Clinical trial NCT02655315: Conservative Iron Chelation as a Disease-modifying Strategy in Parkinson's Disease
Official title: Conservative Iron Chelation as a Disease-modifying Strategy in Parkinson's Disease. European Multicentre, Parallel-group, Placebo-controlled, Randomized Clinical Trial of Deferiprone"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson Disease
Keywords: Parkinson
Deferiprone
Chelation
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: European Commission
name: ApoPharma
First posted: 2016-01-14
Enrollment: 372
Sex: ALL
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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)

Primary outcomes:
measure: Global effect (symptomatic and disease modifying effects) on motor and non motor handicap
timeFrame: at 36 weeks
Secondary outcomes:
measure: Disease-modifying effect on motor and non motor handicap
timeFrame: baseline, at 40 weeks
measure: Effect of the motor symptoms
timeFrame: baseline, at 12, 36 and 40 weeks
measure: Quality of life and autonomy by PDQ-39 score
timeFrame: baseline, at 36 and 40 weeks
measure: Quality of life and autonomy by Clinical Global Impression score
timeFrame: baseline, at 36 and 40 weeks
measure: Health economics assessment
timeFrame: baseline, at 36 and 40 weeks
measure: EQ-5D questionnaire
timeFrame: baseline, at 36 and 40 weeks
measure: Safety criteria
timeFrame: 40 weeks
measure: Effect on overall cognitive status
timeFrame: baseline, at 12, 36 and 40 weeks
measure: Effect on gait disorders
timeFrame: baseline, at 12, 36 and 40 weeks
measure: Effect on daily living
timeFrame: baseline, at 12, 36 and 40 weeks
measure: Effect on non-motor symptoms
timeFrame: baseline, at 12, 36 and 40 weeks
measure: Lack of occurrence of motor fluctuations
timeFrame: baseline, at 12, 36 and 40 weeks
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medizinische Universitat Innsbruck
city: Prague
country: Czechia
facility: Univerzita Karlova V Praze
city: Praha
country: Czechia
facility: Charles University
city: Bordeaux
country: France
facility: CHU Pellegrin
city: Bron
country: France
facility: Hôpital Wertheimer
city: Clermont-Ferrand
country: France
facility: Hôpital Montpied
city: Lille
country: France
facility: Hôpital Salengro, CHRU
city: Marseille
country: France
facility: CHU la TIMONE
city: Paris
country: France
facility: AP-HP, Hôpital Pitié-Salpêtrière
city: Strasbourg
country: France
facility: CHU de Strasbourg, Hôpital de Hautepierre
city: Toulouse
country: France
facility: Chu Purpan
city: Homburg
country: Germany
facility: University Hospital, Saarland University
city: Kiel
country: Germany
facility: Christian-albrechts universität zu kiel
city: Rostock
country: Germany
facility: Klinik und Poliklinik für Neurologie der Universitätsmedizin Rostock
city: Amsterdam
country: Netherlands
facility: Acadamic central center, Amsterdam
city: Nijmegen
country: Netherlands
facility: Radboud university medical center
city: Coimbra
country: Portugal
facility: Centro Hospitalar e universitario de Coimbra
city: Guimarães
country: Portugal
facility: Centro Hospitalar do Alto Ave
city: Lisbon
country: Portugal
facility: Centro Hospitalar Lisboa Norte
city: Barcelona
country: Spain
facility: Hospital Clinic Universitari de Barcelona
city: Barcelona
country: Spain
facility: Hospital de Bellvitge
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospital
city: Glasgow
country: United Kingdom
facility: University of Glasgow
city: Newcastle
country: United Kingdom
facility: Newcastle University
Study officials:
affiliation: University Hospital, Lille
name: David Devos, MD, PhD
role: STUDY_CHAIR
References:
citation: Mahoney-Sanchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC. Ferroptosis and its potential role in the physiopathology of Parkinson's Disease. Prog Neurobiol. 2021 Jan;196:101890. doi: 10.1016/j.pneurobio.2020.101890. Epub 2020 Jul 26.
citation: Moreau C, Duce JA, Rascol O, Devedjian JC, Berg D, Dexter D, Cabantchik ZI, Bush AI, Devos D; FAIRPARK-II study group. Iron as a therapeutic target for Parkinson's disease. Mov Disord. 2018 Apr;33(4):568-574. doi: 10.1002/mds.27275. Epub 2018 Jan 30. No abstract available.