Efficacy and Safety of Minocycline in Patients With Acute Ischaemic Stroke Receiving Intravenous Thrombolysis (EMPHASIS-2)

Efficacy and Safety of Minocycline in Patients With Acute Ischaemic Stroke Receiving Intravenous Thrombolysis (EMPHASIS-2): A Multicenter, Randomized, Double-blind, Placebo-parallel Controlled Trial

The aim of this study is to assess the efficacy and safety of minocycline in improving functional outcome among patients with acute ischaemic stroke receiving intravenous thrombolysis.

Study Overview

• Status: Not yet recruiting
• Conditions: Ischaemic Stroke
• Intervention / Treatment: Drug: Minocycline Hydrochloride Capsule (50 mg per capsule); Drug: Placebo of Minocycline Hydrochloride Capsule (50 mg per capsule, containing 0 mg of minocycline)

Detailed Description

Minocycline, a broad-spectrum tetracycline antibiotic, has been shown to possess a wide range of cytoprotective properties independent of its antibacterial activity, which have translated into promising therapeutic potential for acute ischaemic stroke. Specifically, the drug improves post-stroke outcomes by targeting post-ischaemic neuroinflammation through multiple mechanisms. Early-phase clinical trials first indicated that minocycline treatment, initiated within 6-24 hours after stroke, could improve functional outcomes for up to 90 days. This promise was recently substantiated by the EMPHASIS trial, which demonstrated that minocycline administered within 72 hours of ischaemic stroke onset significantly improved 90-day functional outcomes compared to placebo, with a favorable safety profile. Furthermore, preclinical research has shown that combining minocycline with t-PA can improve thrombolytic efficacy, extend the therapeutic time window, and reduce the risk of hemorrhagic transformation. Hence, this study-a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial-aims to evaluate whether minocycline improves functional outcomes in patients with acute ischaemic stroke undergoing intravenous thrombolysis.

Patients aged 18 to 80 years with a newly diagnosed ischaemic stroke (NIHSS score of 6-25 and Ia ≤1), who have received/are planned to receive intravenous thrombolysis within 4.5 hours of onset or within an extended window of 4.5-24 hours based on guideline recommendations, and can be treated with the study drug either before thrombolysis or within 2 hours after its initiation, will be enrolled. Eligible patients will be randomly assigned in a 1:1 ratio to receive minocycline or placebo.

The primary efficacy outcome is an excellent functional outcome (a mRS score of 0 or 1) at 90 days. The secondary efficacy outcomes include a good functional outcome (a mRS score of 0 to 2) at 90 days, the ordinal distribution of mRS score at 90 days, quality of life (EQ-5D) score at 90 days, a Barthel Index score of at least 95 at 90 days, the change from baseline in the NIHSS score at 6 days, and major neurologic improvement at 6 days (defined as a decrease from baseline of ≥ 4 points on the NIHSS, or an NIHSS score of ≤1). Safety outcomes include diarrhoea, enteritis, and constipation within 6 days, symptomatic intracranial hemorrhage within 6 days, any bleeding events, adverse events or serious adverse events within 90 days.

Randomized participants will be interviewed at screening/baseline period, 6 days, 30±3 days, 60±5 days, and 90±7 days after randomization.

• Study Type: Interventional
• Enrollment (Estimated): 934
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anxin Wang, PhD; Phone Number: 8601059976951; Email: wanganxin@bjttyy.com

Study Locations

• China
  • Beijing, China, 100070
    • Beijing Tiantan Hospital
    • Contact: Anxin Wang, PhD; Phone Number: 8601059976951; Email: wanganxin@bjttyy.com
    • Principal Investigator: Yilong Wang, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age between 18 and 80 years;
2. Patients with acute ischaemic stroke confirmed by CT or MRI;
3. Having received or planning to receive intravenous thrombolysis within 4.5 hours of onset or within an extended window of 4.5-24 hours based on guideline recommendations (The intravenous thrombolytic drugs include: alteplase, tenecteplase, reteplase or recombinant human prourokinase);
4. The study drug can be applied before intravenous thrombolysis or within 2 hours after the initiation of intravenous thrombolysis;
5. 6≤NIHSS≤25, and Ia≤1;
6. Signed informed consent.

