Abstract
BACKGROUND: Disease-modification clinical trials in neurodegenerative disorders have struggled to separate symptomatic effects of putative agents from disease-modification. In response, a variety of clinical trial designs have been developed. A systematic review was undertaken to examine which trial designs have been used in Alzheimer's disease (AD) and Parkinson's disease (PD) to detect disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed to identify novel clinical trial designs used in the past or planned for use in the future. We aimed to critique whether the methods used would have identified true disease-modification. METHODS: MEDLINE, Embase and CENTRAL (1980-2015) were searched to identify papers meriting review in full. ClinicalTrials.gov was searched to identify unpublished or planned randomised controlled trials (RCTs). We included RCTs in PD or AD which aimed to demonstrate the disease-modifying properties of drug therapy and differentiate that benefit from any symptomatic effect. RESULTS: 128 RCTs were finally included: 84 in AD (59 published, 25 unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial designs were applied including long-term follow-up, wash-in and wash-out analyses, randomised delayed-start, the use of time-to-event outcome measures and surrogate disease progression biomarkers. Deficiencies in each of these design strategies, the quantity of missing data in included RCTs and the methods used to deal with missing data, meant that none of the included studies convincingly demonstrated disease-modification. No truly novel clinical trial designs were identified. CONCLUSION: We currently believe that the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.