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

NCT ID: NCT02655315

Last Updated: 2022-11-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 372 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-09
• Study Completion Date: 2020-09-22

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.

Conditions

Parkinson Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

DEFERIPRONE

Half of participants will receive the deferiprone (DFP) to 15 mg / kg twice daily morning and evening (30mg / kg per day).The treatment lasts nine months.

Group Type: ACTIVE_COMPARATOR

Deferiprone

Intervention Type: DRUG

15 mg / kg twice daily morning and evening (30mg / kg per day).The treatment lasts nine months.

PLACEBO

Half of participants will receive the placebo twice daily morning and evening. The treatment lasts nine months.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

the placebo twice daily morning and evening. The treatment lasts nine months

Interventions

Deferiprone

15 mg / kg twice daily morning and evening (30mg / kg per day).The treatment lasts nine months.

Intervention Type: DRUG

Placebo

the placebo twice daily morning and evening. The treatment lasts nine months

Intervention Type: DRUG

Other Intervention Names

active drug; harmless pill; inactive drug

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

• 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)

• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Commission

OTHER

Sponsor Role: collaborator

ApoPharma

INDUSTRY

Sponsor Role: collaborator

University Hospital, Lille

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Devos, MD, PhD

Role: STUDY_CHAIR

University Hospital, Lille

Locations

Medizinische Universitat Innsbruck

Innsbruck, , Austria

Charles University

Prague, , Czechia

Univerzita Karlova V Praze

Prague, , Czechia

CHU Pellegrin

Bordeaux, , France

Hôpital Wertheimer

Bron, , France

Hôpital Montpied

Clermont-Ferrand, , France

Hôpital Salengro, CHRU

Lille, , France

CHU la TIMONE

Marseille, , France

AP-HP, Hôpital Pitié-Salpêtrière

Paris, , France

CHU de Strasbourg, Hôpital de Hautepierre

Strasbourg, , France

Chu Purpan

Toulouse, , France

University Hospital, Saarland University

Homburg, , Germany

Christian-albrechts universität zu kiel

Kiel, , Germany

Klinik und Poliklinik für Neurologie der Universitätsmedizin Rostock

Rostock, , Germany

Acadamic central center, Amsterdam

Amsterdam, , Netherlands

Radboud university medical center

Nijmegen, , Netherlands

Centro Hospitalar e universitario de Coimbra

Coimbra, , Portugal

Centro Hospitalar do Alto Ave

Guimarães, , Portugal

Centro Hospitalar Lisboa Norte

Lisbon, , Portugal

Hospital Clinic Universitari de Barcelona

Barcelona, , Spain

Hospital de Bellvitge

Barcelona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Cambridge University Hospital

Cambridge, , United Kingdom

University of Glasgow

Glasgow, , United Kingdom

Newcastle University

Newcastle, , United Kingdom

Countries

Austria; Czechia; France; Germany; Netherlands; Portugal; Spain; United Kingdom

References

Devos D, Labreuche J, Rascol O, Corvol JC, Duhamel A, Guyon Delannoy P, Poewe W, Compta Y, Pavese N, Ruzicka E, Dusek P, Post B, Bloem BR, Berg D, Maetzler W, Otto M, Habert MO, Lehericy S, Ferreira J, Dodel R, Tranchant C, Eusebio A, Thobois S, Marques AR, Meissner WG, Ory-Magne F, Walter U, de Bie RMA, Gago M, Vilas D, Kulisevsky J, Januario C, Coelho MVS, Behnke S, Worth P, Seppi K, Ouk T, Potey C, Leclercq C, Viard R, Kuchcinski G, Lopes R, Pruvo JP, Pigny P, Garcon G, Simonin O, Carpentier J, Rolland AS, Nyholm D, Scherfler C, Mangin JF, Chupin M, Bordet R, Dexter DT, Fradette C, Spino M, Tricta F, Ayton S, Bush AI, Devedjian JC, Duce JA, Cabantchik I, Defebvre L, Deplanque D, Moreau C; FAIRPARK-II Study Group. Trial of Deferiprone in Parkinson's Disease. N Engl J Med. 2022 Dec 1;387(22):2045-2055. doi: 10.1056/NEJMoa2209254.

Reference Type: DERIVED

PMID: 36449420 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32726602 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29380903 (View on PubMed)

Related Links

http://fairpark2.eu/

Website for informations on the Fairpark2 study

Other Identifiers

2015-003679-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

Grant agreement No 633190

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

HP751

Identifier Type: OTHER

Identifier Source: secondary_id

2015_22

Identifier Type: -

Identifier Source: org_study_id