Minocycline Improves Functional Outcomes After Acute Ischaemic Stroke in Phase III Trial

Original abstract

BACKGROUND: Minocycline has been reported as a multi-target anti-neuroinflammatory drug with potential benefits for ischaemic stroke in preclinical models and small-scale clinical studies. The EMPHASIS trial was designed to provide robust evidence regarding its efficacy and safety in patients with acute ischaemic stroke. METHODS: A multicentre, double-blind, randomised, placebo-controlled trial was conducted at 58 hospitals across China. Patients who had an ischaemic stroke in the previous 72 h with a National Institutes of Health Stroke Scale (NIHSS) score ranging from 4 to 25 and a level of consciousness score (subscale 1a of the NIHSS) of 1 or less were randomly assigned in a 1:1 ratio to receive minocycline or placebo in addition to routine treatment. Minocycline (loading dose of 200 mg, followed by 100 mg every 12 h for the subsequent 4 days) or matching placebo was administered orally. Block randomisation with a fixed block size of four stratified by study site was done with a computer-generated randomisation sequence. All patients, treating clinicians, and investigators involved in the trial were fully masked to treatment allocation. The primary outcome was an excellent functional outcome at 90 days (with a modified Rankin Scale [mRS] score of 0-1) and was analysed in all patients who were randomised and received at least one dose of the study drug, without imputation for missing data. Safety outcomes were assessed in participants who received at least one dose of the study drug and had at least one safety evaluation and included symptomatic intracranial haemorrhage at 24 h and 6 days. This trial was registered with ClinicalTrials.gov (NCT05836740) and is now completed. FINDINGS: Between May 19, 2023, and May 20, 2024, 1724 patients were randomly assigned to minocycline (n=862) or placebo (n=862) groups. Median age was 65 years (IQR 57-71). 1151 (66·8%) patients were male and 573 (33·2%) were female. Median NIHSS score at baseline was 5 (IQR 4-7). Four patients withdrew consent (three in the minocycline group and one in the placebo group) and 19 patients were lost to follow-up (nine in the minocycline group and ten in the placebo group). At 90 days, 447 (52·6%) of 850 patients with minocycline and 403 (47·4%) of 851 with placebo had an mRS score of 0-1 (adjusted risk ratio 1·11, 95% CI 1·03-1·20; p=0·0061). Ordinal analysis across the full range of mRS scores also favoured minocycline, with an adjusted common odds ratio of 1·19 (95% CI 1·03-1·38; p=0·018). The incidence of symptomatic intracranial haemorrhage was similar between the minocycline and placebo groups at 24 h (1/860 [0·1%] vs 0/861 [0%]) and 6 days (3/859 [0·3%] vs 0/861 [0%]). No significant differences were observed in other safety outcomes, including serious adverse events (40/862 [4·6%] in the minocycline group vs 51/862 [5·9%] in the placebo group; p=0·24). INTERPRETATION: Minocycline therapy initiated within 72 h of acute ischaemic stroke provided a significant functional outcome benefit compared with placebo at 90 days, without safety concerns. Future studies are needed to confirm these findings and to establish whether the benefits extend to patients with more severe or minor strokes. FUNDING: National Natural Science Foundation of China, Beijing Healthunion Cardio-cerebrovascular Disease Prevention and Treatment Foundation, Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science & Technology Commission, Chinese Institutes for Medical Research, Capital's Funds for Health Improvement and Research, and National Key R&D Program of China.