In a planned superiority analysis, the between-group difference of the 12-month change in MDS-UPDRS part III score was not statistically significant.
Findings from a randomized, double-blind, placebo-controlled study showed that simvastatin, a statin used to treat high cholesterol and triglyceride levels, was futile as a disease-modifying therapy for patients with moderate forms of Parkinson disease (PD).1
The prespecified primary outcome, 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score, on average, worsened by an additional 1.52 points (2-sided 80% CI, –0.77 to 3.80) for those on simvastatin compared with placebo. According to the study investigators, these findings provide no evidence to support a phase 3 trial.
For the trial, lead author Kara N. Stevens, PhD, MSc, statistician, Exploristics, and colleagues recruited 235 participants aged 40 to 90 years with 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. Patients were allocated 1:1 to either simvastatin or matched placebo through a computer-generated random sequence, stratified by Hoehn and Yahr stage.
In the simvastatin arm, participants entered a 1-month phase of 40 mg daily dosing, following by 23 months of 80 mg daily doses, before a 2-month washout period. A total of 216 patients progressed to the 80-mg dose, and 178 of them were included in the primary outcome analysis. At 24 months, the mean change in MDS-UPDRS part III scores was 2.4 (SD, 11.2) in the placebo group and 4.5 (SD, 12.2) in the simvastatin group. Above all, the test of the futility hypothesis indicated that simvastatin was futile as a treatment for PD (P = .006).
Stevens et al concluded that, "The relationship between PD and cardiovascular risk factors, including cholesterol level, is complicated. A better understanding of the interplay between the potential protective effect of statins, the potential negative effect of low cholesterol level, the stage of disease, and relevant comorbidities might inform whether, when, and in whom statins merit further investigation as disease-modifying therapy in PD."
Throughout the study, there were no serious adverse events (AEs) that occurred while patients were on 40-mg simvastatin; however, there were 37 serious AEs among those taking high-dose simvastatin and 37 serious AEs among those not taking active treatment (ie, 0 mg of simvastatin or placebo), of which 8 were after simvastatin discontinuation of at least 8 days. Three participants, all having discontinued simvastatin or taking placebo, experienced death as a result from their serious AE.
In total, 214 of the 321 AEs identified in the trial were related to simvastatin. The proportion of related AEs associated with known adverse effects increased as the dose of simvastatin increased (0 mg, 54.4%; 40 mg, 72.7%; 80 mg, 85.0%). Additionally, the most frequently observed common AE effect across all groups was myalgia (0 mg, 36.3%; 40 mg, 45.5%; 80 mg, 67.5%). Notably, 6 of the 171 AEs reported by participants not taking active treatment occurred following simvastatin discontinuation of at least 6 days.
The a priori repeated measures model of MDS-UPDRS part III score while not taking medication, under superiority assumptions, showed a mean between-group difference of 2.74 (95% CI, –0.11 to 5.58; P = .06) at 12 months and 1.17 (95% CI, –1.78 to 4.13; P = .43) at 24 months. This prompted a post hoc blinded futility analysis of the 12-month change in MDS-UPDRS part III score, which indicated that the simvastatin group had deteriorated, on average, by 2.74 points (80% CI, 0.75-4.35; P < .001) more than the placebo group. However, in a (planned) superiority analysis, the between-group difference of the 12-month change in MDS-UPDRS part III score was not statistically significant (mean difference in changes, 2.74; 95% CI, −0.38 to 5.85; P = .09).
On secondary outcomes, there were no statistically significant between-group differences at 12 or 24 months, except for difference in levodopa-equivalent daily dose at 12 months, which was 83.4 mg (95% CI, 27.1-139.7; P = .004) lower than in the placebo group. Of note, the expected reductions in total cholesterol level and total/HDL cholesterol ratio in the simvastatin group were observed.