Minocycline for Acute Ischemic Stroke Undergoing Endovascular Treatment Due to Basilar Artery Occlusion (MIST-B) (MIST-B)

Minocycline for Acute Ischemic Stroke Undergoing Endovascular Treatment Due to Basilar Artery Occlusion: a Randomized, Open-label, Proof of Concept Study

This is a multi-center, evaluator-blinded, randomized, open-label, proof of concept trial to explore possible beneficial effect of adjunctive oral minocycline on acute ischemic stroke (AIS) undergoing endovascular treatment due to basilar artery occlusion (BAO). Minocycline has excellent safety profiles, have been previously demonstrated individually to reduce infarction in animal models of stroke, and have potentially mechanisms of antioxidant, anti-inflammatory, anti-apoptotic and protection of blood-brain barrier. However, it is not known whether minocycline can reduce futile recanalization of endovascular treatment, and improve the outcome of patients with AIS due to BAO. Eligible and willing subjects will be randomly assigned to the treatment group or the control group. The treatment group will receive 200 mg oral minocycline, followed by 100 mg every 12 hours times for a total of 5 days. Both groups will receive endovascular thrombectomy and standard medical. The treatment with minocycline will start as soon as possible after randomization. Considering the risk of difficulty in feeding tube before EVT, minocycline administered within one hours after EVT is acceptable. Measures of stroke severity and disability will be recorded at baseline and through the follow-up periods (90 days). The evaluator will be blind to the allocation of patients further minimizing the bias.

Study Overview

• Status: Active, not recruiting
• Conditions: Ischemic Stroke, Acute; Basilar Artery Occlusion; Minocycline; Endovascular Treatment
• Intervention / Treatment: Drug: Minocycline

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Department of Neurology, Xijing Hospital, Fourth Military Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years old.
2. Patients had acute symptoms and signs compatible with ischemia due to basilar artery occlusion (BAO), treated with endovascular therapy. Patients with occlusion of intracranial segments of both vertebral arteries (VA) resulting in no flow to the basilar artery (eg, functional basilar artery occlusion) were also eligible for the study.
3. Last known well to groin puncture between 0 to 24 hours, whether or not patients had thrombolysis with rt-PA.
4. Pre-stroke mRS score of 0-1.
5. Baseline expanded NIHSS (e-NIHSS) score ≥ 6.
6. Signed Informed Consent obtained.
7. Neuroimaging Inclusion Criteria: (1) Proven large vessel occlusion in BAO or VA-V4 occlusion (mTICI score 0-1) determined by MRA or CTA; (2) pc-ASPECTS score ≥ 5 (Non-Contrast CT or DWI); Pons-midbrain-index of<3.

Exclusion Criteria:

