PMID- 36315128 OWN - NLM STAT- MEDLINE DCOM- 20221214 LR - 20230113 IS - 2168-6157 (Electronic) IS - 2168-6149 (Print) IS - 2168-6149 (Linking) VI - 79 IP - 12 DP - 2022 Dec 1 TI - Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial. PG - 1232-1241 LID - 10.1001/jamaneurol.2022.3718 [doi] AB - 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. FAU - Stevens, Kara N AU - Stevens KN AD - Faculty of Health, University of Plymouth, Plymouth, United Kingdom. AD - Exploristics Ltd, Belfast, United Kingdom. FAU - Creanor, Siobhan AU - Creanor S AD - College of Medicine and Health, University of Exeter, Exeter, United Kingdom. FAU - Jeffery, Alison AU - Jeffery A AD - Faculty of Health, University of Plymouth, Plymouth, United Kingdom. FAU - Whone, Alan AU - Whone A AD - Bristol Medical School, University of Bristol, Bristol, United Kingdom. FAU - Zajicek, John AU - Zajicek J AD - School of Medicine, Medical and Biological Sciences, University of St Andrews, St Andrews, United Kingdom. FAU - Foggo, Andy AU - Foggo A AD - School of Biological and Marine Sciences, Faculty of Science and Engineering, University of Plymouth, Plymouth, United Kingdom. FAU - Jones, Ben AU - Jones B AD - College of Medicine and Health, University of Exeter, Exeter, United Kingdom. FAU - Chapman, Rebecca AU - Chapman R AD - Faculty of Health, University of Plymouth, Plymouth, United Kingdom. FAU - Cocking, Laura AU - Cocking L AD - NIHR BioResource, University of Cambridge, Cambridge, United Kingdom. FAU - Wilks, Jonny AU - Wilks J AD - MAC Clinical Research, Blackpool, United Kingdom. FAU - Webb, Doug AU - Webb D AD - Bristol Trials Centre, University of Bristol, Bristol, United Kingdom. FAU - Carroll, Camille AU - Carroll C AD - Faculty of Health, University of Plymouth, Plymouth, United Kingdom. CN - PD STAT Study Group LA - eng SI - ISRCTN/ISRCTN16108482 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - JAMA Neurol JT - JAMA neurology JID - 101589536 RN - AGG2FN16EV (Simvastatin) SB - IM MH - Humans MH - Female MH - Male MH - *Parkinson Disease/drug therapy/diagnosis MH - Simvastatin/therapeutic use MH - State Medicine MH - Treatment Outcome MH - Disease Progression MH - Double-Blind Method PMC - PMC9623477 COIS- Conflict of Interest Disclosures: Ms Creanor has received grants from JP Moulton Charitable Foundation and Cure Parkinson's Trust during the conduct of the study; grants from the National Institute of Health and Care Research, UK Research and Innovation Department of Health and Social Care COVID-19 Rapid Call, MS Society, Horizon2020, Torbay Medical Research Fund, and Chartered Society of Physiotherapists outside the submitted work; and, during the beginning of the current study, was employed by the University of Plymouth. Dr Whone has received research income from North Bristol Trust Charities, University of Birmingham Alumni, Cure Parkinson's Trust, Engineering and Physical Sciences Research Council, Wellcome Trust, Academy of Medical Sciences, Elizabeth Blackwell Institute for Health Research, David Telling Trust, and National Institute of Health and Care Research; honoraria from Novo Nordisk; and consultancy fees from Kyowa Kirin and Vivifi Biotech outside the submitted work. Dr Carroll has received grants from JP Mouton Charitable Foundation and Cure Parkinson's Trust during the conduct of the study; grants from Parkinson's UK, Edmond J. Safra Foundation, National Institute of Health and Care Research, and Cure Parkinson's Trust; and personal fees from AbbVie, Bial, Scient, Orkyn, Abidetex, UCB, Pfizer, EverPharma, Lundbeck, Global