Exclusion Criteria:

1. mRS score ≥ 2 prior to onset of the current stroke;
2. History of pseudomembranous colitis or antibiotic-associated colitis;
3. Known allergy or intolerance to tetracycline antibiotics or any component of minocycline;
4. Known resistance to other tetracyclines;
5. Use of tetracycline antibiotics within the past 7 days;
6. Presence of a known community-acquired bacterial infection (e.g., pneumonia, urinary tract infection) or any other concurrent infection requiring antibiotic treatment;
7. History of intracranial hemorrhagic disease within the past 3 months, for example, parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural or epidural hematoma.
8. Malformation, tumor, abscess, or other major non-ischaemic brain diseases (e.g., multiple sclerosis, other intracranial space-occupying lesions) on baseline cranial CT or MRI;
9. Rare or unknown etiology of large vessel occlusion (e.g., arterial dissection, vasculitis);
10. History of systemic lupus erythematosus;
11. Known severe hepatic insufficiency (ALT or AST > 3 times of the upper limit of normal), severe renal insufficiency (creatinine > 3.0 mg/dL [265.2 μmol/L], estimated glomerular filtration rate <30 mL/min/1.73m², or have received dialysis before randomization);
12. Use of tretinoin, androgen or antiandrogen treatment (e.g., anabolic steroids, spironolactone) within the past 3 months;
13. Pregnant, breastfeeding, or of childbearing potential who are unwilling to use effective contraception throughout the study;
14. Presence of a severe non-cardio-cerebrovascular disease with a life expectancy of less than 6 months;
15. Participation in any other clinical trial within the past 30 days;
16. Any other condition that is not suitable for participating in this clinical trial, such as inability to understand or follow the study procedures due to physical, cognitive, emotional, or mental disorders.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Minocycline Therapy; This group will receive minocycline hydrochloride capsules.	Drug: Minocycline Hydrochloride Capsule (50 mg per capsule); A loading dose of 200 mg will be administered before intravenous thrombolysis or within 2 hours after the initiation of intravenous thrombolysis, followed by a maintenance dose of 100 mg every 12 hours for the subsequent 4 days. A total of 9 times will be administered over a period of 4.5 days. Minocycline hydrochloride capsules will be administered orally or via a nasogastric feeding tube if the participant has dysphagia.
Placebo Comparator: Placebo; This group will receive placebo of minocycline hydrochloride capsules.	Drug: Placebo of Minocycline Hydrochloride Capsule (50 mg per capsule, containing 0 mg of minocycline); A loading dose of 200 mg will be administered before intravenous thrombolysis or within 2 hours after the initiation of intravenous thrombolysis, followed by a maintenance dose of 100 mg every 12 hours for the subsequent 4 days. A total of 9 times will be administered over a period of 4.5 days. Placebo capsules will be administered orally or via a nasogastric feeding tube if the participant has dysphagia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Excellent functional outcome (mRS of 0-1)	Defined as an modified Rankin Scale (mRS) score of 0 or 1. The mRS scores range from 0 (no symptoms) to 5 (severe disability) and 6 (death).	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Distribution of mRS score	The ordinal distribution of mRS score of 0 to 6 points	90 days
Good functional outcome (mRS of 0-2)	Defined as an modified Rankin Scale (mRS) score of 0 or 2. The mRS scores range from 0 (no symptoms) to 5 (severe disability) and 6 (death).	90 days
Quality of life score (EQ-5D scale)	The European Quality of Life 5-Dimension (EQ-5D）questionnaire for measuring generic health status. The 5-level EQ-5D version (EQ-5D-5L) comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The sum score on each of the five dimensions ranges from 5 (all domains have level 1) to 25 (all domains have level 5), with higher scores indicating worse health-related quality of life.	90 days
Barthel Index score ≥ 95	The Barthel index score ranges from 0 to 100, with higher scores indicating better independent function.	90 days
Changes from baseline of National Institutes of Health Stroke Scale (NIHSS) score	Defined as the difference between the 6-day NIHSS score and the baseline NIHSS score. The National Institutes of Health Stroke Scale (NIHSS) score ranges from 0 to 42, with higher scores indicating more severe neurological deficit.	6 days
Major neurologic improvement	Defined as NIHSS score ≤ 1 point at 6 days or an improvement of ≥ 4 points compared to the baseline NIHSS score. The National Institutes of Health Stroke Scale (NIHSS) score ranges from 0 to 42, with higher scores indicating more severe neurological deficit.	6 days
The proportion of participants with diarrhoea, enteritis, and constipation		6 days
The proportion of participants with symptomatic intracranial hemorrhage	Defined by the European Cooperative Acute Stroke Study III (ECASS III)	6 days
The proportion of participants with any bleeding events	Defined by the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries Criteria (GUSTO)	90 days
The proportion of participants with adverse events		90 days
The proportion of participants with serious adverse events		90 days

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Investigators: Principal Investigator: Yilong Wang, MD, PhD, Beijing Tiantan Hospital; Principal Investigator: Anxin Wang, PhD, Beijing Tiantan Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: April 8, 2026
• First Submitted That Met QC Criteria: April 8, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Minocycline; Functional outcome; Intravenous thrombolysis; Ischaemic stroke
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke; cyclopia sequence; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Naphthacenes; Tetracyclines; Minocycline
• Other Study ID Numbers: 2025-B14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No