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  • Periodic Reporting for period 1 - FAIR-PARK-II (Conservative iron chelation as a disease-modifying strategy in Parkinson’s disease: a multicentric, parallel-group, placebo-controlled, randomized clinical trial of deferiprone)

FAIR-PARK-II Report Summary

Project ID: 633190
Funded under: H2020-EU.3.1.3.

Periodic Reporting for period 1 - FAIR-PARK-II (Conservative iron chelation as a disease-modifying strategy in Parkinson’s disease: a multicentric, parallel-group, placebo-controlled, randomized clinical trial of deferiprone)

Reporting period: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

Parkinson’s disease (PD) the 2nd most frequent neurodegenerative disorder worldwide. Excess iron is 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 pilot clinical studies demonstrated that novel iron chelation therapy with the prototypic drug deferiprone (DFP) (i) induces neuroprotection in cell models of PD, (ii) reduces regional siderosis of the brain, (iii) reduces motor and (iv) slows the progression of motor handicap. This project now seeks to demonstrate that DFP slows the progression of handicap in de novo PD patients while not affecting systemic parameters. The primary efficacy criterion will be the change in motor and non motor handicap scores on the Total MDS-UPDRS to identify disease-modifying and symptomatic effects. Potential surrogate radiological and biological biomarkers, health economics and societal impacts will be assessed.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During WP1 a management and coordination framework was implemented for the project, in order to orientate all activities towards the objectives, and to ensure their fulfilment within time plan and budget.
The aim of WP2 is to set up the clinical trial by developing and finalizing the clinical protocol and study documentation. Submissions to competent Authorities and Ethical committees have been done. A monitoring plan has been provided to all sites. Drug procurement, packaging and distribution are provided by ApoPharma. Standard operating procedures were created and are efficient.
In WP3 the final selection European expert centres for patient recruitment was performed.
Almost all investigators have been trained for all rating instruments Initiation visits have been performed in all French centers and in 8 European Centers. Tools are in place (eCRF and IWRS) and procedures have been performed to maximize the recruitment (networks, flyers, patient webpage). Advice and support to clinical sites are provided. As of today, the recruitment is going well (73 patients ad 12 active centers).
In WP4, the implementation of the FAIRPARKII MRI protocol at each selected site has been completed. Centers taking part in the Datscan® and MRI substudy, have received also instructions for a standardized acquisition protocol anda technical manual describing the procedures. All SPECT scans have been quality checked.
A teaching course for Transcranial Ultrasound was organized.
The Biological Resource Center of CHRUL designed the technical feasibility survey for the qualification of the centers. The standardized sampling kits is designed. The laboratory is developed. The centralization of biological samples has begun.
Regarding the analysis of “omics” biomarkers of iron metabolism for the effect of DFP and PD progression, some preliminary experiments for the processing of this WP were performed.
WP5 is providing a health economic evaluation to evaluate the resource use, costs and to calculate the cost-effectiveness of the treatment. The SENSE-PARK device has been presented to centers selected for SENSE-PARK substudy during a training workshop.
In WP 6, FAIR PARK II logo, graphic standard, brochures, flyers and public website were created and are available.
The protocol is registered on the and Fox Trial Finder website, to favor patient recruitment. Key target groups for future communication activities are identified.
Publication Policy and dissemination strategy are also available. In order to raise awareness of IP issues an IP presentation was organized. A list of major events was also presented to present the project and disseminate results. Finally, the setup of the study is compliant with all ethical aspects described in WP7.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

I/ Progress beyond the state of the art: FAIR-PARK II's main objective is to demonstrate the validity of the novel therapeutic concept of conservative iron chelation for a disease-modification in PD.
A- Evaluation of the disease-modifying effect
We expect to demonstrate the validity of the first non-dopaminergic, disease-modifying therapeutic strategy in PD with a positive risk/benefit balance

B- Impact of DFP treatment on the autonomy, quality of life and health economics
We have integrated QoL and health economic assessments into our clinical development from the outset. We use PDQ 39 questionnaire, for assessing quality of life of PD patients and caregivers.
The continuous assessment of PD-relevant domains at home (FP7, SENSE-PARK) is a guideallowing a true picture of the state of the patients. A positive difference would mean that benefit is clearly felt by the patients and the caregivers.
In order to prove the treatment's profound impact, we have set up WP5 to analyse health economics aspect

C- To make iron chelators available to PD patients more rapidly
We seek to promote the clinical development and the regulatory approval of DFP. This study is conducted with ApoPharma as a partner, this collaboration will help to make DFP available to PD patients within 10 years.

D- Surrogate biomarkers and theranostic biomarkers
We want to develop surrogate biomarkers by analysing a large range of biological, radiological and genetic biomarkers. The diagnostic and prognostic value of the biomarkers is assessed in order to designate clusters of patients as a function of the rate of disease progression.
An analysis of theranostic biomarkers could help the choice of treatment after only few months, i.e. long before seeing a clinical impact.
Several biomarkers could change the clinical management of PD and facilitate assessment of the risk/benefit balance for treatment decisions. For instance, pharmacogenetic biomarkers would also help to interpret (and thus to avoid) any efficacy and safety problems with DFP.).
E- European clinical networks for neurodegenerative diseases
This project will promote an efficient European clinical trial network for PD and movement disorders for forthcoming European studies.
Collaboration with the other European studies (NILVAD, SOPHIA, PharmaCOG, etc.) will also reinforce European networks for PD and other neurodegenerative diseases.

II/ Expected impacts:
- A new therapeutic strategy for slowing down the progression of Parkinson’s disease: This new strategy will be ready for further development in PD and other neurodegenative diseases.
- The aim of FAIR PARK II project is to analyze conservative iron chelation and analyses the effect of conservative chelation on iron storage. The project may identified biomarkers of efficacy with a view of personalized care.
Slowing the progression of PD is one of the most important challenges for the society.We hope to delay severe handicap, institutionalization and early death for younger patients with highly favorable socio-economic consequences.

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