Conservative Iron Chelation as a Disease-modifying Strategy in Parkinson's Disease

This study evaluates the effect of iron chelation as a therapeutic strategy to slow the progression of Parkinson's disease. Half of participants will receive the deferiprone to 15 mg / kg twice daily morning and evening (30mg / kg per day), while the other half will receive a placebo. The treatment lasts nine months.

This is the new concept of "conservative iron chelation". We recently demonstrated (for the first time) the feasibility, efficacy and acceptability of the conservative iron chelation approach in pilot translational studies in Parkinson's disease with a prototype drug: deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) (in the FAIR-PARK-I project led by the applicant and funded by French Ministry of Health). The only available blood-brain-barrier-permeable iron chelator deferiprone is approved for treating systemic iron overload in transfused patients with thalassemia. Deferiprone has been on the European Union market since 1999, with a favourable risk/benefit balance at dose of 75 to 100 mg/kg/day. The investigators shall adopt a repositioning strategy by using deferiprone at a lower dose of 30 mg/kg/day in this new indication for local iron overload in Parkinson's disease. Deferiprone will be the first-in-class drug for this novel therapeutic strategy. On the basis of the preclinical and clinical data from (FAIR-PARK-I), the present (FAIR-PARK-II) project should constitute a model for future cytoprotection strategies in neurodegenerative diseases; if deferiprone treatment is associated with significant slower disease progression, it would be the first non-dopaminergic drug to have a proven disease-modifying effect in Parkinson's disease.

Eligibility Criteria:
Inclusion Criteria:

1. Adult patients
2. Parkinson's disease diagnosed according United Kingdom Parkinson's disease Society Brain Bank Clinical Diagnostic Criteria and based on the presence of at least two of the three cardinal features of the disease (rest tremor, bradykinesia and rigidity). If rest tremor is not present, subjects must have unilateral onset of symptoms.
3. Treatment-naïve, i.e. the best population for assessing a disease-modifying effect without the interaction of dopaminergic treatment (no dopaminergic agonists, L-dopa, anticholinergics, monoamine oxidase B inhibitors (e.g. rasagiline) or deep brain stimulation).
4. Patients covered by a Health Insurance System in countries where required by law
5. Written informed consent dated and signed prior to the beginning of any procedures related to the clinical trial

Exclusion Criteria:

1. Disease duration greater than 18 months.
2. Patients with high frequency of comorbidity or vital risks that may reasonably impair life expectancy
3. Subject with handicap required dopaminergic treatment at the inclusion and therefore likely not to bear 9 months without symptomatic treatment
4. Hoehn and Yahr stage 3 or more.
5. Significant cognitive impairment (a Mini Mental State Examination score \<24 or an equivalent impairment on a similar scale) or dementia diagnosed in accordance with the Movement Disorders Society criteria (Emre et al., 2007).
6. Atypical or secondary parkinsonism (supranuclear palsy, multisystem atrophy, etc.) or anomalies on MRI suggestive of vascular involvement or significant cortical or subcortical atrophy (i.e. atypical for Parkinson's Disease).
7. Progressing axis I psychiatric disorders (psychosis, hallucinations, substance addiction, bipolar disorder, or severe depression), in accordance with the Diagnostic and Statistical Manual of Mental Disorders.
8. Subjects undergoing brain stimulation.
9. Positive Human Immunodepression Virus serology.
10. Hypersensitivity to deferiprone.
11. Patients with agranulocytosis or with a history of agranulocytosis.
12. Patients taking a treatment at risk of agranulocytosis (clozapine, Closaril®/Leponex®).
13. Patients with anaemia (regardless of the latter's aetiology) or a history of another haematological disease. Haemochromatosis is not an exclusion criterion.
14. Pregnant or breastfeeding women or women of childbearing potential not taking highly effective contraception.
15. Kidney or liver failure.
16. Other serious diseases.
17. Inability to provide informed consent.
18. Participation in another clinical trial with investigational medicinal product within 3 months prior to inclusion in the study
19. Patient who has suffered mild or moderate depressive episode and isn't in remission and on a stable medication for at least 8 weeks
20. Patient \> 130k

Exclusion criteria for the biomarker study and the ancillary study (i) Magnetic Resonance Imaging:

* Subjects for whom Magnetic Resonance Imaging is contraindicated (metal objects in the body, severe claustrophobia, pacemaker, incompatible surgical material).
* Very severe rest tremor, which could induce Magnetic Resonance Imaging artefacts.

(ii) Lumbar puncture:

* Blood coagulation disorders, antiplatelet drugs or anticoagulants.
* Intracranial hypertension. (iii) Contraindications to nitrous oxide:
* Ventilation with Fraction of inspired Oxygen \>50%, emphysema or pneumothorax
* Altered states of consciousness, non-cooperative patient (need to stop the nitrous oxide)