A Pilot Clinical Trial With the Iron Chelator Deferiprone in Parkinson's Disease
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Parkinson's disease (PD) is a common neurodegenerative disease affecting movement. Although
      drug treatments for PD are available they only treat the symptoms of the disease, fail to
      halt neuronal loss, and are associated with long term side effects and loss of efficacy.
      There is a chronic need to develop neuroprotective therapies. Increased iron and oxidative
      stress have been heavily implicated in the neurodegenerative process in PD, hence removal of
      excess iron by iron chelation represents a potential drug target. Iron chelators are
      extensively utilised to treat peripheral iron overload disorders (e.g. thalassaemia) and
      recently the investigators have demonstrated iron chelators such as Deferiprone can enter the
      brain removing excess iron and are neuroprotective in PD animal models. Although good
      tolerability and efficacy to remove brain iron has also been shown in a pilot study with the
      iron chelators Deferiprone in young patients with Friedreich Ataxia, where iron accumulates
      in the dentate nucleus, no studies have been conducted in aged individuals affected by PD.
      Hence the aims of this study are 1) to assess whether Deferiprone is well tolerated in PD
      patients, 2) whether Deferiprone can remove the excess iron levels found in the brain area
      affected by PD, the substantia nigra, as assessed by Magnetic resonance imaging (MRI) and 3)
      whether Deferiprone has any direct effect on the clinical symptoms of PD. Three groups of 12
      (total 36) early stage drug free PD patients will be treated with 20 or 30mg/kg/d Deferiprone
      or Placebo for 6 months. Over the 6 months patients will receive serial MRI scans,
      neurological examinations not only to assess PD symptoms but also psychological state, plus
      blood test to monitor for potential side effects. Positive results from this pilot will help
      support larger clinical trials to evaluate whether Deferiprone can slow down/halt PD.
    

Detailed description: 
      BACKGROUND Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects
      approximately 2% of the population aged over 60 years. The common clinical motor control
      features are tremor, bradykinesia, postural abnormality and rigidity. However, in many
      patients non-motor features such as cognitive decline, depression, autonomic disturbances
      also occur as the disease progresses. The principal pathology is the degeneration of the
      nigrostriatal dopaminergic system which plays a major role in movement control through the
      release of dopamine in the striatum. Current therapeutic approach focus on dopamine
      replacement strategies either through the dopamine precursor L-DOPA or the use of dopamine
      agonists, and/or the use of monoamine oxidase inhibitors or catecholamine transferase
      inhibitors which prevent the breakdown of dopamine or facilitate L-DOPA entry into the brain.
      However, such therapeutic approaches are associated with declining efficacy and long term
      complications e.g. dyskinesias. Additionally, such therapeutic approaches only treat the
      clinical symptoms of PD and due not protect the neurons against degeneration hence the
      disease continues to progress with the patient experiencing increasing disability. Hence
      there is a chronic need for the development of neuroprotective drugs which prevent further
      neuronal loss and thus prevent the progression of the disease.

      RATIONALE FOR CURRENT STUDY Hypothesis: Increased iron and oxidative stress play a major role
      in the neurodegenerative process in PD and iron chelation therapy can be effective in
      removing excess iron from the brain and potentially slowing the neurodegenerative process.

      Research question: Can iron chelation therapy with Deferiprone remove excess iron in the
      substantia nigra in PD patients without toxic side effects. What effect does Deferiprone
      therapy have on the severity of PD and other brain function e.g. cognition, depression etc.

      Increased iron levels have been heavily implicated in the neurodegenerative process in PD.
      Although many of our cellular processes require iron, when in excessive amounts it can
      trigger the formation of toxic chemicals called free radicals, of which there is extensive
      evidence of their increased formation in the PD brain. Hence removal of excess iron by iron
      chelation (drugs which bind and detoxify iron) represents a potential drug target.

      Iron chelators e.g. Deferiprone in doses around 100mg/kg/day, are extensively utilised to
      treat peripheral iron overload disorders such as beta thalassaemia, where the patients
      requires regular blood transfusions but iron accumulates in the body when the red blood cells
      are removed from the circulation. Iron chelation therapy in such patients is associated with
      minimal side effects with long term use. Recently, in animal models of brain iron overload,
      we have demonstrated iron chelators can enter the brain removing excess iron. Additionally,
      we have recently shown that iron chelation therapy protects neurons against toxins in animal
      models of PD.

      In 2007 20 or 30mg/kg/day Deferiprone was used in a pilot clinical trial in Friedreich ataxia
      (FA)patients, to assess whether the drug was well tolerated, removed excess brain iron and
      improved the clinical symptoms of FA. FA occurs due to a gene defect leading iron
      accumulation in the mitochondria in the cerebellum, toxicity of which leads to ataxia or
      inability to control muscle movements. FA is diagnosed in young individuals (14-26 years of
      age) and has no clinical treatment. In this 6 months FA study Deferiprone at 20 or
      30mg/kg/day was well tolerated by the patients and resulted in a reduction in brain iron, as
      indicated by MRI brain imaging, and led to a clinical improvement in patient symptoms. Whilst
      this represents the first clinical use of an iron chelator to treat a neurodegenerative
      disorder, the FA patients in this study were young (14-23 years old) hence we do not know how
      aged (average age 60years) individuals commonly affected by PD will respond to iron chelator
      treatment. Hence the first aim of this study is to conduct the first pilot clinical trial
      with an iron chelator in newly diagnosed PD patients to assess tolerability along with its
      ability to reduce iron content in the brain area affected in PD, the substantia nigra, as
      assessed by MRI.

      A number of clinical trials have already been conducted in PD with potential neuroprotective
      drugs but their ability to slow the disease process has been controversial since these drugs
      have a direct effects on the symptoms of PD itself. Hence it is difficult to say whether the
      beneficial effects of the drugs are due the prevention of further neuronal loss thus slowing
      the disease or whether they improve the patient's ability to move directly. PD progresses in
      most patients fairly slowly, hence we don't expect to see detectable neuroprotection
      following 6 months Deferiprone treatment but it will allow us to assess whether Deferiprone
      therapy has any direct effects on PD symptoms. Hence the second aim of this study will be to
      examine whether iron chelation therapy has a direct effect on PD symptomology.

      If this pilot study clearly demonstrates good tolerability of Deferiprone in PD patients
      whilst showing good removal of excess SN iron level yet having minimal direct effect on PD
      symptomology this data will form the basis of large funding application for a multicentre
      clinical trials to investigate whether long term Deferiprone treatment can slow/halt the
      progression of PD.
    

Intervention name(s): Deferiprone 20mg; Placebo; Deferiprone 30mg
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 20mg/kg/d Deferiprone divided into two equal doses (morning and evening), every day for 6 months; Feriprox placebo administered orally at the same dosing volume as the 20mg/kg/day feriprox per day; 30mg/kg/d Deferiprone divided into two equal doses (morning and evening), every day for 6 months
Other intervention name(s): Ferriprox; Feriprox placebo; Ferriprox
Intervention MeSH terms: Deferiprone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Parkinson's disease; Brain Iron; Iron chelation; Oxidative stress