient's local clinical lab or Lille University Medical Center's central lab.
Monitoring of blood iron and zinc status and overall tolerance during a brief consultation: V1, V3 and V5
MRI in an external facility at V0, V3 and V6.
Telephone follow-up: V2, V4
Patients will be invited to participate in an ancillary study involving analysis of the cerebrospinal fluid (CSF) at the randomization visit and the final visit, in order to perform a full set of CSF biochemistry assays and with a view to determining biological benefits at the central nervous system level and identifying biological markers.

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 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.

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
Ferritinemia < 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

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

Contacts

Contact: David Devos, MD, PhD	320446752 ext +33	d-devos@chru-lille.fr
Contact: Francine Niset	320446752 ext +33	f-niset@chru-lille.fr

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:	Department of Neurology, EA 2683, IFR 114, IMPRT, CHU de Lille, France ( Dr David Devos / MD, PhD )
Study ID Numbers:	2008-006842-25, CPP 09/04
Study First Received:	July 20, 2009
Last Updated:	July 21, 2009
ClinicalTrials.gov Identifier:	NCT00943748 History of Changes
Health Authority:	France: Afssaps - French Health Products Safety Agency

Study placed in the following topic categories:

Ganglion Cysts
Movement Disorders
Parkinson Disease
Deferiprone
Basal Ganglia Diseases
Central Nervous System Diseases

Chelating Agents
Parkinsonian Disorders
Iron Overload
Neurodegenerative Diseases
Brain Diseases
Iron

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Basal Ganglia Diseases
Nervous System Diseases
Deferiprone
Iron Chelating Agents
Central Nervous System Diseases
Brain Diseases

Neurodegenerative Diseases
Pharmacologic Actions
Parkinson Disease
Movement Disorders
Parkinsonian Disorders
Chelating Agents

ClinicalTrials.gov processed this record on September 10, 2009