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Cited by 194Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

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Minocycline at 2 Different Dosages vs Placebo for Patients With Mild Alzheimer Disease: A Randomized Clinical Trial

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Howard, Robert, Zubko, Olga, Bradley, Rosie, Harper, Emma, Pank, Lynn, O’Brien, John, Fox, Chris, Tabet, Naji, Livingston, Gill, Bentham, Peter, McShane, Rupert, Burns, Alistair, Ritchie, Craig, Reeves, Suzanne, Lovestone, Simon, Ballard, Clive, Noble, Wendy, Nilforooshan, Ramin, Wilcock, Gordon, Gray, Richard, for the Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group·2020·JAMA Neurology
DOI 10.1001/jamaneurol.2019.3762PMC PMC6865324
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Abstract

Importance: There are no disease-modifying treatments for Alzheimer disease (AD), the most common cause of dementia. Minocycline is anti-inflammatory, protects against the toxic effects of β-amyloid in vitro and in animal models of AD, and is a credible repurposed treatment candidate. Objective: To determine whether 24 months of minocycline treatment can modify cognitive and functional decline in patients with mild AD. Design, Setting, and Participants: Participants were recruited into a double-blind randomized clinical trial from May 23, 2014, to April 14, 2016, with 24 months of treatment and follow-up. This multicenter study in England and Scotland involved 32 National Health Service memory clinics within secondary specialist services for people with dementia. From 886 screened patients, 554 patients with a diagnosis of mild AD (Standardised Mini-Mental State Examination [sMMSE] score ≥24) were randomized. Interventions: Participants were randomly allocated 1:1:1 in a semifactorial design to receive minocycline (400 mg/d or 200 mg/d) or placebo for 24 months. Main Outcomes and Measures: Primary outcome measures were decrease in sMMSE score and Bristol Activities of Daily Living Scale (BADLS), analyzed by intention-to-treat repeated-measures regression. Results: Of 544 eligible participants (241 women and 303 men), the mean (SD) age was 74.3 (8.2) years, and the mean (SD) sMMSE score was 26.4 (1.9). Fewer participants completed 400-mg minocycline hydrochloride treatment (28.8% [53 of 184]) than 200-mg minocycline treatment (61.9% [112 of 181]) or placebo (63.7% [114 of 179]; P < .001), mainly because of gastrointestinal symptoms (42 in the 400-mg group, 15 in the 200-mg group, and 10 in the placebo group; P < .001), dermatologic adverse effects (10 in the 400-mg group, 5 in the 200-mg group, and 1 in the placebo group; P = .02), and dizziness (14 in the 400-mg group, 3 in the 200-mg group, and 1 in the placebo group; P = .01). Assessment rates were lower in the 400-mg group: 68.4% (119 of 174 expected) for sMMSE at 24 months compared with 81.8% (144 of 176) for the 200-mg group and 83.8% (140 of 167) for the placebo group. Decrease in sMMSE scores over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). The combined minocycline group had mean sMMSE scores 0.1 points higher than the placebo group (95% CI, -1.1 to 1.2; P = .90). The decrease in mean sMMSE scores was less in the 400-mg group than in the 200-mg group (3.3 vs 4.7 points; treatment effect = 1.2; 95% CI, -0.1 to 2.5; P = .08). Worsening of BADLS scores over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo groups (treatment effect for minocycline vs placebo = -0.53; 95% CI, -2.4 to 1.3; P = .57; treatment effect for 400 mg vs 200 mg of minocycline = -0.31; 95% CI, -0.2 to 1.8; P = .77). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Conclusions and Relevance: Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. This study also found that 400 mg of minocycline is poorly tolerated in this population. Trial Registration: isrctn.org Identifier: ISRCTN16105064.

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Figures

Figure 1. Flowchart of Study
Figure 1. Flowchart of StudyCC BY · PubMed Central
Figure 2. Proportion Taking Trial Treatment Over Time Minocycline hydrochloride, 400 mg, vs placebo: hazard ratio, 3.09; 95% CI, 2.27-4.20; P < .001; minocycline hydrochloride, 200 mg, vs placebo: hazard ratio, 1.11; 95% CI, 0.78-1.57; P = .56. Mean treatment duration for each group: minocycline hydrochloride, 11.4 months in the 400-mg group; minocycline hydrochloride, 18.6 months in the 200-mg group; and 18.9 months in the placebo group.
Figure 2. Proportion Taking Trial Treatment Over Time Minocycline hydrochloride, 400 mg, vs placebo: hazard ratio, 3.09; 95% CI, 2.27-4.20; P < .001; minocycline hydrochloride, 200 mg, vs placebo: hazard ratio, 1.11; 95% CI, 0.78-1.57; P = .56. Mean treatment duration for each group: minocycline hydrochloride, 11.4 months in the 400-mg group; minocycline hydrochloride, 18.6 months in the 200-mg group; and 18.9 months in the placebo group.CC BY · PubMed Central
Figure 3. Change in Mean (SE) Standardised Mini-Mental State Examination (sMMSE) and Bristol Activities of Daily Living Scale (BADLS) Scores From Baseline to Month 24 A, Change in sMMSE score from baseline to 24 months. Any dose of minocycline vs placebo: treatment effect = 0.07; 95% CI, –1.1 to 1.2; P = .90; 400 mg vs 200 mg: treatment effect = 1.17; 95% CI, –0.1 to 2.5; P = .08. B, Change in BADLS score from baseline to 24 months. Any dose of minocycline vs placebo: treatment effect = –0.53; 95% CI, –2.4 to 1.3; P = .57; 400 mg vs 200 mg: treatment effect = –0.31; 95% CI, –0.2 to 1.8; P = .77. Baseline scores are set to zero (baseline sMMSE scores: 26.3 in the 400-mg group, 26.5 in the 200-mg group, and 26.4 in the placebo group; baseline BADLS scores: 5.6 in the 400-mg group, 4.9 in the 200-mg group, and 5.5 in the placebo group). Treatment effect is the estimated difference in 2-year decline from repeated measures analyses; P values are from tests comparing rate of decline between groups (time by treatment interaction) from repeated measures analyses. Results from intention-to-treat analysis of 554 patients.
Figure 3. Change in Mean (SE) Standardised Mini-Mental State Examination (sMMSE) and Bristol Activities of Daily Living Scale (BADLS) Scores From Baseline to Month 24 A, Change in sMMSE score from baseline to 24 months. Any dose of minocycline vs placebo: treatment effect = 0.07; 95% CI, –1.1 to 1.2; P = .90; 400 mg vs 200 mg: treatment effect = 1.17; 95% CI, –0.1 to 2.5; P = .08. B, Change in BADLS score from baseline to 24 months. Any dose of minocycline vs placebo: treatment effect = –0.53; 95% CI, –2.4 to 1.3; P = .57; 400 mg vs 200 mg: treatment effect = –0.31; 95% CI, –0.2 to 1.8; P = .77. Baseline scores are set to zero (baseline sMMSE scores: 26.3 in the 400-mg group, 26.5 in the 200-mg group, and 26.4 in the placebo group; baseline BADLS scores: 5.6 in the 400-mg group, 4.9 in the 200-mg group, and 5.5 in the placebo group). Treatment effect is the estimated difference in 2-year decline from repeated measures analyses; P values are from tests comparing rate of decline between groups (time by treatment interaction) from repeated measures analyses. Results from intention-to-treat analysis of 554 patients.CC BY · PubMed Central

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  1. Alzheimer’s Disease International, 2015, World Alzheimer Report 2015: The Global Impact of Dementia

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Authors
Howard, R., Zubko, O., Bradley, R., Harper, E., Pank, L., O’Brien, J., Fox, C., Tabet, N., Livingston, G., Bentham, P., McShane, R., Burns, A., Ritchie, C., Reeves, S., Lovestone, S., Ballard, C., Noble, W., Nilforooshan, R., Wilcock, G., Gray, R., & for the Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group
Affiliations
  • University College London (GB)
  • King's College London (GB)
  • University of Oxford (GB)
  • Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
  • University of East Anglia (GB)
  • University of Sussex (GB)
  • National Health Service (GB)
  • University of Manchester (GB)
  • University of Edinburgh (GB)
  • University of Exeter (GB)
Corresponding author
Howard, Robert
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2020-02-01
Volume
77
Issue
2
Pages
164
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2019.3762
PMC
PMC6865324
OpenAlex
W2984563923
Cited by
194
References
33
Citations by year
2026: 24 · 2025: 22 · 2024: 30 · 2023: 26 · 2022: 38 · 2021: 26 · 2020: 26
FWCI
15.78
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Neurology (publishedVersion, cc-by)
  • Research Portal (King's College London) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UEA Digital Repository (University of East Anglia) (acceptedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
Funders
  • South London and Maudsley NHS Foundation Trust
  • Sussex Partnership NHS Foundation Trust
  • National Institute for Health and Care Research (NF-SI-0616-10042, NIHR/CS/010/019)
  • St George's University Hospitals NHS Foundation Trust
  • Oxford Health NHS Foundation Trust
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
Keywords
minocycline, Alzheimer's disease, mild Alzheimer disease, disease-modifying therapy, drug repurposing, anti-inflammatory therapy, amyloid-beta, cognitive decline, functional decline, activities of daily living, dose comparison, gastrointestinal adverse effects, dermatologic adverse effects, dizziness, medication adherence, memory clinics, dementia services, Mini-Mental State Examination
MeSH terms
Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Minocycline, Treatment Outcome, Disease Progression, Neuroprotective Agents

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