EMPHASIS: Efficacy and Safety of Minocycline in Patients With Moderate to Severe Acute Ischemic Stroke

Sponsor

Beijing Tiantan Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05836740

Collaborator

NeuroDawn Pharmaceutical Co., Ltd. (Other)

1,672

Enrollment

Arms

17.1

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The aim of this study was to evaluate the efficacy and safety of Minocycline versus placebo in the treatment of patients with moderate to severe acute ischemic stroke.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke, Acute	Drug: Minocycline hydrochloride capsule Drug: Placebo capsules of Minocycline hydrochloride capsules	Phase 3

Detailed Description

The aim of this study was to evaluate the efficacy and safety of 4.5-days Minocycline versus placebo in patients with moderate to severe acute ischemic stroke within 72 hours of onset. In addition, we will explore the effect of Minocycline versus placebo on indicators of venous neuroinflammation and thrombo-inflammation at different time points in patients with moderate to severe acute ischemic stroke within 72 hours of onset.

The primary objective is to evaluate the effect of Minocycline in improving the level of mRS score to 0-1 in patients with moderate to severe acute ischemic stroke within 72 hours of onset.

The trial was divided into three phases: screening/baseline period, treatment period, and follow-up period. The visit schedule is as follows: Randomized participants were interviewed at screening/baseline period, 24±2 hours, 6±1 days, 90±7 days after randomization, and when events occurred.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1672 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This trial was a prospective, randomized, multicenter, double-blind, placebo-controlled parallel trial. Participants were randomly assigned according to the ratio of the experimental group: control group =1:1.This trial was a prospective, randomized, multicenter, double-blind, placebo-controlled parallel trial. Participants were randomly assigned according to the ratio of the experimental group: control group =1:1.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

The Minocycline drug used in the study is indistinguishable from the Minocycline placebo (the shape, color, and appearance are identical). In addition, to ensure the blind method, the drug packaging and batch numbers of the two groups are identical, and the packaging batch numbers are uniformly marked. During the implementation of the study, except for the authorized personnel of the company's supply chain, research management department, and subject security department, members of each research execution group, research center personnel, and CRO data processing personnel cannot view the randomization scheme. The blind method was also used to evaluate the outcome. The participants were randomly divided into groups and blinded to the members of the adjudication committee.

Primary Purpose:

Treatment

Official Title:

Efficacy and Safety of Minocycline in Patients With Moderate to Severe Acute Ischemic Stroke: A Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Phase III Trial

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Minocycline treatment group Minocycline Hydrochloride Capsules (50 mg per capsule) The first dose should be given immediately after randomization (within 30 minutes); 200mg (4 capsules) for the first dose; Subsequently, 100mg (2 capsules) will be administered once every 12 hours, a total of 9 times (lasting 4.5 days; the subject with dysphagia will be administrated through a nasal feeding tube)	Drug: Minocycline hydrochloride capsule 50 mg per capsule, containing 50mg of Minocycline Hydrochloride.
Placebo Comparator: Minocycline placebo-control group Placebo of Minocycline Hydrochloride capsules (50mg per capsule, containing 0 mg of Minocycline) The method of administration was the same as that of treatment group.	Drug: Placebo capsules of Minocycline hydrochloride capsules 50 mg per capsule, containing 0mg of Minocycline Hydrochloride.

Arm

Intervention/Treatment

Active Comparator: Minocycline treatment group

Minocycline Hydrochloride Capsules (50 mg per capsule) The first dose should be given immediately after randomization (within 30 minutes); 200mg (4 capsules) for the first dose; Subsequently, 100mg (2 capsules) will be administered once every 12 hours, a total of 9 times (lasting 4.5 days; the subject with dysphagia will be administrated through a nasal feeding tube)

Drug: Minocycline hydrochloride capsule

50 mg per capsule, containing 50mg of Minocycline Hydrochloride.

Placebo Comparator: Minocycline placebo-control group

Placebo of Minocycline Hydrochloride capsules (50mg per capsule, containing 0 mg of Minocycline) The method of administration was the same as that of treatment group.

Drug: Placebo capsules of Minocycline hydrochloride capsules

50 mg per capsule, containing 0mg of Minocycline Hydrochloride.

