Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

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:

        1. Other radiological criteria: Modification of T2* in MRI of the caudal nucleus head,
           putamen and pallidum.

        2. Evaluate the "disease modifier" effect on the clinical symptoms:

             -  Parkinsonian syndrome: UPDRS III

             -  the Clinical Global Impression scored by the examiner and the patient.

        3. Evaluate the safety on cognitive and behavioral functions

             -  MDS-UPDRS I

             -  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).

        4. Safety: complete blood count (CBC) with weekly leukocyte counts, standard blood
           biochemistry profile, blood iron profile, ECG, blood pressure, bodyweight, adverse event
           reporting.

        5. Specific biochemistry screen: heavy metal profile, oxidative stress and dopamine
           metabolism.

      Study center: Service de Neurologie et Pathologie du Mouvement (Head: Prof. Destée, Clinique
      Neurologique and Service de Neuroradiologie (Head: Prof. Pruvo), Salengro Hospital, Lille
      University Medical Center, Lille, France.

      Study characteristics: a randomized, double-blind, placebo-controlled, parallel-group,
      single-center trial with a delayed onset paradigm (Early-start group with 12 months of
      deferiprone versus delayed -start group with 6 months of placebo then 6 months of
      deferiprone) to study the effect of deferiprone on the relaxation time of the substantia
      nigra during a T2* MRI sequence (R2*=1/T2* reflecting iron overload) with respect to motor
      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 30 mg/kg/day, in 2 doses.

      Study population: 40 adult parkinsonian volunteers, with early-stage PD under their first
      optimised dopaminergic therapeutic strategy (i.e. either dopamine agonist and/or slight dose
      of L-dopa) and free of motor fluctuations or dementia.

      Planned inclusion period: 12 months. Study duration for individual patients: 13 months (2
      weeks between screening and randomization, 6 months of double-blind treatment, then 6 months
      of open label 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), visit after 6 months (V6, at least
           6 months after V0), visit after 12 months (V12, at least 12 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, V5, V7, V9, V11

        -  MRI in an external facility at V0, V6, V12.

        -  Telephone follow-up: V2, V4, V8, V10

        -  Patients will be invited to participate in an ancillary study involving analysis of the
           cerebrospinal fluid (CSF) at the randomization visit and the V6, 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.
    

Intervention name(s): deferiprone; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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; 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 intervention name(s): FERRIPROX
Intervention MeSH terms: Deferiprone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment