Stroke, Acute
Conditions
Keywords
stroke, ischemic, neuroprotection, minocycline, tissue plasminogen activator (tPA), biomarkers, pharmacokinetics, antiapoptotic, anti-inflammatory, treatment, matrix metalloproteinase-9 (MMP-9), thrombolysis, Minocycline to Improve Neurologic Outcome in Stroke (MINOS), cerebrovascular stroke, cerebrovascular accident, cerebral stroke, cerebrovascular accident (CVA)
Brief summary
The primary aim of this study is to find out which of 4 different doses of minocycline are safe and well tolerated so that we will know the optimal dose to test in future patients.
Detailed description
Minocycline is a widely used antibiotic and is approved by the Food and Drug Administration (FDA) for treatment of infections and acne. However, doctors do not know whether minocycline will work in stroke patients. Its use in stroke patients is experimental. There is a lot of information from experimental stroke studies in animals that minocycline lessens the damage from a stroke and the animals recover better. Since minocycline is generally a very safe drug in humans and does not have a lot of side effects, investigators at Georgia Health Sciences University (formerly the Medical College of Georgia) believe that it might be a safe and effective drug to improve the outcome in patients with stroke.
Interventions
DRUGMinocycline
Dose level 1 = 3mg/kg intravenous (IV) initial dose, followed by 1.5mg/kg every 12 hours times 5 more doses. Dose level 2 = 4.5mg/kg intravenous (IV) initial dose, followed by 2.25mg/kg every 12 hours times 5 more doses. Dose level 3 = 6 mg/kg intravenous (IV) initial dose, followed by 3 mg/kg every 12 hours times 5 more doses. Dose level 4 = 10 mg/kg intravenous (IV) initial dose, followed by 5 mg/kg every 12 hours times 5 more doses
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Kentucky
Oregon Health and Science University
David Hess, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* over 18 years of age * acute onset focal neurologic deficit consistent with acute ischemic stroke, or computed tomographic scan consistent with acute cerebral ischemia * onset of symptoms less than 6 hours * measurable neurologic deficit (National Institutes of Health \[NIH\] Stroke Scale \>/= 1)
Exclusion criteria
* allergy to tetracycline antibiotics * women of child-bearing potential * known hepatic and/or renal insufficiency * Thrombocytopenia * history of intolerance to minocycline * dizziness at the time of stroke or in the past month (by self-report) * aphasia likely to interfere with patients ability to report adverse effects * previous functional disability * stuporous or comatose * presence of another serious illness likely to confound the study * unlikely to be available for 90 day follow-up * severe stroke (National Institutes of Health \[NIH\] Stroke Scale \>22) * undergoing an interventional neuro-radiological intervention in first 12 hour
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximally Tolerated Dose of IV Minocycline | 3 days | Investigators closely monitored each subject for evidence of minocycline intolerance. All adverse events were immediately reported for a decision whether to discontinue the study medication and/or reduce the dose. A computer program was used to determine the maximum tolerated dose. After entering information regarding doses and expected toxicities, results for each subject as they were collected were entered. The computer program informed as to (de)escalation, or maintenance of the same dose in the subsequent cohort of enrolled patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Half-life of IV Minocycline | For each subject blood samples were drawn before dose #1 and one hour after starting dose #1. Additional blood was drawn 1, 6, 12, 24, 48, and 72 hours after starting dose #6, which lasted approximately 6 days. | In eligible patients enrolled at Georgia Health Sciences University, blood samples were drawn for quantification of minocycline serum concentrations. This enabled the study team to determine the half life of the study drug. |
| 90 Day Modified Rankin Scale Score | 3 months | The modified Rankin Scale (mRS) was performed in person at the 90 day clinic follow-up appointment. The modified Rankin Scale is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6. 0 represents no symptoms. 1 represents no significant disability. 2 represents slight disability. 3 represents moderate disability. 4 represents moderately severe disability. 5 represents severe disability. 6 represents death. |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred from June 3, 2008 to October 10, 2009. The study was completed ahead of schedule. Study subjects were enrolled in each recruiting centers' Emergency Department or stroke intensive care unit. Many subjects came as transfers from rural or outside hospitals to one of the enrolling centers for further care and study participation.
