Stroke, Ischemic
Conditions
Keywords
neuroprotection, antioxidant
Brief summary
This is a pilot randomized control trial (RCT) to explore the possible beneficial effect of a novel combination therapy consisting of molecular hydrogen H2 plus minocycline (H2M), on neurological recovery after acute ischemic stroke.
Detailed description
This will be a pilot trial exploring the ability of a novel combination (H2M) of molecular hydrogen (an antioxidant) and minocycline (a widely used antibiotic known to inhibit the activation of matrix metallo-proteinase-9 and poly(ADP-ribose) polymerase), to protect brain tissue from ischemia/reperfusion injury that occurs during and after an ischemic stroke. Both hydrogen and minocycline have excellent safety profiles, have been previously demonstrated individually to reduce infarction in animal models of stroke, and have potentially synergistic mechanisms of action against ischemic brain damage. The mechanisms of action of both agents would be specifically relevant to patients receiving tissue plasminogen activator (tPA) or thrombectomy, and achieving some degree of therapeutic reperfusion. This will be a double blinded, placebo-controlled trial. Eligible and willing subjects will be randomly assigned to be treated with either H2M or placebo, in addition to standard treatments. The treatment with H2M or placebo will start as soon as possible after diagnosis of stroke, and continue for three days (hydrogen) and five days (minocycline) respectively. Measures of stroke severity and disability will be recorded at baseline, and through a follow-up phone call (45 days) and clinic visit (90 days).
Interventions
DRUGHydrogen
Hydrogen will be infused into bags of normal saline solution and administered intravenously, or hydrogen generating tablets will be dissolved into water for the patient to drink, as the patient's condition permits. This will be administered TID for 3 days.
DRUGMinocycline
Minocycline 200 mg will be mixed with normal saline and given by i.v. administration, or provided as capsules for the patient to swallow, q 24 hours for 5 days. Once patients regain the ability to swallow capsules, minocycline will be given orally in capsule form (2 capsules of 100 mg each), administered once daily for the remainder of the 5 day period.
OTHERPlacebo Hydrogen
Normal saline solution will be administered intravenously, in place of hydrogen solution. Placebo tablets will be dissolved into water for the patient to drink, as the patient's condition permits. This will be administered TID for 3 days.
OTHERPlacebo Minocycline
Normal saline solution or placebo capsule will be administered i.v. or p.o. respectively, in place of minocycline.
Sponsors
Stony Brook University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Aged 18 years old or over 2. Presenting to/at Stony Brook University Hospital with acute ischemic stroke 3. Baseline (at admission to study) National Institute of Health Stroke Scale (NIHSS) of ≥ 5 4. Administration of study medication possible within 24 hours of last known well
Exclusion criteria
1\. Pre-existing neurological disability (historical NIHSS \> 3); unable to live independently 3. Severe stroke or comorbidities likely to result in patient dying within 3 months 4. Acute or chronic renal failure with calculated creatinine clearance \< 30 5. Liver disease leading to \> 3x elevation in liver transaminases or significant loss of synthetic capacity\* 6. Thrombocytopenia (\<100x10\^9platelets / L blood) 7. Pre-existing infectious disease requiring antibiotic therapy that have a negative interaction with minocycline. (Penicillin, amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, methicillin, mezlocillin, nafcillin, oxacillin, piperacillin, ticarcillin) 8. Pregnancy or nursing. Females of reproductive age will be required to use barrier contraception or abstain from sexual intercourse while on study medications, as minocycline may render oral contraceptives less effective. 9\. Known allergy to tetracycline group of drugs 10. Concurrent treatment with retinoids or ergot alkaloids 11. Inability to safely tolerate the fluid load (iv normal saline or po water) associated with study medication\* 12. Treatment with another investigational drug within the last 30 days that may interfere with this study's medications\* 13. Inability to tolerate or comply with study procedures\*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Favorable Outcome on the Simplified Modified Rankin Scale (sMRSq) | 90 days | rating scale to assess level of functional independence for patients post-stroke. Scores range from 0 (no symptoms) to 6 (dead). mRS scores at 90 days will be classified as favorable or unfavorable based on the baseline NIHSS measured at time of enrollment. Subjects in the lowest baseline severity tertile (NIHSS 5-7) will need to have a 90 day mRS score of 0 to be considered to have a favorable outcome. Subjects with baseline NIHSS 8-14 will need a 90 day mRS score 0-1 to be considered to have a favorable outcome; those with baseline NIHSS 15-25 will need a 90 day mRS score 0-2 to be considered to have a favorable outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Simplified Modified Rankin Scale (sMRSq) | 45 days | rating scale to assess level of functional independence for patients post-stroke. Scores range from 0 (no symptoms) to 6 (dead). |
| NIH Stroke Scale (NIHSS) | 90 days | 15-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. |
Countries
United States
Participant flow
Pre-assignment details
Of the 15 enrolled participants, 14 met inclusion exclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Hydrogen/Minocycline Hydrogen will be infused into aqueous solution (normal saline or water) at as high a concentration as possible (saturation = 1.6 ppm), and administered intravenously or orally respectively, TID for 3 days.
