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

Sponsor

University Hospital, Lille (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02655315

Collaborator

European Commission (Other), ApoPharma (Industry)

372

Enrollment

Locations

Arms

71.8

Anticipated Duration (Months)

14.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease	Drug: Deferiprone Drug: Placebo	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

372 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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"

Actual Study Start Date :

Feb 9, 2016

Anticipated Primary Completion Date :

Feb 1, 2022

Anticipated Study Completion Date :

Feb 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Deferiprone 15 mg / kg twice daily morning and evening (30mg / kg per day).The treatment lasts nine months. Other Names: active drug
Placebo Comparator: PLACEBO Half of participants will receive the placebo twice daily morning and evening. The treatment lasts nine months.	Drug: Placebo the placebo twice daily morning and evening. The treatment lasts nine months Other Names: harmless pill inactive drug

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Deferiprone

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

Other Names:

active drug

Placebo Comparator: PLACEBO

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

Drug: Placebo

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

Other Names:

harmless pill

inactive drug

Outcome Measures

Primary Outcome Measures

Global effect (symptomatic and disease modifying effects) on motor and non motor handicap [at 36 weeks]
the change in the total Movement Disorders Society-Unified Parkinson Disease Rating Scale score between baseline and 36 weeks (i.e. the end of the placebo-controlled phase for analysis of both disease-modifying and symptomatic effects)

Secondary Outcome Measures

Disease-modifying effect on motor and non motor handicap [baseline, at 40 weeks]
It will be measured as the changes in the overall Movement Disorders Society-Unified Parkinson Disease Rating Scale score between baseline and week 40 (i.e. the end of the one-month post-treatment monitoring period), to analyse the disease-modifying effect without bias from the symptomatic effect of ongoing deferiprone treatment) on the study population
Effect of the motor symptoms [baseline, at 12, 36 and 40 weeks]
The effect of the motor symptoms will be analysed as the change in the subscale part III of the Movement Disorders Society-Unified Parkinson Disease Rating Scale score
Quality of life and autonomy by PDQ-39 score [baseline, at 36 and 40 weeks]
It will be analyzed as the change in the Parkinson's Disease Quality of Life (PDQ-39, via a 39-item self-questionnaire)
Quality of life and autonomy by Clinical Global Impression score [baseline, at 36 and 40 weeks]
the Clinical Global Impression scored by the examiner and the patient
Health economics assessment [baseline, at 36 and 40 weeks]
will be performed via a specific questionnaire provides a simple descriptive profile and a single index value for health status
EQ-5D questionnaire [baseline, at 36 and 40 weeks]
the questionnaire provides a simple descriptive profile and a single index value for health status.
Safety criteria [40 weeks]
All the safety concerns will be listed in a table with the number of patients, the type the severity and the time of occurrence for adverse events neutropenia (weekly complete blood count) agranulocytosis (weekly complete blood count) anemia (weekly complete blood count) iron metabolism abnormalities (haemoglobin, serum iron, ferritinemia, transferrin, total binding capacity, transferrin saturation coefficient, 24-hour urine iron). Standard biological abnormalities (fasting glucose, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and (for all sexually active, fertile females) urine pregnancy tests. Abnormal physical examination (including vital signs, bodyweight, electrocardiogram and blood pressure)
Effect on overall cognitive status [baseline, at 12, 36 and 40 weeks]
Measured by the score in the Montreal Cognitive Assessment
Effect on gait disorders [baseline, at 12, 36 and 40 weeks]
Measured by the Stand Walk Sit test
Effect on daily living [baseline, at 12, 36 and 40 weeks]
The effect on daily living will be analysed as the change in the subscale part II (activities of daily living) of the Movement Disorders Society-Unified Parkinson Disease Rating Scale score
Effect on non-motor symptoms [baseline, at 12, 36 and 40 weeks]
The effect on non motor symptoms will be analysed as the change in the subscale part I (cognition and behavior) of the Movement Disorders Society-Unified Parkinson Disease Rating Scale score
Lack of occurrence of motor fluctuations [baseline, at 12, 36 and 40 weeks]
The lack of occurrence of motor fluctuations will be analysed on the subscale part IV of the Movement Disorders Society-Unified Parkinson Disease Rating Scale score

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patients
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.
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).
Patients covered by a Health Insurance System in countries where required by law
Written informed consent dated and signed prior to the beginning of any procedures related to the clinical trial

Exclusion Criteria:

Disease duration greater than 18 months.
Patients with high frequency of comorbidity or vital risks that may reasonably impair life expectancy
Subject with handicap required dopaminergic treatment at the inclusion and therefore likely not to bear 9 months without symptomatic treatment
Hoehn and Yahr stage 3 or more.
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).
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).
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.
Subjects undergoing brain stimulation.
Positive Human Immunodepression Virus serology.
Hypersensitivity to deferiprone.
Patients with agranulocytosis or with a history of agranulocytosis.
Patients taking a treatment at risk of agranulocytosis (clozapine, Closaril®/Leponex®).
Patients with anaemia (regardless of the latter's aetiology) or a history of another haematological disease. Haemochromatosis is not an exclusion criterion.
Pregnant or breastfeeding women or women of childbearing potential not taking highly effective contraception.
Kidney or liver failure.
Other serious diseases.
Inability to provide informed consent.
Participation in another clinical trial with investigational medicinal product within 3 months prior to inclusion in the study
Patient who has suffered mild or moderate depressive episode and isn't in remission and on a stable medication for at least 8 weeks
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)

Contacts and Locations

Locations

	Site	City	Country
1	Medizinische Universitat Innsbruck	Innsbruck	Austria
2	Univerzita Karlova V Praze	Prague	Czechia
3	Charles University	Praha	Czechia
4	CHU Pellegrin	Bordeaux	France
5	Hôpital Wertheimer	Bron	France
6	Hôpital Montpied	Clermont-Ferrand	France
7	Hôpital Salengro, CHRU	Lille	France
8	CHU la TIMONE	Marseille	France
9	AP-HP, Hôpital Pitié-Salpêtrière	Paris	France
10	CHU de Strasbourg, Hôpital de Hautepierre	Strasbourg	France
11	Chu Purpan	Toulouse	France
12	University Hospital, Saarland University	Homburg	Germany
13	Christian-albrechts universität zu kiel	Kiel	Germany
14	Klinik und Poliklinik für Neurologie der Universitätsmedizin Rostock	Rostock	Germany
15	Acadamic central center, Amsterdam	Amsterdam	Netherlands
16	Radboud university medical center	Nijmegen	Netherlands
17	Centro Hospitalar e universitario de Coimbra	Coimbra	Portugal
18	Centro Hospitalar do Alto Ave	Guimarães	Portugal
19	Centro Hospitalar Lisboa Norte	Lisbon	Portugal
20	Hospital Clinic Universitari de Barcelona	Barcelona	Spain
21	Hospital de Bellvitge	Barcelona	Spain
22	Hospital de la Santa Creu i Sant Pau	Barcelona	Spain
23	Cambridge University Hospital	Cambridge	United Kingdom
24	University of Glasgow	Glasgow	United Kingdom
25	Newcastle University	Newcastle	United Kingdom