Three RCTs: neither minocycline nor lanabecestat is better than placebo to treat patients with mild Alzheimer disease

Reference

Howard R, Zubko O, Bradley R, et al, for the Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial. JAMA Neurol 2019;77(2):164-174. Wessels AM, Tariot PN, Zimmer JA, et al. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer disease: the AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol 2019;77(2):199-209.

Synopsis

These 2 papers report the outcomes of 3 different randomized controlled trials that enrolled patients with mild Alzheimer disease (different definitions). In the Minocycline in Alzheimer Disease Efficacy (MADE) trial, the researchers randomized 544 patients to receive 400 mg minocycline daily (n = 184), 200 mg minocycline daily (n = 181), or placebo (n = 179). In the AMARANTH and DAYBREAK-ALZ trials, the patients received either lanabecestat 20 mg daily (both trial numbers combined = 1329), lanabecestat 50 mg daily (combined n = 1309), or placebo (combined n = 1302). Lanabecestat is an experimental drug that aims to inhibit the buildup of beta-amyloid, and is not commercially available. The MADE trial was designed as a 2-year study, while AMARANTH and DAYBREAK-ALZ trials were designed as a 2-year study and an 18-month study of active treatment, respectively. The latter trials also had a planned optional delayed start period when the placebo-treated patients would receive active treatment. Each of the trials had interesting challenges. In the MADE trial, only 29% of the 400 mg minocycline recipients completed the study compared with more than 60% of the 200 mg and placebo recipients. The AMARANTH and DAYBREAK-ALZ trials were each stopped early after a futility analysis. Although each of the studies used different measures of cognitive function, at the end of each study period, the patients who received active treatment were cognitively no better off than those who received placebo. Although the higher dose of minocycline was not well-tolerated (mainly gastrointestinal side effects), the rate of drop-outs due to adverse events was similar in the lanabecestat-treated and placebo-treated patients.