Similarly, Minocycline will be administered either i.v. or p.o. once daily for 5 days.
Hydrogen: Hydrogen will be infused into bags of normal saline solution and administered intravenously, or hydrogen generating tablets will be dissolved into water for the patient to drink, as the patient's condition permits. This will be administered TID for 3 days.
Minocycline: Minocycline 200 mg will be mixed with normal saline and given by i.v. administration, or provided as capsules for the patient to swallow, q 24 hours for 5 days.
Once patients regain the ability to swallow capsules, minocycline will be given orally in capsule form (2 capsules of 100 mg each), administered once daily for the remainder of the 5 day period. | 6 |
| Placebo Hydrogen/Placebo Minocycline Normal saline will be substituted for both Hydrogen and Minocycline for intravenous administration. Water will be substituted for hydrogen when administered p.o., and placebo capsules will be substituted for minocycline.
Placebo Hydrogen: Normal saline solution will be administered intravenously, in place of hydrogen solution.
Placebo tablets will be dissolved into water for the patient to drink, as the patient's condition permits. This will be administered TID for 3 days.
Placebo Minocycline: Normal saline solution or placebo capsule will be administered i.v. or p.o. respectively, in place of minocycline. | 8 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Day 90 Follow up | Death | 0 | 1 |
| Treatment Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Hydrogen/Minocycline | Placebo Hydrogen/Placebo Minocycline | Total |
|---|---|---|---|
| Age, Continuous | 74.17 years STANDARD_DEVIATION 12.32 | 65.13 years STANDARD_DEVIATION 13.92 | 69.00 years STANDARD_DEVIATION 13.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| NIH Stroke Scale (NIHSS) | 8.5 units on a scale | 12.5 units on a scale | 9.5 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 12 Participants |
| Region of Enrollment United States | 6 participants | 8 participants | 14 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 8 |
| other Total, other adverse events | 5 / 6 | 5 / 8 |
| serious Total, serious adverse events | 2 / 6 | 1 / 8 |
Outcome results
Primary
Number of Participants With Favorable Outcome on the Simplified Modified Rankin Scale (sMRSq)
rating scale to assess level of functional independence for patients post-stroke. Scores range from 0 (no symptoms) to 6 (dead). mRS scores at 90 days will be classified as favorable or unfavorable based on the baseline NIHSS measured at time of enrollment. Subjects in the lowest baseline severity tertile (NIHSS 5-7) will need to have a 90 day mRS score of 0 to be considered to have a favorable outcome. Subjects with baseline NIHSS 8-14 will need a 90 day mRS score 0-1 to be considered to have a favorable outcome; those with baseline NIHSS 15-25 will need a 90 day mRS score 0-2 to be considered to have a favorable outcome.
Time frame: 90 days
Population: Subjects lost to follow are considered to have an unfavorable outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hydrogen/Minocycline | Number of Participants With Favorable Outcome on the Simplified Modified Rankin Scale (sMRSq) | Unfavorable outcome | 5 participants |
| Hydrogen/Minocycline | Number of Participants With Favorable Outcome on the Simplified Modified Rankin Scale (sMRSq) | Favorable outcome | 1 participants |
| Placebo Hydrogen/Placebo Minocycline | Number of Participants With Favorable Outcome on the Simplified Modified Rankin Scale (sMRSq) | Unfavorable outcome | 7 participants |
| Placebo Hydrogen/Placebo Minocycline | Number of Participants With Favorable Outcome on the Simplified Modified Rankin Scale (sMRSq) | Favorable outcome | 1 participants |
Secondary
NIH Stroke Scale (NIHSS)
15-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.
Time frame: 90 days
Population: Per protocol the 90 day follow up is done either in person or by phone. The NIHSS is administered subjects who are able to be seen in-person for the follow-up visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrogen/Minocycline | NIH Stroke Scale (NIHSS) | 4 score on a scale | Standard Deviation 4.2 |
| Placebo Hydrogen/Placebo Minocycline | NIH Stroke Scale (NIHSS) | 7.5 score on a scale | Standard Deviation 3.5 |
Secondary
Simplified Modified Rankin Scale (sMRSq)
rating scale to assess level of functional independence for patients post-stroke. Scores range from 0 (no symptoms) to 6 (dead).
Time frame: 45 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrogen/Minocycline | Simplified Modified Rankin Scale (sMRSq) | 2.8 score on a scale | Standard Deviation 1.6 |
| Placebo Hydrogen/Placebo Minocycline | Simplified Modified Rankin Scale (sMRSq) | 3.4 score on a scale | Standard Deviation 1.3 |