Efficacy and Safety of Minocycline in Patients With Acute Ischaemic Stroke Receiving Intravenous Thrombolysis

Official title

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

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.

Interventions

• 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.
• 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.

Primary outcome measures

• Excellent functional outcome (mRS of 0-1) [Time frame: 90 days]

Secondary outcome measures (11)

• Good functional outcome (mRS of 0-2) [Time frame: 90 days]
• Distribution of mRS score [Time frame: 90 days]
• Quality of life score (EQ-5D scale) [Time frame: 90 days]
• Barthel Index score ≥ 95 [Time frame: 90 days]
• Changes from baseline of National Institutes of Health Stroke Scale (NIHSS) score [Time frame: 6 days]
• Major neurologic improvement [Time frame: 6 days]
• The proportion of participants with diarrhoea, enteritis, and constipation [Time frame: 6 days]
• The proportion of participants with symptomatic intracranial hemorrhage [Time frame: 6 days]
• The proportion of participants with any bleeding events [Time frame: 90 days]
• The proportion of participants with adverse events [Time frame: 90 days]
• The proportion of participants with serious adverse events [Time frame: 90 days]

Eligibility criteria

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;
• 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);
• Use of tretinoin, androgen or antiandrogen treatment (e.g., anabolic steroids, spironolactone) within the past 3 months;
• Pregnant, breastfeeding, or of childbearing potential who are unwilling to use effective contraception throughout the study;
• Presence of a severe non-cardio-cerebrovascular disease with a life expectancy of less than 6 months;
• Participation in any other clinical trial within the past 30 days;
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 3 centers

• Liaocheng Third People's Hospital — Liaocheng
• Guanxian People's Hospital — Liaocheng
• Beijing Tiantan Hospital — Beijing

Identifiers

NCT: NCT07526987 · 2025-B14

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