1. Age<18 years old.
2. Complete cerebellar infarct with significant mass effect or has the imaging features of acute hydrocephalus in NCCT.
3. Intracranial hemorrhage.
4. Previous stroke in the past 90 days;
5. cardiopulmonary resuscitation was performed within 10 days prior to onset.
6. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, INR >3, or platelet<40×109/L.
7. Glucose <2.2 or >22 mmol/L.
8. Systolic blood pressure persistently>185mmHg post-MT despite antihypertensive intervention; Diastolic blood pressure persistently>110mmHg post-MT despite antihypertensive intervention.
9. Acute or chronic renal failure of CKD grade 3-4.
10. Known allergy or hypersensitivity to contrast dye or tetracycline group of drugs.
11. Epileptic seizure at symptom onset.
12. Life expectancy (except for stroke) < 3 months.
13. Female who is pregnancy or breastfeeding, or whom do not use effective contraception at childbearing age.
14. Pre-existing mental illness that interferes with neurological evaluation.
15. Known current participation in another clinical investigation with experimental drug.
16. Unlikely to be available for 90 days follow-up.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment group; Patients randomized to the treatment group will receive oral minocycline in addition to endovascular treatment and other standard medical. The first dose of minocycline will be administered 200 mg orally, followed by 100 mg every 12 hours times for a total of 5 days. After randomization, oral minocycline should be given as soon as possible before the EVT treatment. If vomiting occurs within half an hour of the first dose, the clinician should assess the necessary of re-administering 100mg based on the severity of vomiting. If the patient is considered to be at any risk for aspiration or is unable to swallow based on swallowing evaluation, study drug will be oral via feeding tube. Considering the risk of difficulty in feeding tube before EVT, minocycline administered within one hours after EVT is acceptable.	Drug: Minocycline; 200 mg minocycline orally or via feeding tube, followed by 100 mg every 12 hours times for a total of 5 days. If vomiting occurs within half an hour of the first dose, the clinician should assess the necessary of re-administering 100mg based on the severity of vomiting. Considering the risk of difficulty in feeding tube before EVT, minocycline administered within one hours after EVT is acceptable.; Other Names: Minocycline hydrochloride
No Intervention: Control group; Patients randomized to the control group will receive endovascular treatment and other standard treatment, without minocycline treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The expanded NIH Stroke Scale (e-NIHSS) at 5-7 days or at discharge	The primary effectiveness outcome was the e-NIHSS score at 5-7 days or at discharge. 11-item neurologic examination scale for severity of posterior circulation stroke, adding specific elements in existing items of NIHSS.	5-7 days or discharge after onset
Incidence of symptomatic intracranial hemorrhage at 24 hours from randomization	The primary safety outcome was the incidence of symptomatic intracranial hemorrhage, defined as neurological deterioration (≥4-point increase on the NIHSS score) within 24 hours from randomization and evidence of intracranial hemorrhage on imaging studies.	24 hours from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Intensive Care Unit (ICU) stay and hospital stay	Length of ICU or hospital stay	From the date of admission until discharged from ICU or hospital, up to 4 weeks
mRS at 90 (±14) days	Secondary outcome measure is the degree of disability or dependence at 90 (±14) days as assessed by the mRS scale. The scale runs from 0-6 with "0" being perfect health without symptoms to "6" being death.	90 (±14) days from randomization
Good outcome at 90 (±14) days from randomization	An mRS score of 0-3 indicated a good outcome, whereas a score of >3 indicated a poor outcome.	90 (±14) days from randomization
Favorable outcome at 90 (±14) days from randomization	An mRS score of 0-2 indicated a favorable outcome, whereas a score of >2 indicated a poor outcome.	90 (±14) days from randomization
Excellent outcome at 90 (±14) days from randomization	An mRS score of 0-1 indicated an excellent outcome, whereas a score of >1 indicated a poor outcome	90 (±14) days from randomization
NIH Stroke Scale (NIHSS) at 24 hours, 5-7 days or discharge, 30 (±7) days and 90 (±14) days from randomization	11-item neurologic examination scale for severity of stroke. Ratings for each item are scored with 3 to 5 grades. A total NIHSS of 0 is normal; 1-4 is considered a minor stroke; 5-15 moderate; 16-20 moderate to severe; and 21-42 severe.	90 (±14) days from randomization
Modified Barthel Index at 30 (±7) days and 90 (±14) days	The modified Barthel Index (mBI) is an ordinal scale used to measure performance in activities of daily living (ADL). The Barthel Index score are scored, a higher number being a reflection of greater ability to function independently following hospital discharge.	30 (±7) days and 90 (±14) days from randomization
Incidence of symptomatic intracranial hemorrhage at 3 days from randomization	The secondary safety outcome was the incidence of symptomatic intracranial hemorrhage, defined as neurological deterioration (≥4-point increase on the NIHSS score) within 3 days from randomization and evidence of intracranial hemorrhage on imaging studies.	3 days from randomization
Mortality at 90 (±14) days from randomization	All-cause mortality occurring within 90 (±14) days follow-up were recorded.	90 (±14) days from randomization
Change in infarct volume from baseline to day 5-7 or discharge	Changes of infarct volume from baseline (measured by DWI) to day 5-7 or discharge of stroke onset (measured by Flair). Images are processed by imSTROKE software.	5-7 days from randomization or discharge
Pneumonia at 5-7 days or discharge, 30 (±7) days and 90 (±14) days	Determine whether rates of pneumonia are different in the two arms. Rates will be measured as percentages of the entire population at risk.	90 (±14) days from randomization
Time of mechanical ventilation or non-invasive ventilation at 5-7 days or at discharge	Determine whether time of mechanical ventilation or non-invasive ventilation are different in the two arms. Rates will be measured as percentages of the entire population at risk.	5-7 days from randomization or discharge
Change in hematology assessments: percentage of the lymphocyte subpopulations (%) at 5-7 days or at discharge as compared to Baseline	The percentage of lymphocyte subpopulations in % will be assessed by flow cytometry.	5-7 days from randomization or discharge
Change in hematology assessments: matrix metalloproteinase-9 (ng/ml) at 5-7 days or at discharge as compared to Baseline	The level of matrix metalloproteinase-9 in ng/ml will be assessed by ELISA method.	5-7 days from randomization or discharge
Change in hematology assessments: IL-6 (pg/ml) at 5-7 days or at discharge as compared to Baseline	The level of IL-6 in pg/ml will be assessed by ELISA method.	5-7 days from randomization or discharge
Change in hematology assessments: IL-10 (pg/ml) at 5-7 days or at discharge as compared to Baseline	The level of IL-10 in pg/ml will be assessed by ELISA method.	5-7 days from randomization or discharge
Change in hematology assessments: TNF-α (nmol/L) at 5-7 days or at discharge as compared to Baseline	The level of TNF-α in nmol/L will be assessed by ELISA method.	5-7 days from randomization or discharge
Change in hematology assessments: leucocytes (x 10^9 /L) at 5-7 days or at discharge as compared to Baseline	Change in the level of leucocytes x 10^9 /L.	5-7 days from randomization or discharge
Change in hematology assessments: neutrophilic granulocyte percentage (%) at 5-7 days or at discharge as compared to Baseline	Change in the neutrophilic granulocyte percentage in %.	5-7 days from randomization or discharge
Change in hematology assessments: absolute neutrophil value (x 10^9 /L) at 5-7 days or at discharge as compared to Baseline	Change in the level of absolute neutrophil value x 10^9 /L.	5-7 days from randomization or discharge

