Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05367362 |
| Other study ID # |
STUDY00006145 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
December 1, 2024 |
| Est. completion date |
June 1, 2026 |
Study information
| Verified date |
February 2024 |
| Source |
State University of New York at Buffalo |
| Contact |
Adnan H Siddiqui, MD PhD |
| Phone |
7162181000 |
| Email |
asiddiqui[@]ubns.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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
Patients will be screened upon presentation to the emergency room with symptoms of acute
stroke. All patients considered to have acute ischemic strokes undergo a routine
non-contrasted head CT with a subsequent CT perfusion and CT angiogram. A neuroradiologist, a
stroke neurologist and a neuroendovascular fellow (with a background training in
neurosurgery, neurology or radiology) evaluate these three scans immediately. Based on this
immediate screen, patients are triaged to appropriate treatment i.e., intravenous
thrombolysis and or intra-arterial in endovascular intervention based on CT angiography and
CT perfusion imaging demonstrating salvageable brain tissue.
We will exclude all patients with intracranial hemorrhage. Patients who meet the eligibility
criteria for undergoing endovascular revascularization therapy will be presented the option
to enroll in the study. An IRB approved informed consent will be obtained from either the
patient if he/she can give consent or from an immediate family member or heath care proxy.
Patient will then be randomized to intervention or placebo in 1:1 fashion. The randomization
will be performed by pharmacy using interactive web response system. The pharmacy will
maintain the coding for the patient and intervention given.
Study Population To be eligible for inclusion in the trial patients must meet the following
criteria;
1. provision of consent, either by self or authorized representative, willingness and
ability to participate in study procedures
2. Acute onset focal neurologic deficit consistent with acute ischemic stroke, or computed
tomographic scan consistent with acute cerebral ischemia
3. Age more than 18 years
4. Premorbid Rankin score ≤ 3
5. Treatment with intra-arterial endovascular revascularization methods.
6. Patients should be given first dose of minocycline as soon as possible, latest by 24
hours after the endovascular stroke intervention
All individuals meeting any of the exclusion criteria at baseline will be excluded from study
participation:
1. Allergy/ Intolerance to tetracycline antibiotics
2. Pregnant women - positive pregnancy test on admission or known to be pregnant
3. ALT or AST > 3 times the upper limit of normal
4. Serum creatinine > 2 mg/dL
5. 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
6. Has a severe health condition that may potentially result in death within 6 months.
Study Intervention Administration Minocycline or placebo will be administered to the patients
within two hour before or after the endovascular procedure and continued for 21 days.
Endovascular revascularization procedure will be performed as planned.
Dosing and Administration
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.
Acquisition and Accountability
Minocycline will be acquired from Kaleida Health Pharmacy. Minocycline and placebo will be
prepared and distributed by the pharmacy responsible for providing medicine to the patients
in the emergency department and/or angiography suite. Pharmacy shall be responsible for
assessing the expiry date of the drug.
Formulation, appearance, packaging, and labeling
Minocycline 200 mg will be mixed with normal saline and given by IV administration, or
provided as capsules for the patient to swallow. The placebo will be packaged in a look-alike
wrapping. The placebo will have same color and odor. It will not be possible to differentiate
it from the placebo which will have same appearance as the drug. The packaging will be
performed by the pharmacy.
Product Storage and Stability
The drug will be stored at the room temperature in the pharmacy.
Discontinuation of Study Intervention
If adverse effect is noticed while the patient is admitted, a neurologist will assess the
patient and decide on the continuation or discontinuation of the intervention. A form will be
filled out by that physician and reported to Dr. Siddiqui who is the PI for this trial. After
discharge the patients will be provided a 24 hour emergency line and email of a designated
nurse coordinator. The nurse will schedule a visit to the clinic or emergency room. For
details on the assessment of adverse events and safety monitoring plan, please see section
"Adverse event categorization and safety monitoring".
Participant Discontinuation/Withdrawal from the Study Participants are free to withdraw from
participation in the study at any time upon request. An investigator may discontinue or
withdraw a participant from the study for the following reason;
1. Pregnancy
2. If the neurologist finds any clinical adverse event, laboratory abnormality, or other
medical condition or situation occurs such that continued participation in the study
would not be in the best interest of the participant.
3. If the participant meets an exclusion criterion (either newly developed or not
previously recognized) that precludes further study participation.
4. Participant unable to receive the intervention for more than 72 hours. The reason for
participant discontinuation or withdrawal from the study will be recorded on the Case
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do
not receive the study intervention may be replaced. Subjects who sign the informed
consent form, and are randomized and receive the study intervention, and subsequently
withdraw, or are withdrawn or discontinued from the study, will not be replaced.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she fails to return for scheduled
three months visit starting from the date of initiation of therapy and is unable to be
contacted by the study site staff.
