Minocycline at 2 Different Dosages vs Placebo for Patients With Mild Alzheimer Disease A Randomized Clinical Trial
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Robert Howard; Olga Zubko; Rosie Bradley; Emma Harper; Lynn Pank; John O’Brien; Chris Fox; Naji Tabet; Gill Livingston; Peter Bentham; RupertMcShane; Alistair Burns; Craig Ritchie; Suzanne Reeves; Simon Lovestone; Clive Ballard;Wendy Noble; Ramin Nilforooshan; Gordon Wilcock; Richard Gray. Minocycline at 2 Different Dosages vs Placebo for Patients With Mild Alzheimer Disease A Randomized Clinical Trial. JAMA Neurol. Published online November 18, 2019
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 Participantswere 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 (400mg/d or 200mg/d) or placebo for 24 months. MAIN OUTCOMES AND MEASURES Primary outcome measureswere 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 (241women and 303 men), the mean (SD) agewas 74.3 (8.2) years, and the mean (SD) sMMSE scorewas 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 rateswere 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 groupwas 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 scoreswas 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 monthswas 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 400mg vs 200mg of minocycline = –0.31; 95%CI, −0.2 to 1.8; P = .77). Resultswere 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 also found that 400mg of minocycline is poorly tolerated in this population.
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- Dementia