Effect of Oral Minocycline in Patients With Acute Stroke - a Randomized, Open Label, Prospective Trial
Phase: PHASE2
Conditions: Stroke, Ischemia Stroke, Hemorrhagic Strokes, Mortality, Morbidity, Cerebrovascular Accident (Stroke), Intracerebral Haemorrhage (ICH)
Sponsor: Joyce Chen

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TITLE: Effect of Oral Minocycline in Patients with Acute Stroke – a Randomized, 
Open Label, Prospective Trial 
 
 
 
 
 
 
 
 
 
Unique Protocol ID: 2024-05-01 
 
 
 
 
 
Document Date:  September 18, 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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INTRODUCTION 
 
Background and significance:  
Stroke is the 5th leading cause of death and the leading cause of severe long-term disability in the 
US. The stroke-related cost is estimated to be $53 billion between 2017 and 2018 and keeps 
increasing every year1. Besides intravenous Alteplase (tPA) and Tenecteplase (TNK) has been 
shown to be safe,  effective and recently approved by FDA for the treatment of acute ischemic 
stroke. Endovascular mechanical thrombectomy (EVT) has been demonstrated also as safe and 
effective treatment for large vessel occlusion (LVO) type of stroke in addition to IV thrombolytic 
therapy with tPA or TNK. In addition, numerous neuroprotective regimen trials have been 
conducted, including those for stroke patients. However, effective treatments or agents offering 
significant neuroprotective benefits in acute stroke patient remain elusive.  
Minocycline is an FDA-approved second-generation, semi-synthetic broad-spectrum antibiotic 
that exhibits promising neuroprotective effects with multiple proposed mechanisms of action in 
various injury models2. Clinically, Lampl et al. observed that a 5-day course of oral minocycline 
significantly reduced neurological impairment in acute ischemic stroke in a small cohort study in 
20073. Hemorrhagic transformation rates did not differ by treatment groups. Acute hemorrhagic 
stroke accounts for about 12 – 20 % of all types of strokes, accounting for about 2 million cases 
worldwide annually, leading to high mortality and disability rates of up to 50%. Early initiation of 
oral Minocycline continues to be promising for potential neuroprotection in intracerebral 
hemorrhage (ICH) and possible ischemic stroke4. 
 
At our institution, since the Lampl study, we have used Minocycline for all eligible patients with 
acute strokes in clinical practice until March 2019 given its limited clinical evidence from large-
scale randomized placebo-controlled trials (RCTs). Therefore, after a consensus discussion among 
stroke clinicians at our institution, we discontinued the program-wide routine use of Minocycline 
in acute stroke patient during their hospitalization in March 2019. Retrospective data analysis 
comparing stroke patients’ outcomes measured in NIHSS (NIH stroke scale) and mortality mRS=6 
(Modified Rankin Scale) between minocycline treatment period (January 2018 to March 2019) 
and post minocycline stoppage periods (after April 2019 and before and after COVID pandemic) 
demonstrated statistically significant benefits of both NIHSS and mortality (mRS =6) at discharge 
for patients with admission NIHSS severity between 5-20 (see below data analysis), similarly with 
the above reported clinical functional benefits in the Lampl study although they did not report 
on the mortality benefits as we had observed. In this study, we set out to conduct a prospective 
analysis of acute stroke patients’ clinical outcomes measured by NIHSS at discharge and 90 days 
post stroke as primary outcome, and NIHSS at 30 days as well as mRS at discharge, 30 days and 
90 days post stroke as secondary outcomes which will also include all-cause mortality (mRS=6) at 
discharge, 30 days and 90 days post stroke. As secondary outcome, the study will assess the rate 
of hemorrhagic transformation of ischemic strokes following stroke treatments such as IV 
thrombolytics and/or thrombectomy using ECASS II/III (European Cooperative Acute Stroke 
Study). The study will prospectively enroll all eligible stroke patients with moderate severity 

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(NIHSS 5-20 on admission) to be consecutively block randomized to either Minocycline treatment 
along with the best clinical treatment group or the best clinical treatment group alone (from TBD 
2025 to TBD 2028), comparing the above clinical outcomes. We will have interim analysis at 
intervals 33%, and 66% incremental enrollment and 100% of data acquisition for safety and 
primary outcomes threshold examination. The results of this study may help us better 
understand the efficacy and safety profile of Minocycline in acute stroke treatment in both 
ischemic and hemorrhagic strokes, which could improve the clinical stroke care at our institution 
and possibly world-wide. 
 
