FAIRPARK II | EU funded research project | Parkinson's disease

Objective

The trial's overall objective can be summarized as follows:

to demonstrate for the first time in a large phase II, multicentre, parallel-group, placebo-controlled, randomized clinical trial (RCT) that conservative iron chelation, with the prototype drug deferiprone (DFP), will slow down the progression of handicap in PD patients and will not be associated with clinically significant adverse haematological events or other systemic effects.

Approach and Design

A putative slow-down in the progression of handicap will be monitored in a multicentre, placebo-controlled RCT with 338 patients with de novo PD (169 patients per arm).

They will be assigned to receive either DFP (15 mg/kg bis in die (BID)) or placebo. Based on the two pilot studies, the optimal dose of 30 mg/kg/day will be used.

A 9-month treatment period (period 1) will be followed by a 1-month post-treatment monitoring period (period 2), in order to assess the disease-modifying effect in the absence of a symptomatic effect (i.e. an effect of Inhibition of Catechol-O-Methyl Transferase (ICOMT) activity on dopamine metabolism) of DFP (versus placebo).

The project will run for 60 months and we shall address:

(i) the risk/benefit balance of this new disease-modifying treatment strategy for PD.

(ii) surrogate and theranostic biomarkers of efficacy and safety.

(iii) health economics and societal impacts.

Primary and Secondary Outcomes

For the risk/benefit balance, the primary efficacy criterion will be the total score on the Movement Disorders Society- Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which encompasses motor handicaps and non-motor handicaps (i.e. cognition and behaviour) and activities of daily living.

The secondary criteria will include the separate analysis of the MDS-UPDRS subscale scores, quality of life, personal autonomy, safety criteria, and biomarkers of efficacy and safety.

The surrogate and theranostic biomarkers will include:

Magnetic resonance imaging (MRI), i.e. indirect measurements of iron with an R2* sequence
Transcranial ultrasound (i.e. indirect measurements of iron via the hyperechogenicity of substantia nigra).
Dopamine transporter SPECT imaging (¹²³I-FP-CIT, DATscan®)
Biochemical biomarkers (in blood and cerebrospinal fluid (CSF)).
Pharmacogenetic markers (i.e. ceruloplasmin genotypes for the disease-modifying effect of iron chelation and COMT genotypes for the symptomatic action of DFP; Grolez et al., 2015).

Linking to other projects and health economics

Moreover, by taking advantage of collaborations and involvement in other European studies, we shall assess DFP's impact and the prognostic value of biomarkers obtained from large-scale, on-going studies.

This will increase the scientific impact and dissemination of our study and limit the risk of failure and negative results.

Finally, the health economics and societal impacts will be monitored. We shall concomitantly analyse the drug's impact on health economics aspects and the PD patients' and caregivers' quality of life via questionnaires and the continuous quantitative monitoring of PD-associated handicaps in the home environment (i.e., bradykinesia, gait and balance, tremor, sleep) using the SENSE PARK device (previously developed in the frame of FP7).

A number of previous studies already suggest that deferiprone (DFP), as a conservative iron chelation approach, might give some benefits in Parkinson's Disease.

Our previous preclinical, translational and pilot clinical studies (Devos et al, 2014) have demonstrated the following about iron chelation with DFP:

induced greater neuroprotection in cell models (dopaminergic neurons: LHUMES model, patients’ lymphocytes) than deferoxamine (used as a reference iron chelator) through a powerful antioxidant effect.
reduced regional siderosis of the brain and the motor handicap in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin mouse model.
reduced regional siderosis of the brain in PD patients.
reduced motor handicap of PD patients (possibly through central and peripheral inhibition of catechol-O-methyl transferase (ICOMT))in a double-blind, placebo-controlled study in 40 patients.
slowed the progression of motor handicap in a pilot study in early-stage PD patients (thus suggesting a disease-modifying effect) in a double-blind, placebo-controlled study in 40 patients with a delayed start paradigm.
had a good safety profile, although weekly blood counts are required during the first six months to detect the (reversible) neutropenia that typically occurs in 2-3% of treated patients.

Interestingly, these clinical results were recently supported by another independent pilot study on 18 PD patients, which showed a reduction in brain iron overload and a better clinical effect for DFP at 30 mg/kg/day than for placebo and DFP at 20 mg/kg/day (Dexter et al., publication in progress).

Thus, the two pilot studies have been used to calculate the required sample size to lead our project based upon a large randomised clinical trial to demonstrate this new therapeutic concept.

Overview

FairPark II is a major EU-funded research project that will primarily investigate the effects of an iron chelation therapy on the progression of handicap in Parkinson's disease.

The project will run for five years (2015 - 2020) and will see 15 partners collaborate on a range of investigations including a multicentre clinical trial of the therapy in Parkinson's disease patients.

The full title of the project is: "Conservative iron chelation as a disease-modifying strategy in Parkinson's disease: a multicentric, parallel group, placebo-controlled, randomized clinical trial of deferiprone."

