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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - FAIR-PARK-II (Conservative iron chelation as a disease-modifying strategy in Parkinsonâ€™s disease: a multicentric, parallel-group, placebo-controlled, randomized clinical trial of deferiprone)

Teaser

Summary

Parkinsonâ€™s disease (PD) the 2nd most frequent neurodegenerative disorder worldwide. Excess iron is detected in the substantia nigra, where dopaminergic neurons are exposed to high levels of oxidative stress.
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 handicap 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 Movement disorder society- unified Parkinsonâ€™s disease rating scale (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

In WP1 the management and coordination framework was implemented to ensure their fulfilment within time plan and budget. In WP2 the clinical trial is set up by developing and finalizing the clinical protocol and study documentation. FAIR PARK II study protocol has been updated, the current version of protocol is V7 dated on 14/10/2019. This version has been submitted and approved by the Voluntary Harmonization Procedure (initial submission: 09/07/2019 and positive opinion: 24/10/2019). All clinical trial units of the ECRIN network have submitted the updated protocol to their national competent authority and national ethical committee and adapted the protocol and study documentation according to their national regulation when it was needed. As of 31/10/2019, the responses of the competent authorities and the ethical committees are pending. Study documentation is reviewed and updated on regular basis. Drug procurement, packaging and distribution are provided by ApoPharma. SOPs were created and are efficient. In WP3, the sponsor selected 24 European expert centres, to perform patientsâ€™ recruitment. Almost all investigators have been trained for all rating instruments. Initiation visits have been performed in every centres. Tools are in place (eCRF and IWRS) and procedures to maximize the recruitment are still running. FCRIN and the sponsor schedule teleconferences with each sites to answer questions or discuss any issue, with a particular focus on the recruitment and advice to avoid drop out. Due to the high dropout rate, the sponsor has raised the recruitment objective to 372, to maintain the statistical power in the analysis. The recruitment period has been expanded until December 2019, and approved by the VHP. In WP4, the MRI protocol has been validated in 14 centres and out of 216 baseline MRI datasets 146 termination visit MRI data have been received and quality controlled. A total of 310 SPECT scans have also been checked for quality with only 2 significant protocol deviations. Optimized reconstruction parameters have been developed to minimize between centre variability. The ultrasound substudy has enrolled a total of 23 subjects. All technical procedures for genotyping the stored DNA samples are in place and analyses are expected to begin at the end of 2019 and wet biomarker analyses of the CSF are ongoing. WP5 provides a health economic evaluation to evaluate the resource use, costs and health status in order to calculate the cost-effectiveness of the treatment. The CRF has been implemented in the study protocol. The compilation of the basic cost data for the different countries is almost finished, the analysis of the clinical trial will start when the clinical data are available. The SENSE-PARK device has been presented to centers selected for the substudy. All the centres have received sensor sets which they have handed out to the participants willing to contribute to this substudy. The coordinating study centre in Kiel is in contact with the participating centres, provides them with information, study material (sensor sets, diaries, user manuals) and gives technical support. CAU has already developed the database and started with first analyses demonstrating the usability and efficacy of the database and the collected data. In WP6, the protocol is registered on the ClinicalTrials.gov and Fox Trial Finder website. Key target groups for communication activities are identified. A twitter page has been published and communication with networks of neurologists, liberal practitioners is strong. Publication Policy and dissemination strategy are available.

Final results

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 quality of life (QoL) and health economic assessments into our clinical development from the outset. Parkinsonâ€™s disease questionnaire (PDQ39) and SENSE PARK are used to collect these data. A positive difference would mean that benefit is clearly felt by the patients and the caregivers.

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 Parkinsonâ€™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.