Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer’s disease: the MADE Phase II, three-arm RCT
Authors: Howard Robert , Zubko Olga , Gray Richard , Bradley Rosie , Harper Emma , Kelly Linda , 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 , Wilcock Gordon , Nilforooshan Ramin 
Published: April 2020

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.