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A clinical trial of minocycline has found that it does not significantly delay the progression of cognitive and functional impairment in people with mild Alzheimer’s disease.

The Minocycline in Alzheimer Disease Efficacy (MADE) trial was a double-blind randomised trial, which 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.

The researchers recruited 554 people diagnosed with early Alzheimer’s disease (AD) 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.

The results, published in JAMA Neurology, found that 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 that worsening of BADLS scores over 24 months was also similar in all groups.

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.

However, the study found that even 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.

The study’s senior author, Richard Gray from the Nuffield Department of Population Health, said ‘The finding that minocycline fails to slow the progression of cognitive and functional decline in people with mild Alzheimer disease is disappointing but robust. There are many other commonly used drugs that might slow the relentless progress of dementia, and we need more trials like MADE to evaluate these.'  

In a linked editorial Lon S Schneider commented ‘Under many circumstances, pragmatic and cheap clinical trials can accomplish as much or more than complicated and expensive trials in learning safety, tolerability, effectiveness and whether a particular drug has a future or not.’ He concluded that the MADE trial was ‘an example of an efficient use of resources, a potentially rapid way to bring a re-purposed drug forward and to get an answer.’