Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease
Authors: Stevens Kara N. , Creanor Siobhan , Jeffery Alison , Whone Alan , Zajicek John , Foggo Andy , Jones Ben , Chapman Rebecca , Cocking Laura , Wilks Jonny , Webb Doug , Carroll Camille ,   PD STAT Study Group, Inches Jemma , Underwood Donna , Frost Julie , James Ali , Schofield Christine , James Rob , O’Reilly Clare , Sheridan Ray , Statton Sarah , Goff Anita , Russell Tamlyn , Whitcher Alison , Craw Sarah , Lewis Alison , Sophia Rani , Amar Khaled , Hernandez Rochelle , Pitcher Alison , Carvey Samantha , Hamlin Ruth , Lyell Veronica , Aubry Louisa , Carey Gillian , Coebergh Jan , Mojela Idah , Molloy Sophie , Berceruelo Bergaz Yolanda , Camera Bintou , Campbell Philip , Morris Huw , Samakomva Tinashe , Schrag Anette , Fuller Sarah , Misbahuddin Anjum , Parker Laura , Visentin Elisa , Gallehawk Stephanie , Rudd Jacqueline , Singh Sudhir , Wilson Sarsha , Creven Julie , Croucher Yvonne , Tluk Susan , Watts Paul , Hargreaves Simone , Johnson Danielle , Worboys Lucy , Worth Paul , Brooke Judith , Kobylecki Christopher , Parker Victoria , Johnson Linda , Joseph Rosane , Melville Julie , Raw Jason , Birt Janice , Hare Marianne , Shaik Saifuddin , Alty Jane , Cosgrove Jeremy , Burn David , Green Angela , McNichol Ann , Pavese Nicola , Pilkington Helen , Price Maria , Walker Kathryn , Chaudhuri Ray , Podlewska Aleksandra , Reddy Prashanth , Trivedi Dhaval , Bandmann Oliver , Clegg Rosie , Cole Grace , Emery Anna , Dostal Vaclav , Graham Jodie , Keshet-Price Jocelyn , Mamutse Godwin , Miller-Fik Alex , Wiltshire Alison , Wright Catherine , Dixon Kathryn , Abdelhafiz Ahmed , Rose Joanne 
Published: October 2022

ImportanceCurrent 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.ObjectiveTo determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD.Design, Setting, and ParticipantsThis 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.InterventionsParticipants 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 MeasuresThe 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.ResultsOf 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 RelevanceIn 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 RegistrationISRCTN Identifier: 16108482