Pre-assignment details
Potential patients that met all of the inclusion criteria, did not meet any of the exclusion criteria, and were willing to participate were enrolled in the study. All study subjects were given one of the four doses of minocycline. The dose of minocycline given was assigned by a computer program.
Participants by arm
| Arm | Count |
|---|---|
| Minocycline All 60 participants were treated with minocycline. 11 participants were treated at 3mg/kg, 4 were treated at 4.5mg/kg, 4 were treated at 6mg/kg, and 41 were treated at 10mg/kg. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 4 |
| Overall Study | Lost to Follow-up | 3 |
Baseline characteristics
| Characteristic | Minocycline |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 30 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age Continuous Overall age | 65 years STANDARD_DEVIATION 13.7 |
| NIH Stroke Scale at baseline | 8.7 Units on a scale STANDARD_DEVIATION 5.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 50 Participants |
| Region of Enrollment United States | 60 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 32 Participants |
| Subjects receiving t-PA then minocycline Total amount of subjects that did not receive t-PA | 24 Participants |
| Subjects receiving t-PA then minocycline Total amount of subjects that received t-PA | 36 Participants |
| Symptom onset to study drug infusion time | 307.4 minutes STANDARD_DEVIATION 50 |
| Weight | 81.6 Kg STANDARD_DEVIATION 21.6 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 50 / 60 |
| serious Total, serious adverse events | 29 / 60 |
Outcome results
Primary
Maximally Tolerated Dose of IV Minocycline
Investigators closely monitored each subject for evidence of minocycline intolerance. All adverse events were immediately reported for a decision whether to discontinue the study medication and/or reduce the dose. A computer program was used to determine the maximum tolerated dose. After entering information regarding doses and expected toxicities, results for each subject as they were collected were entered. The computer program informed as to (de)escalation, or maintenance of the same dose in the subsequent cohort of enrolled patients.
Time frame: 3 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Minocycline | Maximally Tolerated Dose of IV Minocycline | 10 mg/kg |
Secondary
90 Day Modified Rankin Scale Score
The modified Rankin Scale (mRS) was performed in person at the 90 day clinic follow-up appointment. The modified Rankin Scale is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6. 0 represents no symptoms. 1 represents no significant disability. 2 represents slight disability. 3 represents moderate disability. 4 represents moderately severe disability. 5 represents severe disability. 6 represents death.
Time frame: 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Minocycline | 90 Day Modified Rankin Scale Score | 90 day mRS score of 0 overall | 15 Participants |
| Minocycline | 90 Day Modified Rankin Scale Score | 90 day mRS score of 1 overall | 15 Participants |
| Minocycline | 90 Day Modified Rankin Scale Score | 90 day mRS score of 2 overall | 9 Participants |
| Minocycline | 90 Day Modified Rankin Scale Score | 90 day mRS score of 3 overall | 11 Participants |
| Minocycline | 90 Day Modified Rankin Scale Score | 90 day mRS score of 4 overall | 2 Participants |
| Minocycline | 90 Day Modified Rankin Scale Score | 90 day mRS score of 5 overall | 3 Participants |
| Minocycline | 90 Day Modified Rankin Scale Score | 90 day mRS score of 6 overall | 5 Participants |
Secondary
Half-life of IV Minocycline
In eligible patients enrolled at Georgia Health Sciences University, blood samples were drawn for quantification of minocycline serum concentrations. This enabled the study team to determine the half life of the study drug.
Time frame: For each subject blood samples were drawn before dose #1 and one hour after starting dose #1. Additional blood was drawn 1, 6, 12, 24, 48, and 72 hours after starting dose #6, which lasted approximately 6 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Half-life of IV Minocycline | 23.8 hours | Standard Error 1.9 |