Basilar Artery Occlusion, Endovascular Treatment, Ischemic Stroke, Acute, Minocycline
Conditions
Keywords
Ischemic Stroke, Basilar Artery Occlusion, Endovascular Treatment, Minocycline, Neuroprotection, Futile Recanalization
Brief summary
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.
Interventions
DRUGMinocycline
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.
Sponsors
Xi'an No.3 Hospital
Xi'an Gaoxin Hospital
First People's Hospital of Xianyang
Xi'an XD Group Hospital
Central Hospital of Gansu Province
Xijing Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
All study staff is not masked to randomization except the following: independent outcome assessor and statistician.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The expanded NIH Stroke Scale (e-NIHSS) at 5-7 days or at discharge | 5-7 days or discharge after onset | 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. |
| Incidence of symptomatic intracranial hemorrhage at 24 hours from randomization | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Favorable outcome at 90 (±14) days from randomization | 90 (±14) days from randomization | An mRS score of 0-2 indicated a favorable outcome, whereas a score of \>2 indicated a poor outcome. |
| Excellent outcome at 90 (±14) days from randomization | 90 (±14) days from randomization | An mRS score of 0-1 indicated an excellent outcome, whereas a score of \>1 indicated a poor outcome |
| NIH Stroke Scale (NIHSS) at 24 hours, 5-7 days or discharge, 30 (±7) days and 90 (±14) days from randomization | 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. |
| Modified Barthel Index at 30 (±7) days and 90 (±14) days | 30 (±7) days and 90 (±14) days from randomization | 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. |
| Incidence of symptomatic intracranial hemorrhage at 3 days from randomization | 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. |
| Mortality at 90 (±14) days from randomization | 90 (±14) days from randomization | All-cause mortality occurring within 90 (±14) days follow-up were recorded. |
| Change in infarct volume from baseline to day 5-7 or discharge | 5-7 days from randomization 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. |
| Length of Intensive Care Unit (ICU) stay and hospital stay | From the date of admission until discharged from ICU or hospital, up to 4 weeks | Length of ICU or hospital stay |
| Pneumonia at 5-7 days or discharge, 30 (±7) days and 90 (±14) days | 90 (±14) days from randomization | Determine whether rates of pneumonia are different in the two arms. Rates will be measured as percentages of the entire population at risk. |
| mRS at 90 (±14) days | 90 (±14) days from randomization | 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. |
| Change in hematology assessments: percentage of the lymphocyte subpopulations (%) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | The percentage of lymphocyte subpopulations in % will be assessed by flow cytometry. |
| Change in hematology assessments: matrix metalloproteinase-9 (ng/ml) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | The level of matrix metalloproteinase-9 in ng/ml will be assessed by ELISA method. |
| Change in hematology assessments: IL-6 (pg/ml) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | The level of IL-6 in pg/ml will be assessed by ELISA method. |
| Change in hematology assessments: IL-10 (pg/ml) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | The level of IL-10 in pg/ml will be assessed by ELISA method. |
| Change in hematology assessments: TNF-α (nmol/L) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | The level of TNF-α in nmol/L will be assessed by ELISA method. |
| Change in hematology assessments: leucocytes (x 10^9 /L) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | Change in the level of leucocytes x 10\^9 /L. |
| Change in hematology assessments: neutrophilic granulocyte percentage (%) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | Change in the neutrophilic granulocyte percentage in %. |
| Change in hematology assessments: absolute neutrophil value (x 10^9 /L) at 5-7 days or at discharge as compared to Baseline | 5-7 days from randomization or discharge | Change in the level of absolute neutrophil value x 10\^9 /L. |
| Time of mechanical ventilation or non-invasive ventilation at 5-7 days or at discharge | 5-7 days from randomization or 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. |
| Good outcome at 90 (±14) days from randomization | 90 (±14) days from randomization | An mRS score of 0-3 indicated a good outcome, whereas a score of \>3 indicated a poor outcome. |
Countries
China
Outcome results
None listed