Collaborators and Investigators

• Sponsor: Xijing Hospital
• Collaborators: Xi'an Gaoxin Hospital; Xi'an No.3 Hospital; First People's Hospital of Xianyang; Xi'an XD Group Hospital; Central Hospital of Gansu Province

Publications and helpful links

General Publications

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• Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011 Jul 7;17(7):796-808. doi: 10.1038/nm.2399.
• Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, Baigent C, Sandercock P, Hacke W; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014 Nov 29;384(9958):1929-35. doi: 10.1016/S0140-6736(14)60584-5. Epub 2014 Aug 5.
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• Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019 Dec;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. Epub 2019 Oct 30.
• Jovin TG, Nogueira RG, Lansberg MG, Demchuk AM, Martins SO, Mocco J, Ribo M, Jadhav AP, Ortega-Gutierrez S, Hill MD, Lima FO, Haussen DC, Brown S, Goyal M, Siddiqui AH, Heit JJ, Menon BK, Kemp S, Budzik R, Urra X, Marks MP, Costalat V, Liebeskind DS, Albers GW. Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis. Lancet. 2022 Jan 15;399(10321):249-258. doi: 10.1016/S0140-6736(21)01341-6. Epub 2021 Nov 11.
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Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2023
• Primary Completion (Actual): March 11, 2025
• Study Completion (Estimated): June 4, 2025

Study Registration Dates

• First Submitted: August 18, 2022
• First Submitted That Met QC Criteria: August 20, 2022
• First Posted (Actual): August 23, 2022

Study Record Updates

• Last Update Posted (Actual): May 30, 2025
• Last Update Submitted That Met QC Criteria: May 24, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Ischemic Stroke; Neuroprotection; Minocycline; Endovascular Treatment; Basilar Artery Occlusion; Futile Recanalization
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Brain Infarction; Brain Ischemia; Infarction; Necrosis; Ischemic Stroke; Stroke; Cerebral Infarction; Ischemia; Arterial Occlusive Diseases; Anti-Bacterial Agents; Anti-Infective Agents; Minocycline
• Other Study ID Numbers: XJLL-KY20222184

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