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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hydrogen/Minocycline | Experimental | 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. |
|
| Placebo Hydrogen/Placebo Minocycline | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hydrogen | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 90 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 45 days |
| NIH Stroke Scale (NIHSS) |
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Inclusion Criteria:
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*
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| Name | Affiliation | Role |
|---|---|---|
| Dennis Choi, MD, PhD | Stony Brook University Hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stony Brook University Hospital | Stony Brook | New York | 11794-8121 | United States |
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Of the 15 enrolled participants, 14 met inclusion exclusion criteria and were randomized to treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period |
|
| ||||||||||||||||||
| Day 45 Follow up |
| |||||||||||||||||||
| Day 90 Follow up |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Subjects lost to follow are considered to have an unfavorable outcome. | Posted | Number | participants | 90 days |
|
90 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| stroke | Cardiac disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Christine Pol | Stony Brook Medicine | 6314449083 | christiana.pol@stonybrookmedicine.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 27, 2022 | Nov 17, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 19, 2022 | Oct 19, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000083242 | Ischemic Stroke |
| ID | Term |
|---|---|
| D020521 | Stroke |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D006859 | Hydrogen |
| D008911 | Minocycline |
| ID | Term |
|---|---|
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D005740 | Gases |
| D013754 | Tetracyclines |
| D009279 |
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|
| Minocycline | Drug | 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. |
|
|
| Placebo Hydrogen | Other | 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 | Other | Normal saline solution or placebo capsule will be administered i.v. or p.o. respectively, in place of minocycline. |
|
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.
| 90 days |
| NOT COMPLETED |
|
| NOT COMPLETED |
|
|
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| 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. | Median | Inter-Quartile Range | units on a scale |
|
| OG001 | 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. |
|
|
| 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). | Posted | Mean | Standard Deviation | score on a scale | 45 days |
|
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | 90 days |
|
|
|
| 0 |
| 6 |
| 2 |
| 6 |
| 5 |
| 6 |
| EG001 | 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. | 1 | 8 | 1 | 8 | 5 | 8 |
| bradycardia and syncope | Cardiac disorders | Non-systematic Assessment |
|
| hematochezia | Gastrointestinal disorders | Non-systematic Assessment |
|
| thrombus | Cardiac disorders | Non-systematic Assessment |
|
| Hypotension | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| urinary tract infection | Renal and urinary disorders | Non-systematic Assessment |
|
| vaginal bleeding | Reproductive system and breast disorders | Non-systematic Assessment |
|
| bradycardia | Cardiac disorders | Non-systematic Assessment |
|
| ecchymotic penis and scrotum | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| pulmonary congestion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| hypotension | Cardiac disorders | Non-systematic Assessment |
|
| twitching with anisocoria | Eye disorders | Non-systematic Assessment |
|
| Wound complication | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| skin redness and swelling | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| hematuria | Renal and urinary disorders | Non-systematic Assessment |
|
| petechial hemorrhagic stroke conversion | Cardiac disorders | Non-systematic Assessment |
|
| headache | Nervous system disorders | Non-systematic Assessment |
|
| inflammation in foot | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| black lesion in foot | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| hyponatremia | Renal and urinary disorders | Non-systematic Assessment |
|
| increased BUN/creatinine | Renal and urinary disorders | Non-systematic Assessment |
|
| diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| nausea | General disorders | Non-systematic Assessment |
|
| decreased sensation | Nervous system disorders | Non-systematic Assessment |
|
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| D009422 |
| Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |