A Comparison of Estimand and Estimation Strategies for Clinical Trials in Early Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a chronic, degenerative neurological disorder. PD cannot be prevented, slowed, or cured as of today but highly effective symptomatic treatments are available. We consider relevant estimands and treatment effect estimators for randomized trials of a novel treatment which aims to slow down disease progression versus placebo in early, untreated PD. A commonly used endpoint in PD trials is the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which is longitudinally assessed at scheduled visits. The most important intercurrent events (ICEs) which affect the interpretation of the MDS-UPDRS are study treatment discontinuation and initiation of symptomatic treatment. Different estimand strategies are discussed; Hypothetical or treatment policy strategies, respectively, for different types of ICEs seem most appropriate in this context. Several estimators based on multiple imputation which target these estimands are proposed and compared in terms of bias, mean-squared error, and power in a simulation study. The investigated estimators include methods based on a missing-at-random (MAR) assumption, with and without the inclusion of time-varying ICE-indicators, as well as reference-based imputation methods. Simulation parameters are motivated by data analyses of a cohort study from the Parkinson’s Progression Markers Initiative (PPMI).

KEYWORDS:

• Clinical trials
• Estimands
• Missing data
• Multiple imputation
• Parkinson’s disease
• Reference-based methods

Supplementary Materials

The supplementary materials describe data analyses of a cohort study from the Parkinson’s Progression Markers Initiative (PPMI) (Marek et al. 2011) which informed the simulation study.

Acknowledgments

We thank Annabelle Monnet and Judith Anzures-Cabrera from Roche and Khadija Rantell and Sabine Lenton from the UK Medicines and Healthcare products Regulatory Agency (MHRA) for helpful comments on an earlier draft of the manuscript which helped to improve the final presentation.

Data Availability Statement

Data for the supplementary analyses which informed the simulation study were obtained from the Parkinson’s Progression Markers Initiative (PPMI) (www.ppmi-info.org/, download of data on 30 Nov2020). Qualified researchers may obtain access to the full breadth of individual-level PPMI data via www.ppmi-info.org/access-data-specimens/download-data.

Disclosure statement

The authors report that there are no competing interests to declare.

Additional information

Funding

PPMI—a public-private partnership—is funded by the Michael J. Fox Foundation for Parkinson’s Research funding partners 4D Pharma, Abbvie, Acurex Therapeutics, Allergan, Amathus Therapeutics, ASAP, Avid Radiopharmaceuticals, Bial Biotech, Biogen, BioLegend, Bristol-Myers Squibb, Calico, Celgene, Dacapo Brain Science, Denali, The Edmond J. Safra Foundaiton, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, and Voyager Therapeutics.