Ischaemic Stroke
Conditions
Keywords
Ischaemic stroke, Intravenous thrombolysis, Minocycline, Randomized Controlled Trial, Functional outcome
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.
Interventions
DRUGMinocycline 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.
DRUGPlacebo 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.
Sponsors
Beijing Tiantan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Eligible patients will be randomly assigned in a 1:1 ratio to receive minocycline or placebo. Treatment will be initiated before intravenous thrombolysis or within 2 hours after its initiation, and last for 4.5 days. The primary outcome is an excellent functional outcome (a mRS score of 0 or 1) at 90 days.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Excellent functional outcome (mRS of 0-1) | 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
| Measure | Time frame | Description |
|---|---|---|
| Good functional outcome (mRS of 0-2) | 90 days | 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). |
| Distribution of mRS score | 90 days | The ordinal distribution of mRS score of 0 to 6 points |
| Quality of life score (EQ-5D scale) | 90 days | 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. |
| Barthel Index score ≥ 95 | 90 days | The Barthel index score ranges from 0 to 100, with higher scores indicating better independent function. |
| Changes from baseline of National Institutes of Health Stroke Scale (NIHSS) score | 6 days | 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. |
| Major neurologic improvement | 6 days | 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. |
| The proportion of participants with diarrhoea, enteritis, and constipation | 6 days | — |
| The proportion of participants with symptomatic intracranial hemorrhage | 6 days | Defined by the European Cooperative Acute Stroke Study III (ECASS III) |
| The proportion of participants with any bleeding events | 90 days | Defined by the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries Criteria (GUSTO) |
| The proportion of participants with adverse events | 90 days | — |
| The proportion of participants with serious adverse events | 90 days | — |
Countries
China
Contacts
CONTACTAnxin Wang, PhD
PRINCIPAL_INVESTIGATORYilong Wang, MD, PhD
Beijing Tiantan Hospital
PRINCIPAL_INVESTIGATORAnxin Wang, PhD
Beijing Tiantan Hospital
Outcome results
None listed