Neuroprotection in Acute Ischemic Stroke (H2M)

Pilot Study of the Neuroprotective Effects of Hydrogen and Minocycline in Acute Ischemic Stroke

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.

Study Overview

• Status: Completed
• Conditions: Stroke, Ischemic
• Intervention / Treatment: Drug: Hydrogen; Drug: Minocycline; Other: Placebo Hydrogen; Other: Placebo Minocycline

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).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Kamil Stefanowski, MD; Email: kamil.stefanowski@stonybrookmedicine.edu

Study Locations

• United States
  • New York
    • Stony Brook, New York, United States, 11794-8121
      • Stony Brook University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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*

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; Other Names: H2; Drug: 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.; Other Names: Minocin; Minomycin; Akamin
Placebo Comparator: 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.	Other: 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.; Other: Placebo Minocycline; Normal saline solution or placebo capsule will be administered i.v. or p.o. respectively, in place of minocycline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	90 days
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

Collaborators and Investigators

• Sponsor: Stony Brook University
• Investigators: Study Director: Dennis Choi, MD, PhD, Stony Brook University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2017
• Primary Completion (Actual): August 13, 2019
• Study Completion (Actual): August 13, 2019

Study Registration Dates

• First Submitted: October 20, 2017
• First Submitted That Met QC Criteria: October 20, 2017
• First Posted (Actual): October 24, 2017

Study Record Updates

• Last Update Posted (Estimated): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 15, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: neuroprotection; antioxidant
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Ischemia; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: 932805

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No