Primary:  
• NIHSS score at discharge and on 90-day (+/- 7 days) post-stroke  
Secondary:  
• NIHSS at 30-day (+/- 7 days) as well as mRS at discharge, 30- (+/- 7 days) and 90-day (+/- 
7 days) post stroke  
• Rate of hemorrhagic transformation of ischemic strokes following stroke treatments such 
as IV thrombolytics and/or thrombectomy using ECASS II/III 
• All-cause mortality (mRS =6) at discharge, 30- (+/- 7 days) and 90-day (+/- 7 days) post 
stroke 
 
HYPOTHESIS: 
Minocycline 200 mg daily oral intake for five days in addition to standard care, when 
administered orally in less than 24 hours after onset of acute stroke (both ischemic and 
hemorrhagic), improves survival and functional outcome as assessed by improvement in NIHSS 
score and mRS scores on discharge (including mortality, mRS=6) and on day 30, and 90 post 
stroke.  
 

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STUDY DESIGN:  
  
 
The prospective study will enroll 1164 patients who arrive in the ER at Maimonides Hospital for 
suspected acute stroke. After obtaining informed consent, 1164 patients will be screened, 
minimum 1058 will be enrolled from TBD 2025 to TBD 2028. Consecutive block randomization 
will be done, and minimum of 529 patients will be assigned to either Minocycline or Standard 
Care arm. The minimum of 529 patients in the Minocycline arm will receive Minocycline 200 mg 
every 24 hours for five days in addition to standard care, while the Standard Care arm will accept 
only standard care. NIHSS and mRS scores will be measured on presentation, on discharge, and 
days 30 and 90 post stroke. A comparison will be made between both arms for their significance. 
Rate of hemorrhagic transformation of ischemic strokes following stroke treatments such as IV 
thrombolytics and/or thrombectomy will be compared using ECASS II/III (European Cooperative 
Acute Stroke Study) which involves follow-up brain imaging (CT or MRI) during hospitalization to 
detect any symptomatic intracranial hemorrhage (sICH). Statistical analysis will be done with the 
help of a Maimonides statistician. We will have interim analysis at intervals of subject 388 (33%), 
and subject 766 (66%) of enrollment/data acquisition and at 100% trial completion for safety and 
primary outcomes threshold examination. 
 
SUBJECTS: Patients with clinical suspicion of stroke – both ischemic and hemorrhagic or 
computer tomography consistent with acute stroke consistent with WHO (World Health 
Organization) guidelines.  
 
Study Duration: 
3 years
Participation Period: 
3 months 
Acute Ischemic 
Stroke
Minocycline 
treatment + 
standard care
Standard Care only
Acute Hemorrhagic 
Stroke
Minocycline 
treatment + 
standard care
Standard Care only

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ELIGIBILITY CRITERIA:  
• Inclusion criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
 
1) Age >/=18 
2) NIHSS 5-20 
3) Acute onset neurological deficit consistent with acute ischemic stroke or on imaging 
consistent with acute ischemia as defined by WHO guidelines  
OR 
Acute onset of neurological deficits with intracerebral Hemorrhage on imaging consistent 
with intracerebral bleed 
4) The onset of neurological symptoms less than 24 hours 
• Exclusion criteria 
An individual who meets any of the following criteria is excluded from participation in this 
study: 
1) Clinically stroke is not suspected  
2) Allergic to the Tetracycline group of medications or Intolerance to Minocycline 
3) Pregnancy or suspected pregnancy or breastfeeding 
4) Previous history of intolerance to Minocycline  
5) Acute or chronic renal failure (stage III with GFR or Creatinine threshold) 
6) Any patients with contraindications to undergo CT/ MRI  
7) Life expectancy less than one year or severe co-morbidities or comfort measure only 
(CMO) on admission 
8) Pre-existing infectious disease requiring antibiotics 
9) Inability to tolerate enteral medications/feeds 
10) Patient/ family refusal  
 
