BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer’s and other neurodegenerative diseases? Protocol for an observational cohort study in the UK Clinical Practice Research Datalink For peer review only Journal: BMJ Open Manuscript ID bmjopen-2016-012044 Article Type: Protocol Date Submitted by the Author: 23-Mar-2016 Complete List of Authors: Walker, Venexia; University of Bristol Davies, Neil; University of Bristol Jones, Tim; NIHR CLAHRC West Kehoe, Patrick; University of Bristol Martin, Richard; University of Bristol <b>Primary Subject Pharmacology and therapeutics Heading</b>: Secondary Subject Heading: Neurology, Epidemiology Dementia < NEUROLOGY, Parkinson-s disease < NEUROLOGY, Motor Keywords: neurone disease < NEUROLOGY, EPIDEMIOLOGY, THERAPEUTICS http://bmjopen.bmj.com/ on September 25, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 1 2 3 TITLE 4 5 Can commonly prescribed drugs be repurposed for the prevention or treatment of 6 Alzheimer’s and other neurodegenerative diseases? Protocol for an observational cohort 7 study in the UK Clinical Practice Research Datalink 8 9 10 CO-AUTHORS 11 1, 2 1, 2 3 4 1, 2 12 Venexia M Walker , Neil M Davies , Tim Jones , Patrick G Kehoe , Richard M Martin 13 14 1 School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom 15 2 MRC UniversityFor of Bristol peer Integrative reviewEpidemiology Unit, Bristol,only United Kingdom 16 3 NIHR CLAHRC West, Bristol, United Kingdom 17 4 Dementia Research Group, School of Clinical Sciences, University of Bristol, Bristol, 18 19 United Kingdom 20 21 CORRESPONDING AUTHOR 22 23 Venexia M Walker 24 25 Address: School of Social and Community Medicine, University of Bristol, Oakfield House, 26 Oakfield Grove, Bristol, BS8 2BN 27 28 29 Email: [email protected] 30 31 Telephone: +441173310128 32 33 KEYWORDS 34 http://bmjopen.bmj.com/ 35 Alzheimer’s disease, Neurodegenerative Disease, Drug Repurposing, Clinical Practice 36 Research Datalink, Pharmacoepidemiology 37 38 39 WORD COUNT 40 41 42 3569 words excluding title page, abstract, references, figures and tables. on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 1 2 3 ABSTRACT 4 5 Introduction: Current treatments for Alzheimer’s and other neurodegenerative diseases have 6 only limited effectiveness meaning there is an urgent need for new medications that could 7 influence disease incidence and progression. We will investigate the potential of a selection 8 9 of commonly prescribed drugs, as a more efficient and cost-effective method of identifying 10 new drugs for the prevention or treatment of Alzheimer’s disease, non-Alzheimer’s disease 11 dementias, Parkinson’s disease and amyotrophic lateral sclerosis. Our research will focus on 12 drugs used for the treatment of hypertension, hypercholesterolaemia and type 2 diabetes, all 13 of which have previously been identified as potentially cerebroprotective and have variable 14 levels of pre-clinical evidence that suggest they may have beneficial effects for various 15 aspects of dementiaFor pathology. peer Methods review and analysis: We will only conduct a hypothesis testing 16 observational cohort study using data from the Clinical Practice Research Datalink (CPRD). 17 Our analysis will consider four statistical methods, which have different approaches for 18 19 modelling confounding. These are multivariable adjusted Cox regression; propensity matched 20 regression; instrumental variable analysis; and marginal structural models. We will also use 21 an intention-to-treat analysis, whereby we will define all exposures based on the first 22 prescription observed in the database so that the target parameter is comparable to that 23 estimated by a randomised controlled trial. Ethics and dissemination: This protocol has 24 been approved by the CPRD’s Independent Scientific Advisory Committee (ISAC). We will 25 publish the results of the study as open-access peer-reviewed publications and disseminate 26 findings through national and international conferences as are appropriate. 27 28 29 STRENGTHS AND LIMITATIONS OF THIS STUDY 30 31 • This study will involve a large sample of data and has considerable power to detect 32 even relatively small effects, even under highly conservative Bonferroni corrections. 33 For example, the sample to assess the progression of dementia contains 105,471 34 patients and has a minimum detectable hazard ratio of 0.931. http://bmjopen.bmj.com/ 35 • We plan to use four different statistical methods in our analysis, which have different 36 approaches for modelling confounding. By doing this, we will be able to assess the 37 38 merits of each method in the given situation in order to minimize confounding. 