Objective: Design an early CT program to detect a neuroprotective signal in PD.

Background: Attempts to develop PD modifying therapies have been largely disappointing so far. Many incriminating factors impacting early clinical trial designs have been identified: heterogeneity of disease and progression rate, slowly evolving symptoms, absence of objective and validated progression biomarker with endpoints based on subjective clinical scores only, and finally a placebo effect that can be marked and long-lasting.

Method: To overcome some of these challenges in the First-in-patient (FIP) study of a novel innovative potential treatment, an observational trial is added. It consists in the evaluation of a cohort of patients responding to the enrolment criteria of the FIP trial, to monitor their natural history over 12-18 months. At the end of this observation period, patients are offered to join the FIP trial. The number of patients participating in this longitudinal exploration is estimated to account for potential drop-outs.

Results: PARK001 is an ongoing longitudinal exploratory prospective evaluation of the clinical evolution of a cohort of PD patients, with disease onset not older than 6 years, evidence of dopamine deficit at DAT-scan, fluctuations and/or dyskinesia, and univoqual response to L-DOPA. Patients disease progression is evaluated every 6 months through usual clinical (MDS-UPDRS, RDysRS, PDQ39, LEDD calculation) and neuropsychological evaluations, as well as MRI exploratory sequences such as neuromelanin, iron and DTI, performed at baseline and 1 year after. For patients joining the FIP trial, the PARK001 last evaluation point will be used as the baseline in the subsequent study. In the FIP trial, in addition to the primary objective of evaluating safety, identical pharmacodynamic endpoints will be measured allowing comparison of the disease progression slope before and after treatment.

Conclusion: Evaluating individual patient trajectory and progression based on clinical and imaging parameters prior to the FIP trial of a novel therapy should increase the statistical power of a small size PD early clinical trial. It will also allow to assess exploratory imaging biomarkers. Interestingly, from a drug development perspective, this strategy offers a significant time effective advantage: this exploration can be conducted in parallel to preclinical development activities and should enable a faster enrollment in the FIP.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/increasing-chances-of-detecting-a-neuroprotective-signal-in-phi-ii-pd-clinical-trials/