RANDOMIZATION: Consecutive block randomization with fixed block sizes will be used. 
 
BLINDING TECHNIQUE: Evaluator-blinded study 
 
DATA COLLECTION PROCEDURES: 
 
Informed consent will be obtained from the patient or legally authorized representative (LAR) 
prior to any study procedures. If the patient lacks decision-making capacity, the LAR will be 
approached in accordance with institutional policy and state law. Consent discussions will occur 
in private settings with ample time for questions. The IRB-approved consent form will describe 
study purpose, risks, benefits, alternatives, and participant rights. 
 
Patients presented to Maimonides Medical Center from TBD 2025 to TBD 2028 for acute stroke 
symptoms will be evaluated, and their eligibility for the trial will be assessed. The eligible patients 

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will be randomized to the Minocycline or the Standard Care arm within their respective Ischemic 
or Hemorrhagic group.  Acute Ischemic and Hemorrhagic patients will be treated with 
Minocycline in addition to the standard care versus the standard care alone. Patient demographic 
details and information on co-morbidities will be collected. Their NIHSS and mRS scores will be 
measured at the time of presentation and discharge and again at 30- and 90-days post-discharge. 
Rate of hemorrhagic transformation of ischemic strokes following stroke treatments such as IV 
thrombolytics and/or thrombectomy will be assessed and recorded. All-cause mortality will also 
be obtained at 30 days and 90 days. The outcomes will be documented, and the results will be 
analyzed at intervals of subject 388 (33%) enrollment/data acquisition and subject 776 (66%) 
enrollment/data acquisition and 100% completion. 
 
Data Analysis: Data analysis will be performed with the assistance of the MMC biostatistician.  
All numeric variables will be summarized with mean and 95% confidence interval where 
appropriate and median and IQR if necessary. All categorical variables will be summarized with 
frequency and percentage. Continuous variables that are risk factors or demographics will be 
compared across groups using a t-test or Wilcoxon rank sum test. Categorical risk factors and 
demographics will be compared between groups using a chi-square or Fisher exact test. 
 
The primary outcome of reduced NIHSS and mRS at discharge will be evaluated using a student’s 
T-test. The outcome of mortality will be evaluated using a Fisher exact test. 90-day outcomes will 
be evaluated similarly. To control for additional risk factors, including baseline NIHSS and mRS, 
we will also create a generalized linear model with a normal link function for continuous 
outcomes, controlling for risk factors significantly different between groups. For mortality, we 
will use a generalized liner model with a logistic link function to control for risk factors that varied 
considerably between groups. 
 
 
 
Target power   
 
: 0.8 
Actual power                               : 0.800 
Alpha                                             : 0.05 
Assumed population means     : 7.1 for the placebo group and 6.1 for the Minocycline group (with  
                                                         an expected difference between the population’s means is 1.0) 
Calculated size                             : 529 in each arm with a total of 1058 patients; after considering   
   a 10% attrition rate, 582 in each arm with a total of 1164 patients. 
   
This will include 2 interim analyses after 388 (33%) subject enrollment and data acquisition, 776 
(66%), and 1164 (100%) subject enrollment and data acquisition respectively. The study will be 
stopped at the 1st interim analysis if the group difference in NIHSS is statistically significant at 
alpha = 0.0002, at the 2nd interim analysis at alpha = 0.0118. The threshold for significance at 
100% data will be alpha = 0.03790 for a total study alpha = 0.05