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      Simvastatin as a neuroprotective treatment for Parkinson’s disease (PD STAT): protocol for a double-blind, randomised, placebo-controlled futility study

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          Abstract

          Introduction

          Parkinson’s disease (PD) is a progressive neurodegenerative condition affecting approximately 185,000 people in the UK. No drug has been proven to slow disease progression. Epidemiological and pre-clinical data support simvastatin, a widely used cholesterol-lowering drug with a well-established safety profile, having neuroprotective properties. The aim of this study (Simvastatin as a neuroprotective treatment for PD (PD STAT)) is to determine whether simvastatin has the potential to slow PD progression. The study is part of the International Linked Clinical Trials initiative coordinated by The Cure Parkinson’s Trust. This paper describes the protocol for the PD STAT study.

          Methods and analysis

          PD STAT is a double-blind, randomised, placebo-controlled, multi-centre, parallel group, futility trial in patients with PD of mild–moderate severity. 235 participants have been recruited and randomly allocated in a 1:1 ratio to receive either oral simvastatin or matched placebo. Treatment involves a 1-month low-dose phase (40 mg daily), followed by a 23-month high-dose phase (80 mg daily) and ends with a 2-month washout period. Participants are reviewed at clinic visits at 1 month, 6, 12, 18, 24 and 26 months post-baseline, with interim telephone follow-up to monitor for adverse events.

          The primary outcome is the change in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale part III motor subscale score in the practically defined OFF medication state (OFF state) between baseline and 24 months. Primary analysis will be on a modified intention to treat basis and will include only those participants who progress to the high-dose phase of the study.

          Ethics and dissemination

          The protocol has been approved by the North East–Newcastle and North Tyneside 2 Research Ethics Committee. The results will be disseminated via research articles in peer-reviewed journals and presentations at local, national and international scientific meetings, as well as disseminated via patient groups, websites and networks. A summary of the study findings will be posted to participants at the end of the study.

          Trial Registration

          ISRCTN16108482 (prospectively registered); EudraCT 2015-000148-40; ClinicalTrials.gov NCT02787590; Pre-results.

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          Most cited references15

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          CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.

          The CONSORT (Consolidated Standards of Reporting Trials) statement is used worldwide to improve the reporting of randomized, controlled trials. Schulz and colleagues describe the latest version, CONSORT 2010, which updates the reporting guideline based on new methodological evidence and accumulating experience.
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            Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease.

            Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. We investigated whether simvastatin, a Food and Drug Administration-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice. First, MPP(+) induced the activation of p21(ras) and nuclear factor-kappaB (NF-kappaB) in mouse microglial cells. Inhibition of MPP(+)-induced activation of NF-kappaB by Deltap21(ras), a dominant-negative mutant of p21(ras), supported the involvement of p21(ras) in MPP(+)-induced microglial activation of NF-kappaB. Interestingly, simvastatin attenuated activation of both p21(ras) and NF-kappaB in MPP(+)-stimulated microglial cells. Consistently, we found a very rapid activation of p21(ras) in vivo in the substantia nigra pars compacta of MPTP-intoxicated mice. However, after oral administration, simvastatin entered into the nigra, reduced nigral activation of p21(ras), attenuated nigral activation of NF-kappaB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Similarly, pravastatin, another cholesterol-lowering drug, suppressed microglial inflammatory responses and protected dopaminergic neurons in MPTP-intoxicated mice, but at levels less than simvastatin. Furthermore, both the statins administered 2 d after initiation of the disease were still capable of inhibiting the demise of dopaminergic neurons and concomitant loss of neurotransmitters, suggesting that statins are capable of slowing down the progression of neuronal loss in the MPTP mouse model. Therefore, we conclude that statins may be of therapeutic benefit for PD patients.
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              Statin use and risk of developing diabetes: results from the Diabetes Prevention Program

              Objective Several clinical trials of cardiovascular disease prevention with statins have reported increased risk of type 2 diabetes (T2DM) with statin therapy. However, participants in these studies were at relatively low risk for diabetes. Further, diabetes was often based on self-report and was not the primary outcome. It is unknown whether statins similarly modify diabetes risk in higher risk populations. Research design and methods During the Diabetes Prevention Program Outcomes Study (n=3234), the long-term follow-up to a randomized clinical trial of interventions to prevent T2DM, incident diabetes was assessed by annual 75 g oral glucose tolerance testing and semiannual fasting glucose. Lipid profile was measured annually, with statin treatment determined by a participant’s own physician outside of the protocol. Statin use was assessed at baseline and semiannual visits. Results At 10 years, the cumulative incidence of statin initiation prior to diabetes diagnosis was 33%–37% among the randomized treatment groups (p=0.36). Statin use was associated with greater diabetes risk irrespective of treatment group, with pooled HR (95% CI) for incident diabetes of 1.36 (1.17 to 1.58). This risk was not materially altered by adjustment for baseline diabetes risk factors and potential confounders related to indications for statin therapy. Conclusions In this population at high risk for diabetes, we observed significantly higher rates of diabetes with statin therapy in all three treatment groups. Confounding by indication for statin use does not appear to explain this relationship. The effect of statins to increase diabetes risk appears to extend to populations at high risk for diabetes. Trial registration number NCT00038727; Results.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2019
                7 October 2019
                : 9
                : 10
                : e029740
                Affiliations
                [1 ] departmentFaculty of Medicine and Dentistry , University of Plymouth , Plymouth, UK
                [2 ] departmentPeninsula Clinical Trials Unit , University of Plymouth , Plymouth, UK
                [3 ] departmentMedical Statistics Group , University of Plymouth , Plymouth, UK
                [4 ] departmentNIHR CLAHRC South West Peninsula (PenCLAHRC) , University of Exeter Medical School , Exeter, UK
                [5 ] The Cure Parkinson's Trust , London, UK
                [6 ] departmentPPI Representative , University of Plymouth , Plymouth, UK
                [7 ] departmentSchool of Medicine , University of St Andrews , St Andrews, UK
                [8 ] departmentSchool of Translational Health Sciences , University of Bristol , Bristol, UK
                Author notes
                [Correspondence to ] Dr Camille B Carroll; camille.carroll@ 123456plymouth.ac.uk
                Author information
                http://orcid.org/0000-0001-7472-953X
                http://orcid.org/0000-0003-4898-1795
                http://orcid.org/0000-0002-7373-8263
                Article
                bmjopen-2019-029740
                10.1136/bmjopen-2019-029740
                6797358
                31594876
                260e90ec-ccff-4518-b2a8-6639d224c3ed
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 13 February 2019
                : 05 July 2019
                : 19 August 2019
                Funding
                Funded by: The Cure Parkinson's Trust;
                Funded by: The JP Moulton Charitable Foundation;
                Funded by: The Garfield Weston Foundation;
                Funded by: The Hoover Foundation;
                Categories
                Neurology
                Protocol
                1506
                1713
                Custom metadata
                unlocked

                Medicine
                parkinson’s disease,statin,randomised controlled futility study,neuroprotective effect,mds-updrs

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