Minocycline Doesn't Slow Progression in Mild Alzheimer Disease

Robert Howard, MD

Results from a study comparing 2 doses of minocycline to placebo demonstrate that the agent did not slow progression of cognitive or functional impairment in people with mild Alzheimer disease (AD) over a 2-year period.

The Minocycline in Alzheimer Disease Efficacy (MADE) trial was a double-blind, randomized study that included 554 patients (241 women and 303 men; mean age, 74.3) with a diagnosis of mild AD (Standardized Mini-Mental State Examination [sMMSE] score >24). Patients were randomly assigned 1:1:1 to receive either dose of minocycline (400 mg/d or 200 mg/d) or placebo over a 24-month treatment period. The primary endpoints were decrease in sMMSE score and the Bristol Activities of Daily Living Scale (BADLS). The mean (standard deviation [SD]) sMMSE score among eligible participants was 26.4 (1.9).

Eligible participants must have had a diagnosis of possible or probable AD, were older than 50 years and have a caregiver supervise medication. Those excluded from the trial included people with uncontrolled serious concomitant illness, stage 3b to 5 chronic kidney disease, moderate liver disease, and participation in another clinical trial within the previous 28 days.

Among the 3 dose groups, fewer patients who received the 400 mg minocycline dose completed the study (28.8% [53 of 184]) compared to those who received the 200-mg treatment (61.9% [112 of 181]) and placebo (63.7% [114 of 179]; P <.001) mainly due to 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 = .01), and dizziness (14 in the 400-mg group, 3 in the 200-mg group, and 1 in the placebo group; P = .01).

The combined minocycline groups had mean sMMSE scores 0.1 point higher than the placebo group (95% CI, -1.1 to 1.2; P = .90), and saw a similar decrease in mean sMMSE scores over 24 months (4.1 vs 4.3 points). Notably, patients who received the 400-mg dose saw a smaller decrease in sMMSE scores compared to those who received the 200-mg dose (3.3 vs 4.7 points; treatment effect = 1.2; 95% CI, -0.1 to 2.5; P = .08). Each group had a similar regression in BADLS scores: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo group (treatment effect for minocycline vs placebo = -0.53; 95% CI, −2.4 to 1.3; P = .57; treatment effect for 400 mg vs 200 mg of minocycline = -0.31; 95% CI, −0.2 to 1.8; P = .77).

Not only do the results show little difference in alleviating progression of cognitive or functional impairment, but the high number of patients who received the 400-mg who failed to complete the trial demonstrates that the drug has a low tolerability as well.

“The failure of minocycline treatment to slow the progression of cognitive and functional decline in patients with mild AD is disappointing given the evidence suggesting that neuroinflammation is instrumental in AD progression and given minocycline’s antiinflammatory and neuroprotective effects, as well as the positive data from experimental AD models,” the investigators concluded.

REFERENCE

Howard R, Zubko O, Bradley R, et al. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease. JAMA Neurol. Published online November 18, 2019. doi:10.1001/jamaneurol.2019.3762.