EMPHASIS
(2026)Objective
To evaluate the efficacy and safety of minocycline in addition to routine treatment for improving 90-day functional outcomes in patients with acute ischaemic stroke.
Study Summary
• Ordinal mRS shift analysis also favored minocycline (cOR 1.19, p=0.018)
• No significant safety concerns; similar rates of symptomatic ICH and serious adverse events between groups
Intervention
Minocycline 200mg loading dose followed by 100mg every 12 hours for 4 days (4.5-day course) versus matching placebo, both added to routine stroke treatment
Inclusion Criteria
Age 18-80 years, ischaemic stroke confirmed by CT/MRI within 72 hours of onset, NIHSS 4-25, level of consciousness score (NIHSS 1a) ≤1, first-ever stroke or pre-stroke mRS ≤1
Study Design
Arms: Minocycline plus routine treatment vs Placebo plus routine treatment
Patients per Arm: 862 per arm (1724 total)
Outcome
• Secondary: mRS 0-2 at 90 days: 72.4% vs 67.8% (RR 1.07, p=0.0056)
• Safety: Symptomatic ICH at 6 days 0.3% vs 0%; SAEs 4.6% vs 5.9% (p=0.24)
Bottom Line
Minocycline initiated within 72 hours of acute ischaemic stroke significantly improved the rate of excellent functional outcome (mRS 0-1) at 90 days compared with placebo, with no significant safety concerns. This supports minocycline as a potential safe, cost-effective adjunctive therapy for acute ischaemic stroke.
Major Points
- First large-scale, double-blind RCT of minocycline in acute ischaemic stroke (n=1724)
- Minocycline (200mg load, then 100mg q12h for 4 days) given within 72 hours of stroke onset
- Primary outcome achieved: mRS 0-1 at 90 days was 52.6% vs 47.4% (adjusted RR 1.11, p=0.0061)
- Ordinal mRS shift analysis also favored minocycline (cOR 1.19, p=0.018)
- Significant improvement in mRS 0-2 (72.4% vs 67.8%, p=0.0056) but not mRS 0-3
- NIHSS improved significantly at 6 days (β -0.28, p=0.015) but not at 24 hours
- No significant difference in symptomatic ICH, serious adverse events, or mortality
- Subgroup analysis suggested benefit in patients with alcohol use history and in large-artery/small vessel disease
- Trial conducted exclusively in China; median baseline NIHSS was 5 (mild-moderate stroke)
- Minocycline targets post-ischaemic neuroinflammation through microglial modulation
Study Design
- Study Type
- Prospective multicentre double-blind randomised placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; all patients, treating clinicians, investigators, and outcome assessors were fully masked to treatment allocation. Minocycline and placebo capsules were identical in appearance and taste.
- Sample Size
- 1724
- Follow-up
- 90 days
- Centers
- 58
- Countries
- China
Primary Outcome
Definition: Excellent functional outcome at 90 days, defined as modified Rankin Scale (mRS) score of 0-1
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 403/851 (47.4%) | 447/850 (52.6%) | - (1.03-1.20) | 0.0061 |
Limitations & Criticisms
- Trial conducted exclusively in China with all Chinese participants; results may not be generalizable to non-Asian populations
- Upper age limit of 80 years excluded older patients who may be at higher risk of complications
- Median baseline NIHSS was 5 (mild-moderate stroke); generalizability to more severe or minor strokes uncertain
- Observed treatment effect (52.6% vs 47.4%) and proportion achieving excellent outcome were lower than anticipated (68% vs 60%)
- Borderline statistical significance; worst-case imputation sensitivity analysis showed attenuated, marginally non-significant result (p=0.054)
- Only 1.3% lost to follow-up, but missing data direction could affect results
- hs-CRP concentrations not centrally analysed; inter-site variability in reagents/instruments
- Block randomisation with fixed block size of 4 posed minimal risk of allocation predictability
- Only 14.2% received reperfusion therapy; limited power to assess interaction with EVT/tPA
- Short treatment duration (4.5 days) limits assessment of prolonged anti-inflammatory effects
- No reduction in recurrent stroke or composite vascular events observed
- Potential discrepancies between preclinical models and clinical patients require further mechanistic investigation
Citation
Lu Y, Guan L, Wu J, et al. Efficacy and safety of minocycline in patients with acute ischaemic stroke (EMPHASIS): a multicentre, double-blind, randomised controlled trial. Lancet. 2026. Published online January 30, 2026.