Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease
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Published:2022-12-01
Issue:12
Volume:79
Page:1232
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ISSN:2168-6149
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Container-title:JAMA Neurology
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language:en
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Short-container-title:JAMA Neurol
Author:
Stevens Kara N.12, Creanor Siobhan3, Jeffery Alison1, Whone Alan4, Zajicek John5, Foggo Andy6, Jones Ben3, Chapman Rebecca1, Cocking Laura7, Wilks Jonny8, Webb Doug9, Carroll Camille1, Inches Jemma10, Underwood Donna10, Frost Julie10, James Ali10, Schofield Christine10, James Rob10, O’Reilly Clare10, Sheridan Ray10, Statton Sarah10, Goff Anita10, Russell Tamlyn10, Whitcher Alison10, Craw Sarah10, Lewis Alison10, Sophia Rani10, Amar Khaled10, Hernandez Rochelle10, Pitcher Alison10, Carvey Samantha10, Hamlin Ruth10, Lyell Veronica10, Aubry Louisa10, Carey Gillian10, Coebergh Jan10, Mojela Idah10, Molloy Sophie10, Berceruelo Bergaz Yolanda10, Camera Bintou10, Campbell Philip10, Morris Huw10, Samakomva Tinashe10, Schrag Anette10, Fuller Sarah10, Misbahuddin Anjum10, Parker Laura10, Visentin Elisa10, Gallehawk Stephanie10, Rudd Jacqueline10, Singh Sudhir10, Wilson Sarsha10, Creven Julie10, Croucher Yvonne10, Tluk Susan10, Watts Paul10, Hargreaves Simone10, Johnson Danielle10, Worboys Lucy10, Worth Paul10, Brooke Judith10, Kobylecki Christopher10, Parker Victoria10, Johnson Linda10, Joseph Rosane10, Melville Julie10, Raw Jason10, Birt Janice10, Hare Marianne10, Shaik Saifuddin10, Alty Jane10, Cosgrove Jeremy10, Burn David10, Green Angela10, McNichol Ann10, Pavese Nicola10, Pilkington Helen10, Price Maria10, Walker Kathryn10, Chaudhuri Ray10, Podlewska Aleksandra10, Reddy Prashanth10, Trivedi Dhaval10, Bandmann Oliver10, Clegg Rosie10, Cole Grace10, Emery Anna10, Dostal Vaclav10, Graham Jodie10, Keshet-Price Jocelyn10, Mamutse Godwin10, Miller-Fik Alex10, Wiltshire Alison10, Wright Catherine10, Dixon Kathryn10, Abdelhafiz Ahmed10, Rose Joanne10,
Affiliation:
1. Faculty of Health, University of Plymouth, Plymouth, United Kingdom 2. Exploristics Ltd, Belfast, United Kingdom 3. College of Medicine and Health, University of Exeter, Exeter, United Kingdom 4. Bristol Medical School, University of Bristol, Bristol, United Kingdom 5. School of Medicine, Medical and Biological Sciences, University of St Andrews, St Andrews, United Kingdom 6. School of Biological and Marine Sciences, Faculty of Science and Engineering, University of Plymouth, Plymouth, United Kingdom 7. NIHR BioResource, University of Cambridge, Cambridge, United Kingdom 8. MAC Clinical Research, Blackpool, United Kingdom 9. Bristol Trials Centre, University of Bristol, Bristol, United Kingdom 10. for the PD STAT Study Group
Abstract
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
Publisher
American Medical Association (AMA)
Subject
Neurology (clinical)
Cited by
8 articles.
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