Objective: To further understanding of the diversity and impact of trial design choices in trials of disease modifying therapy (DMT) in Parkinson’s disease (PD).

Background: No trial of a DMT in PD has successfully identified new treatments. Population heterogeneity, efficacious symptomatic therapy and lack of sensitive, objective outcome measures are challenges which diverse trial designs have attempted to mitigate.

Method: We developed a PICOS framework to identify unpublished, planned and published randomised controlled Parkinson’s trials with at least one efficacy measure investigating disease modifying interventions. We searched Medline, Web of Science, Cochrane and ClinicalTrials.gov (search date 01 Nov 21; 7865 records identified). Phase 1 trials, conference abstracts, records not in English language and studies not published after 5 years from study end date were excluded. Study design choices, eligibility criteria and outcome measures of 155 studies were extracted. Logistic linear regression analysis was used to investigate changes in design features over time.

Results: 142 phase 2 and 13 phase 3 trials were identified. 52 (37%) of phase 2 and 12 (92%) of phase 3 trials selected early-stage PD participants (disease duration ≤ five years, Hoehn and Yahr stage ≤ 2.5 or drug naïve), although eligibility criteria have become more inclusive with regard to disease stage over time (p= 0.0001). Of 92 trials with published results, 60 (65%) either met or partially met their primary endpoint of which 26 (28%) investigated a motor, 7 (8%) investigated a safety/tolerability and 12 (13%) an imaging/biomarker primary outcome. 57 phase 2 trials investigating 44 different interventions reported either full or partial success in phase 2. Only 5 interventions (11%) were followed up in a phase 3 trial of which 0 reported a positive outcome.

Conclusion: Eligibility criteria for neuroprotective PD trials have become more inclusive over the years, despite a rationale for more restrictive inclusion criteria.  Only a minority of interventions showing promise in phase 2 trials have undergone phase 3 evaluation.  Phase 2 trial success is not translated into positive phase 3 outcomes. This comprehensive scoping review will allow us to critically appraise the design of DMT trials for Parkinson’s.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuroprotective-trial-design-methodology-for-parkinsons-a-scoping-review/