Efficacy of Minocycline in Improving Neurological Outcomes of Patients Who Undergo Endovascular Revascularization for Acute Ischemic Stroke
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 入组人数
- 134
- 主要终点
- mRS at 90-days
研究概览
简要总结
The study will be a prospective, randomized, double- blinded placebo, single center pilot clinical trial. Patients with acute ischemic stroke due to large vessel occlusion undergoing endovascular thrombectomy will be included. The treatment group will receive 200 mg intravenous/oral minocycline hydrochloride in addition to endovascular thrombectomy for a total of 21 days. The control group will receive standard medical and endovascular care along with a similar looking placebo. Patients will be randomized to the treatment or control group by the Pharmacy eliminating the selection bias. The patient and evaluator will be blind to the allocation of patients further minimizing the bias. Through randomization we expect to achieve two groups that are comparable in their baseline clinical characteristics.
详细描述
Overall Design and Rationale for the Study Design The study will be a prospective, randomized, double- blinded placebo, single center pilot clinical trial. Patients with acute ischemic stroke due to large vessel occlusion undergoing endovascular thrombectomy will be included (please see section II - Protocols, for detailed criteria of inclusion and exclusion). The treatment group will receive 200 mg intravenous/oral minocycline hydrochloride in addition to endovascular thrombectomy for a total of 21 days. The control group will receive standard medical and endovascular care along with a similar looking placebo. Patients will be randomized to the treatment or control group by the Pharmacy eliminating the selection bias. The patient and evaluator will be blind to the allocation of patients further minimizing the bias. Through randomization we expect to achieve two groups that are comparable in their baseline clinical characteristics.
Justification of Dose The trial performed by Fagan et al showed minocycline to be safe in patients with acute ischemic stroke at doses as high as 10 mg/kg daily over 72 hours. However, they reported one dose-limiting toxicity being observed at that dose 2. A study by Gordon et al on patients with amyotrophic lateral sclerosis (ALS) showed that minocycline was tolerated well when the dose was at least 300mg daily. However, elevations of nitrogen and liver enzymes were noted over 6-month treatment period 6. On the other hand, when 200-400mg of IV minocycline was used for treatment of infectious disease, 18% of the patients reported at least some adverse effects, half of which were gastrointestinal in nature7.
Considering the above studies, we will administer minocycline at a dose of 200 mg per day for 21 days. This dose is lower than the minimal safe dose reported by Fagan et al2 and does not go over the dose used for ALS or infectious diseases that resulted in some adverse effects. The dose has been used in previous clinical trials on stroke and has proven to be safe and effective. Pharmacokinetic studies have shown that minocycline has a half line approaching 24 hours permitting once daily dosing 2. Unlike previous trials which administered minocycline for 5 days our duration is prolonged i.e., 21 days. This is because of the fact that microglia is one of the main targets for minocycline8, 9. Microglia remain active for several days to weeks after an acute ischemic episode9. Therefore, it may be prudent to continue the drug for that duration.
End of Study Definition A participant will be considered to have completed the study if he or she has completed all phases of the study's last clinical follow up up-to three months. The trial will be concluded after the last participant has completed a 90 day follow up.
II - Protocols Strategies for Recruitment and Retention
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •provision of consent, either by self or authorized representative, willingness and ability to participate in study procedures
- •Acute onset focal neurologic deficit consistent with acute ischemic stroke, or computed tomographic scan consistent with acute cerebral ischemia
- •Age more than 18 years
- •Premorbid Rankin score ≤ 3
- •Treatment with intra-arterial endovascular revascularization methods.
- •Patients should be given first dose of minocycline as soon as possible, latest by 24 hours after the endovascular stroke intervention
排除标准
- •Allergy/ Intolerance to tetracycline antibiotics
- •Pregnant women - positive pregnancy test on admission or known to be pregnant
- •ALT or AST > 3 times the upper limit of normal
- •Serum creatinine > 2 mg/dL
- •Patient is participating in another clinical trial at any time during the duration of the study that could confound the treatment or outcomes of this investigation; and/or
- •Has a severe health condition that may potentially result in death within 6 months.
研究组 & 干预措施
Intervention
Patients randomized to minocycline will receive 200mg administered once a day for 21 days. The first dose will be administered in the emergency room or the angiography suite prior to endovascular intervention or within the first two hours of endovascular stroke intervention. If the patient is considered able to swallow as per the routine swallow test, the study drug will be administered orally as intact capsules. If the patient is considered to be at any risk for aspiration or is unable to swallow based on swallowing evaluation, study drug may be started using intravenous route and later switched to oral or via feeding tube as it becomes available.
干预措施: Minocyclin (Drug)
Control
Patients randomized to control arm will receive look-alike placebo administered once a day for 21 days. The first dose will be administered in the emergency room or the angiography suite prior to endovascular intervention or within the first two hours of endovascular stroke intervention. If the patient is considered able to swallow as per the routine swallow test, the placebo will be administered orally as intact capsules. If the patient is considered to be at any risk for aspiration or is unable to swallow based on swallowing evaluation, placebo may be started using intravenous route and later switched to oral or via feeding tube as it becomes available.
结局指标
主要结局
mRS at 90-days
时间窗: 90 days post op
The primary study end-point is the degree of disability or dependence at 90 days as assessed by the mRS shift. A global measure of disability, the mRS comprises of seven grades ranging from 0 (no symptoms) to 6 (death). The mRS will be assessed in a formally operationalized manner by use of the Rankin Focused Assessment - Ambulation (RFA-A). The 90-day mRS will be assessed by study personnel certified in the scoring of the mRS using the RFA-A and will be blinded to treatment assignment.
次要结局
- mRS at discharge(24 hours post procedure)
- National Institute of Health Stroke Scale (NIHSS) at 24 hours(90 days post op)
- Barthel Index at 7,30, and 90 days(7 days, 30 days, and 90 days post procedure)
- Change in Infarct Volume(90 days)
- Volume of cerebral infarction(72 hours)
研究者
Adnan H. Siddiqui
Vice Chairman University at Buffalo Neurosurgery
State University of New York at Buffalo