39 • Dementia is a heterogeneous outcome, and electronic codes used to define cases in 40 primary care may not be as accurate as cases in clinical cohorts. We will undertake 41 sensitivity analyses to explore how this may affect our results. 42 on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 1 2 3 INTRODUCTION 4 5 Rationale 6 7 Alzheimer’s disease is a progressive disease affecting brain function and independent living, 8 9 and eventually requires full-time care. There are only a few treatments that temporarily help 10 symptoms such as memory loss; however, these eventually become ineffective as the 11 underlying disease progresses unabated. Part of the difficulty of treating Alzheimer’s disease 12 is that it involves the activation of many destructive processes in the brain, each of which is 13 likely to need simultaneous treatment if the progression of the disease is to be halted. 14 15 For this reason,For there is urgentpeer need for newreview evidence about medications only that could influence 16 the incidence and progression of Alzheimer’s disease. One promising approach is to 17 investigate drug repositioning[1], which offers a time- and cost-effective alternative to 18 19 traditional drug development. A recent consensus study of dementia experts identified a 20 short-list of individual and classes of prescribed drugs that may be repurposed as novel 21 treatments for dementia.[2] The short-list included compounds used to treat hypertension, 22 hypercholesterolemia and type 2 diabetes, all of which can be classed as having 23 ‘cerebroprotective’ properties and have variable levels of pre-clinical evidence that suggest 24 they may have beneficial effects for various aspects of dementia pathology. However as yet 25 there is limited pharmacoepidemiological data to support their effects in human populations. 26 Therefore, we plan to investigate whether these existing medications could be repurposed to 27 prevent or treat Alzheimer’s disease. 28 29 30 Furthermore, the overlap of different forms of neurodegenerative disease would suggest that 31 there may be scope to translate existing or newly identified interventions for testing in 32 neurodegenerative diseases where similarities exist. Thus we will start by examining the most 33 common form of neurodegenerative disease - Alzheimer’s disease.[3,4] We will then 34 investigate whether the drug candidates could also be repurposed to treat or prevent other http://bmjopen.bmj.com/ 35 neurodegenerative diseases – these will include other non-Alzheimer’s disease dementias (i.e. 36 the group for dementias in which Alzheimer’s disease is not thought to play a part), 37 Parkinson’s disease and amyotrophic lateral sclerosis. Collectively these findings will allow 38 39 the prioritisation of drugs to be tested as repurposed treatments in clinical trials of 40 Alzheimer’s and other neurodegenerative diseases in the future. 41 42 Objectives on September 25, 2021 by guest. Protected copyright. 43 44 To investigate whether commonly prescribed medications, previously identified as potentially 45 cerebroprotective, are associated with the incidence or progression of neurodegenerative 46 disease. 47 48 49 We will focus on the following medications: 50 a. Treatments for hypertension 51 b. Treatments for hypercholesterolemia 52 c. Treatments for type 2 diabetes 53 54 Along with the following neurodegenerative diseases: 55 a. Alzheimer’s disease (AD) 56 b. Non-Alzheimer’s disease dementias (NADD) 57 c. Parkinson’s disease (PD) 58 d. Amyotrophic lateral sclerosis (ALS) 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 1 2 3 METHODS AND ANALYSIS 4 5 Study Design 6 7 8 We will conduct a hypothesis testing observational cohort study of neurodegenerative disease 9 incidence and progression, using data from the Clinical Practice Research Datalink (CPRD). 10 11 Participants 12 13 We will include men and women older than 40 years, with at least 12 consecutive months of 14 records classified as ‘acceptable’ by the CPRD from all “up to standard” practices.[5] 15 Patients registeredFor at a practicepeer less than review 365 days before their only 40th birthday, or those with a 16 th 17 first record of one of the index drug classes of interest before their 40 birthday will be 18 excluded.