Outcome Measures

Primary Outcome Measures

mRS score 0-1 [At 90±7 days after randomization.]
Modified Rankin Scale score.

Secondary Outcome Measures

mRS score. [At 90±7 days after randomization.]
Modified Rankin Scale score.
Changes in NIHSS score compared with baseline score. [At 24±1 hours and 6±1 days after randomization.]
NIHSS score
Changes in hs-CRP level compared with baseline level. [At 6±1 days after randomization.]
hs-CRP was examined to evaluate the level of systematic inflammation
Early neurological deterioration. [At 24±2 hours and 6±1 days after randomization.]
Early neurological deterioration was defined as any new neurological symptoms or signs that occur within several hours or days of onset, as well as the progression of existing neurological deficit symptoms or signs.
Recurrent stroke. [At 90±7 days after randomization.]
Recurrent stroke includes recurrent ischemic stroke and recurrent hemorrhagic stroke.
Recurrent ischemic stroke. [At 90±7 days after randomization.]
The condition of recurrent ischemic stroke.
Combined vascular events. [At 90±7 days after randomization.]
Combined vascular events referred to stroke, myocardial infarction, and vascular death.
Quality of life (EQ-5D) score. [At 90±7 days after randomization.]
Scores of EuroQol (Quality of life) -5 Dimensions.

Other Outcome Measures

Changes in the levels of venous neuroinflammation indicators and thrombotic inflammation indicators compared with baseline levels. [At 24±2 hours and 6±1 days after randomization.]
Venous neuroinflammation indicators (NF-L, S100B, copeptin, etc.) and thrombotic inflammation indicators (plasma sGPVI, sADAMTS 13, sCD40L, sP-selectin, etc.)
Cerebral hemodynamic function. [At 6±1 days and 90±7 days after randomization.]
Cerebral hemodynamics was reflected by cerebral autoregulation function, and autonomic nervous function was evaluated by heart rate variability.
Changes in the levels of venous intestinal flora metabolites compared with baseline levels [At 6±1 days after randomization.]
plasma TMAO and its precursors, etc.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

18≤Age≤80 years old;
Patients with acute ischemic stroke confirmed by CT or MRI within 72 hours of onset;
4≤NIHSS≤25, and Ia≤1;
First stroke or mRS 0-1 before the onset of current stroke;
Patients or his/her legal representatives are able to understand and sign the informed consent.

Exclusion criteria:

History of pseudomembranous colitis or antibiotic-related colitis.
Allergic to tetracycline antibiotics or any component of the investigational drug.
Known to be resistant to other tetracyclines.
Took tetracycline antibiotics within previous one week.
Known community-acquired bacterial infection, such as pneumonia or urinary tract infection.
History of intracranial hemorrhagic diseases within previous 3 months, including parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural/external hematoma, etc.
Intracranial tumors, vascular malformations and other intracranial space-occupying lesions.
Rare or unknown etiology of LVO, such as dissection and vasculitis.
Severe hepatic insufficiency, renal insufficiency or receiving dialysis before randomization for various reasons (Severe hepatic insufficiency was defined as ALT >3 times the upper limit of normal value or AST >3 times the upper limit of normal value; Severe renal insufficiency was defined as creatinine > 3.0 mg/dl [265.2 μmol/L] or glomerular filtration rate<30 ml/min/1.73m2).
Bleeding tendency (including but not limited to): platelet count <100×109/L; Administration of oral warfarin and INR>2; Administration of heparin within previous 48 hours and APTT≥35s; Hereditary bleeding disorders, such as hemophilia.
Received any of the following treatments within previous 3 months: systemic retinoic acid, androgen/antiandrogen therapy (e.g., anabolic steroids, andiolactone).
History of intracranial or spinal surgery within previous 3 months; History of therapeutical surgery or major physical trauma within previous 1 month.
Women of childbearing age who do not use effective contraception and have no negative pregnancy test records; Women during lactation and pregnancy.
Life expectancy of less than 6 months due to advanced stage of comorbidity.
Participated in other interventional clinical trials within previous 3 months.
Other conditions that are not suitable for participating in this clinical trial, such as inability to understand and/or follow the research procedures due to mental, cognitive, emotional, or physical disorders, etc.