The MADE (Minocycline in Alzheimer’s Disease Efficacy trial) is a double-blind randomised trial that investigated whether a daily dose of either 200 mg or 400 mg of minocycline hydrochloride over two years would slow the decline in cognitive and functional ability compared to a placebo.
Minocycline is an antibiotic medication used most commonly to treat infections and acne. Laboratory research suggested that minocycline might also slow the progress of Alzheimer's disease (AD).
AD is a huge public health problem, with approximately 700,000 people in the UK suffering from dementia of whom some 400,000 have Alzheimer’s disease. At the moment, there are no drugs that slow disease progress.
Minocycline is known to have anti-inflammatory and neuroprotective effects and evidence suggests that neuroinflammation is instrumental in the progression of Alzheimer disease. 200 mg per day is the top recommended oral dose; however, evidence from animal studies suggests that higher doses may be needed to achieve the full anti-inflammatory and anti-AD effects of minocycline. The MADE trial therefore included the 400 mg dose to investigate whether a higher dose enhanced efficacy.
The researchers recruited 554 people diagnosed with early Alzheimer’s disease from 32 NHS memory clinics in England and Scotland between May 2014 and April 2016. Participants were randomly allocated to receive 200mg or 400mg of minocycline or a placebo and were followed up for two years. Deterioration in the Mini Mental State Examination score (sMMSE) and the Bristol Activities of Daily Living Scale (BADLS) were used as outcome measures.
MADE was funded by the UK Medical Research Council.
The results, published in JAMA Neurology in November 2019, found that minocycline does not significantly delay the progression of cognitive and functional impairment in people with mild Alzheimer’s disease. The decrease in the sMMSE score over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points) and the worsening of BADLS scores over 24 months was similar in all groups.
The study also found that the 400 mg dose had no apparent benefit and was also poorly tolerated, with only 29% of participants completing two years of treatment, significantly fewer than the group who received the 200 mg dose (62%) or the placebo group (64%). The main reasons for stopping treatment were gastro-intestinal symptoms, skin related toxic effects and dizziness.
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