Objective: To show how the estimand framework can be used to improve design of clinical trials testing treatments in early-stage Parkinson’s disease (PD).

Background: The new ICH E9 (R1) addendum on “Estimands and Sensitivity Analyses in Clinical Trials” framework was developed to overcome limitations of current approaches for the design, conduct, analysis and interpretation of clinical trials (e.g. intention-to-treat vs. per-protocol analysis) and handling intercurrent events, e.g. change in concomitant medications, rescue medication or treatment discontinuation. Clinical trials in Type 2 diabetes and chronic obstructive pulmonary disease populations are now designed using this framework.^1,2 There is a pressing need for the PD community to embrace this methodology.

Method: Five estimand framework attributes aim to improve clinical trial design (Figure 1). Here, their potential use in PD is described: 1) the treatments of condition of interest and comparison should be clearly specified; 2) the population comprises patients targeted by the clinical question; 3) the variable/endpoint is collected for each patient to address the clinical question of interest; 4) the population-level summary is the basis for comparing treatment conditions; and 5) handling of intercurrent events affecting the observation of the treatment effect.

Results: A case study for early-stage PD populations is shown (e.g. treatment-naive), where different estimand strategies were applied to clinical endpoints in the handling of the intercurrent event of starting/increasing symptomatic therapy (Figure 2). The most common strategies to analyse the outcome of interest include: 1) treatment-policy strategy (regardless of the occurrence of the intercurrent event); 2) hypothetical strategy (scenario which assumes that the intercurrent event did not occur); and 3) composite strategy (intercurrent event incorporated into the outcome variable). Moreover, the different strategies link to different clinical questions and advocate the use of estimands in the objectives section of the protocol to increase study reporting transparency.

Conclusion: The estimand framework is a powerful tool for designing clinical trials in PD that brings transparency to the objectives of the study, increases alignment across stakeholders, and provides clarity of treatment effects targeted in trials to overcome masking effects of starting/increasing symptomatic therapy.

References: 1. Aroda VR, et al. Diabetes Obes Metab. 2019; 21:2203–2210.
2. Darken P, et al. Pharm Stat. 2020; 19(5):626–635.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/improving-the-design-of-clinical-trials-in-early-stage-parkinsons-disease-by-using-the-estimand-framework/