BACKGROUND: The outcome of clinical trials in neurodegeneration can be highly uncertain due to the presence of a strong placebo effect. OBJECTIVES: To develop a longitudinal model that can enhance the success of future Parkinson's disease trials by quantifying trial-to-trial variations in placebo and active treatment response. METHODS: A longitudinal model-based meta-analysis was conducted on the total score of Unified Parkinson's Disease Rating Scale (UPDRS) Parts 1, 2, and 3. The analysis included aggregate data from 66 arms (observational [4], placebo [28], or investigational-drug-treated [34]) from 4 observational studies and 17 interventional trials. Inter-study variabilities in key parameters were estimated. Residual variability was weighted by the size of study arms. RESULTS: The baseline total UPDRS was estimated to average at 24.5 points. Disease score was estimated to worsen by 3.90 points/year for the duration of the treatments; whilst notably, arms with a lower baseline progressed faster. The model captured the transient nature of the placebo response and sustained symptomatic drug effect. Both placebo and drug effects peaked within 2 months; although, 1 year was needed to observe the full treatment difference. Across these studies, the progression rate varied by 59.4%, the half-life for offset of placebo response varied by 79.4%, and the amplitude for drug effect varied by 105.3%. CONCLUSION: The longitudinal model-based meta-analysis describes UPDRS progression rate, captures the dynamics of the placebo response, quantifies the effect size of the available therapies, and sets the expectation of uncertainty for future trials. The findings provide informative priors to enhance the rigor and success of future trials of promising agents, including potential disease modifiers. © 2023 GSK. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.