The following actions will be taken if a participant fails to return to the clinic for a
required study visit:
- The site will attempt to contact the participant and reschedule the missed visit within
a week of missed appointment and counsel the participant on the importance of
maintaining the assigned visit schedule and ascertain if the participant wishes to
and/or should continue in the study.
- Before a participant is deemed lost to follow-up, the investigator or designee will make
every effort to regain contact with the participant (3 telephone calls and a certified
letter to the participant's last known mailing address will be dispatched). These
contact attempts will be documented in the participant's medical record or study file.
- Should the participant continue to be unreachable, he or she will be considered to have
withdrawn from the study with a primary reason of lost to follow-up.
Follow-up and assessment of clinical outcomes A 24h National Institute of Health Stroke Scale
(NIHSS) examination will be recorded. MR imaging will be performed as part of routine care.
Subsequent follow-up visits will be scheduled at 7-10 days after discharge, 30 days, and 90
days, and include the modified Rankin Scale (mRS) assessing global disability, the Barthel
Index assessing instrumental activities of daily living, the NIHSS exam assessing neurologic
deficit. The attending neurologist who will be blind to the treatment group will assess the
patients on follow up.
Primary outcome 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.
Secondary outcomes
The study secondary end-points are: 1) NIHSS score at 24h; 2) mRS at discharge and 90 days;
3) Barthel Index at 7,30, and 90 days; 4) volume of cerebral infarction as measured by a CT
or MRI scan within 72 hours post-procedure. A routine MRI obtained within 72 hours after
intervention and at 90 days will be used to calculate the infarct volume. The change in the
size of infarct will be also be compared with the infarct size predicted by the pre procedure
CT perfusion imaging. Study safety end-points are: 1) all serious adverse events; 2)
symptomatic intracranial hemorrhage; 3) any intracranial hemorrhage; 4) myocardial
infarction; 5) liver function; 6) mortality and 7) rate of decompressive craniectomies in
each group.
NIHSS is a 15-item impairment scale, intended to evaluate neurologic outcome and degree of
recovery for patients with stroke. The scale assesses level of consciousness, extraocular
movements, visual fields, facial muscle function, extremity strength, sensory function,
coordination (ataxia), language (aphasia), speech (dysarthria), and hemi-inattention
(neglect)10, 11. The NIHSS was designed to assess differences in interventions in clinical
trials, although its use is increasing in patient care as an initial assessment tool and in
planning post-acute care disposition10.
The BI was developed in 196512 and later modified by Granger and coworkers13 as a scoring
technique that measures the patient's performance in 10 activities of daily life. The BI is
considered a reliable disability scale for stroke patients. The items can be divided into a
group that is related to self-care (feeding, grooming, bathing, dressing, bowel and bladder
care, and toilet use) and a group related to mobility (ambulation, transfers, and stair
climbing). The maximal score is 100 if 5-point increments are used, indicating that the
patient is fully independent in physical functioning. The lowest score is 0, representing a
totally dependent bedridden state.
Adverse events and safety monitoring Adverse event categorization A clinical events committee
will validate and categorize the adverse events. This committee will comprise of three expert
physicians. Relatedness categories will include: (1) study disease-related: event clearly
attributable to underlying disease state with no temporal relationship to the device,
treatment, or medication; (2) concomitant disease-related: event attributable to disease
other than the study disease with no temporal relationship to the device, treatment, or
medication; (3) IV tPA-related: event clearly attributable to IV tPA medication with no
temporal relationship to the device or treatment; (4) procedure-related: event has strong
temporal relationship to the procedure or treatment of the device implantation or any user
handling; (5) Minocycline related: event has a strong temporal relationship to the
minocycline and alternate etiology is less likely; (6) other; and (7) unknown.
Patient safety is of paramount importance in this trial, and extensive sets of procedures are
in place for monitoring adverse events in the trial. These procedures are as follows:
1. Data Safety Monitoring Board (DSMB). A Data Safety Monitoring Board (DSMB) will meet
every 3 months to review the progress of this study (e.g., enrollment, performance) and
data on the safety. Before the study begins, the DSMB (in consultation with the study
statisticians and principal investigator) will decide on the necessity of an interim
analysis, and, if so, the timing of this analysis. Using guidelines established by the
committee and the investigators before the study begins, the DSMB may recommend
termination of the study if any of the endpoints exceeds pre-established safety
thresholds. Additionally, the DSMB may recommend modifications to the protocol if a
reversible safety issue is identified. After each meeting, the DSMB Chair will prepare a
letter to the study principal investigator, Dr. Adnan Siddiqui, which will describe the
safety review that took place at the meeting and that indicates whether any safety
concerns exist.
