Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer’s disease: the MADE Phase II, three-arm RCT

Robert Howard; Olga Zubko; Richard Gray; Rosie Bradley; Emma Harper; Linda Kelly; Lynn Pank; John O’Brien; Chris Fox; Naji Tabet; Gill Livingston; Peter Bentham; Rupert McShane; Alistair Burns; Craig Ritchie; Suzanne Reeves; Simon Lovestone; Clive Ballard; Wendy Noble; Gordon Wilcock; Ramin Nilforooshan

doi:10.3310/eme07020

Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer’s disease: the MADE Phase II, three-arm RCT

Efficacy and Mechanism Evaluation, No. 7.2

Authors

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 and Ramin Nilforooshan¹⁵.

Affiliations

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: ku.ca.lcu@drawoh.trebor

Southampton (UK): NIHR Journals Library; 2020 Apr.

Copyright © Queen’s Printer and Controller of HMSO 2020. This work was produced by Howard et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Read

Headline

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.

Abstract

Background:

Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out.

Objectives:

The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed.

Design:

A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months.

Setting:

Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN).

Participants:

Patients with standardised Mini Mental State Examination scores of > 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.

About the Series

Efficacy and Mechanism Evaluation

ISSN (Print): 2050-4365

ISSN (Electronic): 2050-4373

Article history

The research reported in this issue of the journal was funded by the EME programme as project number 11/47/01. The contractual start date was in June 2013. The final report began editorial review in April 2019 and was accepted for publication in November 2019. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Robert Howard reports membership of the Health Technology Assessment (HTA) Commissioning Board between 2013 and 2018. John O’Brien reports personal fees from TauRx Pharmaceuticals Ltd (Singapore) and GE Healthcare (Chicago, IL, USA), Eli Lilly and Company (Indianapolis, IN, USA) and Eisai Co., Ltd (Tokyo, Japan), outside the submitted work. Gill Livingston reports membership of the HTA Clinical Trials Board Associate from 2007 to 2010. Peter Bentham reports personal fees from TauRx Pharmaceuticals Ltd outside the submitted work. Craig Ritchie reports other payments from Roche Holding AG (Basel, Switzerland), Nutricia International B.V. (Zoetermeer, the Netherlands), Actinogen Medical (Sydney, NSW, Australia), Kyowa Hakko Kirin Co., Ltd (Singapore), Biogen Inc. (Cambridge, MA, USA) and Merck Sharp & Dohme Corp. (Kenilworth, NJ, USA) and grants from Janssen Pharmaceutica (Beerse, Belgium) outside the submitted work. Simon Lovestone reports other from Janssen-Cilag Ltd (High Wycombe, UK) and grants from AstraZeneca plc (Cambridge, UK) and European Federation of Pharmaceutical Industries and Associations (Brussels, Belgium) outside the submitted work. In addition, Simon Lovestone has patents issued and pending related to biomarkers for Alzheimer’s disease. He also reports membership of the Efficacy and Mechanism Evaluation Strategy Group from 2015 to 2019 and of the Medical Advisory Board of SomaLogic (Boulder, CO, USA) up to 2019 and other consultancy for Merck Sharp & Dohme Corp., Eli Lilly and Company and Optum, Inc. (Eden Prairie, MN, USA). Clive Ballard reports grants and personal fees from Acadia Pharmaceutical Company (San Diego, CA, USA) and Lundbeck A/S (Copenhagen, Denmark) and personal fees from Roche Holding AG, Otusaka Pharmaceutical Co., Ltd (Tokyo, Japan), Novartis International AG (Basel Switzerland), Eli Lilly and Company and Pfizer Inc. (New York, NY, USA) outside the submitted work.

Last reviewed: April 2019; Accepted: November 2019.

Copyright © Queen’s Printer and Controller of HMSO 2020. This work was produced by Howard et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Bookshelf ID: NBK556206PMID: 32338849DOI: 10.3310/eme07020