Background

Parkinson’s disease (PD) is a major, chronic, non-communicable disease and the 2nd most frequent neurodegenerative disorder worldwide.

Excess iron is primarily detected in the substantia nigra pars compacta, where dopaminergic neurons are exposed to high levels of oxidative stress produced by mitochondrial disorders and dopamine metabolism.

Our previous preclinical, translational and pilot clinical studies demonstrated that novel iron chelation therapy with the prototypic drug deferiprone (DFP)

induces neuroprotection in cell models of PD via a powerful antioxidant effect,
reduces regional siderosis of the brain,
reduces motor handicap via inhibition of catechol-o-methyl transferase, and
slows the progression of motor handicap in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model and in early PD patients.

Clinical Trial - Aims

This project now seeks to demonstrate that conservative iron chelation therapy with moderate-dose DFP (30 mg/kg/day) slows the progression of handicap in de novo PD patients while not affecting systemic parameters. The 9-month, parallel-group, randomized, placebo-controlled, multicentre trial will be followed by a 1-month wash-out period.

Primary and Secondary Outcomes

The primary efficacy criterion will be the change in motor and non-motor handicap scores on the Total Movement Disorders Society Unified Parkinson’s Disease Rating Scale to identify disease-modifying and symptomatic effects.

The secondary efficacy criterion will be the change in score between baseline and 40 weeks (i.e. probing the disease-modifying effect only).

Potential surrogate radiological and biological biomarkers, health economics and societal impacts will also be assessed.

Who is involved?

17 national, European and international studies will be linked to the project.

Expected impact

The study results should prompt academic and industrial research on iron chelation and other disease-modifying treatments (which slow down disease progression) in Parkinson's disease and other neurodegenerative diseases.

In short...

You can find out much more about our project and clinical study on this site. We have included details on the context of the project, the background studies, our project strategy and the expected outcomes.
If you are a patient with Parkinson's disease and want to find out more about participating in the study, take a look at our dedicated patient pages.
We have included a detailed FAQ that we hope will answer any questions you might have about the project and study.
Want to know who we are? You can find out much more about the consortium here.
Latest updates about the project? News and events covers all of that.
Results? When we have them, they will be here.
Want to contact us? Go here.

The Problem

Parkinson’s disease (PD) is a common, chronic, fast-progressing, non-communicable disease. As the second most frequent neurodegenerative disorder worldwide, PD affects millions of people - about 1% of the over-60s. It is estimated that the prevalence will at least double by 2030.

None of the currently available drugs can slow down the dramatic progression of the motor handicap (e.g. falls) and non-motor handicap (dementia), which generally lead to institutionalization and death.

Today, most patients with PD irremediably progress to a severe state of dependence. In Europe, the cost of PD was estimated to be at least €13.9 billion in 2010. The huge and increasing socio-economic impact of PD and the immense emotional burden placed on patients and their caregivers represent a great challenge to society.

There is an urgent need for a “game-changer” strategy, with the development of disease-modifier treatments with neuroprotective effects that can help to avoid this dramatic situation in PD and, more generally, in other neurodegenerative diseases with common physiopathological mechanisms.

Iron and Oxidative Stress in PD

For many years, the excess oxidative stress related to mitochondriopathy has been considered as one of the main mechanisms involved in cell death (Schapira and Patel, 2014). Oxidative stress is exacerbated by free iron. Chelation of this free iron has powerful antioxidant properties known to dramatically increase cell survival.

However, we reasoned that to develop this therapeutic approach in humans, chelation strategies that target local and regional iron overload in the brain will necessarily need to avoid systemic iron depletion via the redistribution of iron to endogenous acceptors (i.e. in order to prevent harmful systemic metal loss).

This is the new concept of “conservative iron chelation” (Cabantchik et al. 2013).

Pilot studies

We recently demonstrated for the first time the feasibility, efficacy and acceptability of the conservative iron chelation approach in pilot translational studies in PD with a prototype drug: deferiprone (DFP) (in the FAIR-PARK-I project that was led by FAIR-PARK-II's coordinator, David Devos and funded by French Ministry of Health).

In this pilot translational study, conservative iron chelation was assessed in cell-based models, corroborated in an animal model and then translated into a clinical setting (Devos et al., 2014).

Repositioning of an approved drug

DFP is approved for treating systemic iron overload in transfused patients with thalassemia. DFP has been on the EU market since 1999, with a favourable risk/benefit balance at 100 mg/kg/day.

We shall adopt a repositioning strategy by using DFP at a lower dose of 30 mg/kg/day in this new indication for local iron overload in PD. DFP will be the first-in-class drug for this novel therapeutic strategy.

Expected outcomes

At present, no neuroprotective drugs are available.

If DFP treatment were associated with significant slower disease progression, it would be the first non-dopaminergic drug to have a proven disease-modifying effect in PD.

Indeed, if our academic proof-of-concept study is successful, this new approach could be offered to the population of patients with PD as a whole. This would represent a considerable advance for patients and would have a huge socio-econoomic impact.