2. Medical Safety Monitor: We have also appointed a safety monitor for the study who will
review all adverse events in the study as they occur and consult with the DSMB, if
necessary. Before the study begins, the DSMB, after consulting with the study principal
investigator and principal statistician will establish a plan for how the monitor will
report safety concerns that arise during the trial.
3. Principal Investigator: Dr. Siddiqui will be informed of the DSMB's quarterly assessment
of study performance and safety and any other safety issues detected by the Medical
Safety Monitor. Additionally, Dr. Siddiqui will monitor any complications, any protocol
violations, medication compliance, and risk factor management at the participating
sites. If any problems are identified in these areas, Dr. Siddiqui will contact the
concerned physicians to rectify the problem.
4. Project Coordinator: Every month, the project coordinator will compile a copy of the
adverse event forms to review for events other than primary and secondary endpoints. The
purpose of this review is to ensure that these events are recorded and reported and to
look for any indications that more serious events may have not been reported.
Drug Related Risks Minocycline is associated with a number of adverse reactions for which
patients should be carefully monitored. Our plan to monitor patients according to each
adverse reaction described in the drug label is listed below.
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): during recruitment patients will
be screened for any allergic reactions under the use of tetracycline class drugs in the past,
either by direct interview with the patient in case of adequate mental status or interview
with the family. If allergic reaction occurs during hospitalization, the drug will be
discontinued immediately. Patients will also be monitored with complete blood count every 48h
to assess for eosinophilia. If patients are discharged home prior to 21 days and continue
receiving the drug, instructions will be given to immediately contact medical help in case of
rashes, difficulty breathing, pruritus, edema or any other symptoms suggestive of an allergic
reaction.
Renal dysfunction: patients will be screened prior to recruitment to exclude those with
significant renal function impairment. In those who are enrolled, laboratory assessment of
BUN and creatinine levels will be performed every 48h during hospitalization to ensure renal
function is under the normal range during treatment period.
Photosensitivity: patients will be oriented to avoid exposure to sun while taking
minocycline.
Central nervous system side-effects (lightheadedness, dizziness, vertigo or symptoms): as
part of standard of care, patients who undergo endovascular thrombectomy at our institution
are constantly monitored by a team including nurses, advanced care practitioners and
physicians. Neurological assessment is performed twice a day during rounds to detect any
clinical deterioration in these patients.
Hepatotoxicity: patients will be screened prior to recruitment to exclude those with
significant liver function impairment and structural compromise. Laboratory assessment of
liver enzymes (AST and ALT) and bilirubin will be monitored every 72h during hospitalization.
Laboratory tests mentioned above will also be performed at 7-10 days visit. Protection of
Patient Data Research material will include the patient's baseline clinical data (i.e., the
patient's history and physical findings, medications), and the results of laboratory tests
such as brain CT or MR imaging, CT angiography, electrocardiogram, and blood tests performed
to determine the cause of the patient's stroke. Tests done during follow-up as part of
routine care such as lipid profile, hemoglobin A1C (if the patient is diabetic), brain CT or
MR imaging (if a stroke is suspected), and electrocardiogram (if an MI is suspected) and
events that occur as part of the follow-up in the study will be recorded. The results of the
24-48-hours MRI and CTP-CTA acquired as part of the study protocol will be collected. Patient
data will be recorded on data forms and it will be stored in a secured database. Information
collected during the trial that can be identified with an individual patient will remain
confidential and will be disclosed only with the patient's permission. Specific care will be
taken so that patient identification will not be disclosed inadvertently in publications that
result from this trial (e.g., names on published CT or MRI scans will be covered).
Sample Size Calculation We based our calculation on the clinical trial conducted by Kohler et
al4. In order to achieve 80% power at 5% significance level in the Chi-square test, 62
subjects are required for each group to detect a 20% proportion difference of % mRS ≤ 2
between two groups. Anticipating a loss of follow up of 10% we reached a final sample size of
67 per each group.
Statistical analyses A descriptive analysis will performed. Continuous variables with normal
distribution will be presented as means and standard deviation while medians and range will
be used for skewed data. We will use percentage and proportions to present categorical data.
The two groups will be compared for baseline clinical characteristics including age, gender,
comorbidities, onset of stroke to intervention delay, NIH score at presentation and pre
morbid mRS. We will also compare TICI scores for revascularization in each group. Independent
T test will be used to compare continuous variable while chi square will be used to compare
categorical data. All the secondary and safety outcomes will also be compared between the
groups.
Cochran-Mantel-Haenszel test will be conducted for the shift in Rankin scores. mRS will
dichotomized into ≤ 2 and > 2 to estimate the proportion of disability free patients in each
group. The odds ratio with 95% confidence interval will be calculated for an mRS ≤ 2 for
patients on minocycline. A alpha error of more than 0.05 will be considered significant.
