23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies. Trial registration Current Controlled Trials ISRCTN16105064 and EudraCT 2013-000397-30. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 2. See the NIHR Journals Library website for further project information. ">
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Minocycline did not delay the progress of cognitive or functional impairment in people with mild Alzheimer's disease over 2 years and minocycline 400 mg was poorly tolerated.

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Robert Howard 1,*, Olga Zubko 2, Richard Gray 3, Rosie Bradley 4, Emma Harper 4, Linda Kelly 4, Lynn Pank 4, John O’Brien 5, Chris Fox 6, Naji Tabet 7, Gill Livingston 1, Peter Bentham 8, Rupert McShane 9, Alistair Burns 10, Craig Ritchie 11, Suzanne Reeves 1, Simon Lovestone 9, Clive Ballard 12, Wendy Noble 13, Gordon Wilcock 14, Ramin Nilforooshan 15

1 Division of Psychiatry, University College London, London, UK
2 Department of Old Age Psychiatry, King’s College London, London, UK
3 Nuffield Department of Population Health, University of Oxford, Oxford, UK
4 Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK
5 Department of Psychiatry, University of Cambridge, Cambridge, UK
6 Norwich Medical School, University of East Anglia, Norwich, UK
7 Department of Old Age Psychiatry, University of Sussex, Brighton, UK
8 The Barberry Centre, Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK
9 Department of Psychiatry, University of Oxford, Oxford, UK
10 Department of Old Age Psychiatry, University of Manchester, Manchester, UK
11 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
12 Medical School, University of Exeter, Exeter, UK
13 Department of Basic and Clinical Neuroscience, King’s College London, London, UK
14 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
15 Abraham Cowley Unit, Surrey and Borders Partnership NHS Foundation Trust, Redhill, UK
* Corresponding author Email: robert.howard@ucl.ac.uk

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