Kinetics, Kyowa Kirin, Britannia, and MedScape outside the submitted work. No other disclosures were reported. FIR - Inches, Jemma IR - Inches J FIR - Underwood, Donna IR - Underwood D FIR - Frost, Julie IR - Frost J FIR - James, Ali IR - James A FIR - Schofield, Christine IR - Schofield C FIR - James, Rob IR - James R FIR - O'Reilly, Clare IR - O'Reilly C FIR - Sheridan, Ray IR - Sheridan R FIR - Statton, Sarah IR - Statton S FIR - Goff, Anita IR - Goff A FIR - Russell, Tamlyn IR - Russell T FIR - Whitcher, Alison IR - Whitcher A FIR - Craw, Sarah IR - Craw S FIR - Lewis, Alison IR - Lewis A FIR - Sophia, Rani IR - Sophia R FIR - Amar, Khaled IR - Amar K FIR - Hernandez, Rochelle IR - Hernandez R FIR - Pitcher, Alison IR - Pitcher A FIR - Carvey, Samantha IR - Carvey S FIR - Hamlin, Ruth IR - Hamlin R FIR - Lyell, Veronica IR - Lyell V FIR - Aubry, Louisa IR - Aubry L FIR - Carey, Gillian IR - Carey G FIR - Coebergh, Jan IR - Coebergh J FIR - Mojela, Idah IR - Mojela I FIR - Molloy, Sophie IR - Molloy S FIR - Berceruelo Bergaz, Yolanda IR - Berceruelo Bergaz Y FIR - Camera, Bintou IR - Camera B FIR - Campbell, Philip IR - Campbell P FIR - Morris, Huw IR - Morris H FIR - Samakomva, Tinashe IR - Samakomva T FIR - Schrag, Anette IR - Schrag A FIR - Fuller, Sarah IR - Fuller S FIR - Misbahuddin, Anjum IR - Misbahuddin A FIR - Parker, Laura IR - Parker L FIR - Visentin, Elisa IR - Visentin E FIR - Gallehawk, Stephanie IR - Gallehawk S FIR - Rudd, Jacqueline IR - Rudd J FIR - Singh, Sudhir IR - Singh S FIR - Wilson, Sarsha IR - Wilson S FIR - Creven, Julie IR - Creven J FIR - Croucher, Yvonne IR - Croucher Y FIR - Tluk, Susan IR - Tluk S FIR - Watts, Paul IR - Watts P FIR - Hargreaves, Simone IR - Hargreaves S FIR - Johnson, Danielle IR - Johnson D FIR - Worboys, Lucy IR - Worboys L FIR - Worth, Paul IR - Worth P FIR - Brooke, Judith IR - Brooke J FIR - Kobylecki, Christopher IR - Kobylecki C FIR - Parker, Victoria IR - Parker V FIR - Johnson, Linda IR - Johnson L FIR - Joseph, Rosane IR - Joseph R FIR - Melville, Julie IR - Melville J FIR - Raw, Jason IR - Raw J FIR - Birt, Janice IR - Birt J FIR - Hare, Marianne IR - Hare M FIR - Shaik, Saifuddin IR - Shaik S FIR - Alty, Jane IR - Alty J FIR - Cosgrove, Jeremy IR - Cosgrove J FIR - Burn, David IR - Burn D FIR - Green, Angela IR - Green A FIR - McNichol, Ann IR - McNichol A FIR - Pavese, Nicola IR - Pavese N FIR - Pilkington, Helen IR - Pilkington H FIR - Price, Maria IR - Price M FIR - Walker, Kathryn IR - Walker K FIR - Chaudhuri, Ray IR - Chaudhuri R FIR - Podlewska, Aleksandra IR - Podlewska A FIR - Reddy, Prashanth IR - Reddy P FIR - Trivedi, Dhaval IR - Trivedi D FIR - Bandmann, Oliver IR - Bandmann O FIR - Clegg, Rosie IR - Clegg R FIR - Cole, Grace IR - Cole G FIR - Emery, Anna IR - Emery A FIR - Dostal, Vaclav IR - Dostal V FIR - Graham, Jodie IR - Graham J FIR - Keshet-Price, Jocelyn IR - Keshet-Price J FIR - Mamutse, Godwin IR - Mamutse G FIR - Miller-Fik, Alex IR - Miller-Fik A FIR - Wiltshire, Alison IR - Wiltshire A FIR - Wright, Catherine IR - Wright C FIR - Dixon, Kathryn IR - Dixon K FIR - Abdelhafiz, Ahmed IR - Abdelhafiz A FIR - Rose, Joanne IR - Rose J EDAT- 2022/11/01 06:00 MHDA- 2022/12/15 06:00 PMCR- 2022/10/31 CRDT- 2022/10/31 11:33 PHST- 2022/11/01 06:00 [pubmed] PHST- 2022/12/15 06:00 [medline] PHST- 2022/10/31 11:33 [entrez] PHST- 2022/10/31 00:00 [pmc-release] AID - 2797508 [pii] AID - noi220070 [pii] AID - 10.1001/jamaneurol.2022.3718 [doi] PST - ppublish SO - JAMA Neurol. 2022 Dec 1;79(12):1232-1241. doi: 10.1001/jamaneurol.2022.3718.