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
Overview
- Phase
- Phase 3
- Status
- Not yet recruiting
- Sponsor
- Beijing Tiantan Hospital
- Enrollment
- 934
- Locations
- 1
- Primary Endpoint
- Excellent functional outcome
Overview
Brief Summary
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.
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
This study adopts a double-blind design. Study drugs and placebos are identically packaged. The dosage form, size, color, weight, smell, and taste of the placebo are basically similar to those of the research drug, and there is no risk of blinding. Personnel involved in randomization or potentially exposed to treatment allocation (including pharmacy staff) are not involved in patient care, outcome assessment, or data analysis. Blinded investigators and outcome assessors remain unaware of treatment assignments throughout the study.
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age between 18 and 80 years;
- •Patients with acute ischaemic stroke confirmed by CT or MRI;
- •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);
- •The study drug can be applied before intravenous thrombolysis or within 2 hours after the initiation of intravenous thrombolysis;
- •6≤NIHSS≤25, and Ia≤1;
- •Signed informed consent.
Exclusion Criteria
- •mRS score ≥ 2 prior to onset of the current stroke;
- •History of pseudomembranous colitis or antibiotic-associated colitis;
- •Known allergy or intolerance to tetracycline antibiotics or any component of minocycline;
- •Known resistance to other tetracyclines;
- •Use of tetracycline antibiotics within the past 7 days;
- •Presence of a known community-acquired bacterial infection (e.g., pneumonia, urinary tract infection) or any other concurrent infection requiring antibiotic treatment;
- •History of intracranial hemorrhagic disease within the past 3 months, for example, parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural or epidural hematoma.
- •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;
- •Rare or unknown etiology of large vessel occlusion (e.g., arterial dissection, vasculitis);
- •History of systemic lupus erythematosus;
Arms & Interventions
Minocycline Therapy
This group will receive minocycline hydrochloride capsules.
Intervention: Minocycline Hydrochloride Capsule (50 mg per capsule) (Drug)
Placebo
This group will receive placebo of minocycline hydrochloride capsules.
Intervention: Placebo of Minocycline Hydrochloride Capsule (50 mg per capsule, containing 0 mg of minocycline) (Drug)
Outcomes
Primary Outcomes
Excellent functional outcome
Time Frame: 90 days
An modified Rankin Scale (mRS) score of 0 or 1
Excellent functional outcome (mRS of 0-1)
Time Frame: 90 days
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).
Secondary Outcomes
- Serious adverse events(90 days)
- Good functional outcome(90 days)
- Distribution of mRS score(90 days)
- Quality of life score(90 days)
- Changes in NIHSS scores(6 days)
- Diarrhoea, enteritis, and constipation(6 days)
- Symptomatic intracranial hemorrhage(6 days)
- Any bleeding events(90 days)
- Adverse events(90 days)
- Barthel Index score ≥ 95(90 days)
- Major neurologic improvement(6 days)
- Good functional outcome (mRS of 0-2)(90 days)
- The proportion of participants with adverse events(90 days)
- The proportion of participants with serious adverse events(90 days)
- Quality of life score (EQ-5D scale)(90 days)
- Changes from baseline of National Institutes of Health Stroke Scale (NIHSS) score(6 days)
- The proportion of participants with diarrhoea, enteritis, and constipation(6 days)
- The proportion of participants with symptomatic intracranial hemorrhage(6 days)
- The proportion of participants with any bleeding events(90 days)
Investigators
yilong Wang
Principal Investigator
Beijing Tiantan Hospital