Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial

Abstract

Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy.

Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD.

Design, setting, and participants: This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021.

Interventions: Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period.

Main outcomes and measures: The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event.

Results: Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE.

Conclusions and relevance: In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial.

Trial registration: ISRCTN Identifier: 16108482.

Figure 1.. CONSORT Diagram of the PD STAT Study

One participant who did not progress to the high dose was also missing valid primary outcome data. IMP indicates investigational medicinal product; PD, Parkinson disease. ^aMultiple reasons provided for withdrawal.

Figure 2.. Mean Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part III Score by Allocated Group

MDS-UPDRS part III score while not taking medication and mean of the change in MDS-UPDRS part III score from baseline to follow-up time point, including participants who progressed to the high dose at 1 month who had valid outcome data at each time point.