The Placebo Response in Double-Blind Randomised Trials Evaluating Regenerative Therapies for Parkinson’s Disease: A Systematic Review and Meta-Analysis

Article type: Systematic Review

Authors: Polgar, Stephen^a | Buultjens, Melissa^a | Wijeratne, Tissa^b | Finkelstein, David I.^c | Mohamed, Sheeza^d | Karimi, Leila^{e; f; *}

Affiliations: [a] School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia | [b] Department of Neurology, Western Health, VIC, Australia | [c] Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia | [d] School of Life Sciences, La Trobe University, Melbourne, VIC, Australia | [e] School of Psychology, RMIT University, Melbourne, VIC, Australia | [f] The Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Monash University, Melbourne, VIC, Australia

Correspondence: [*] Correspondence to: Leila Karimi, The Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Monash University, Melbourne, VIC, Australia. E-mail: [email protected].

Abstract: In the field of stem cell technologies, exciting advances are taking place leading to translational research to develop cell-based therapies which may replace dopamine releasing neurons lost in patients with Parkinson’s disease (PD). A major influence on trial design has been the assumption that the use of sham operated comparator groups is required in the implementation of randomised double-blind trials to evaluate the placebo response and effects associated with the surgical implantation of cells. The aim of the present review is to identify the improvements in motor functioning and striatal dopamine release in patients with PD who have undergone sham surgery. Of the nine published trials, there was at the designated endpoints, a pooled average improvement of 4.3 units, with 95% confidence interval of 3.1 to 5.6 on the motor subscale of the Unified Parkinson’s Disease Scale in the ‘OFF’ state. This effect size indicates a moderate degree of improvement in the motor functioning of the patients in the sham surgical arms of the trials. Four of the nine trials reported the results of 18F-Fluorodopa PET scans, indicating no improvements of dopaminergic nigrostriatal neurones following sham surgery. Therefore, while the initial randomised trials relying on the use of sham operated controls were justified on methodological grounds, we suggest that the analysis of the evidence generated by the completed and published trials indicates that placebo controlled trials are not necessary to advance and evaluate the safety and efficacy of emerging regenerative therapies for PD.

Keywords: Parkinson’s disease, regenerative therapy, cell therapy, gene therapy, sham surgery, stem cells, placebo response

DOI: 10.3233/JPD-212610

Journal: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 759-771, 2022