Clinical trial NCT03320018
Conditions: Stroke, Ischemic
Keywords: neuroprotection antioxidant
Sponsor: Stony Brook University
Start date: 2017-08-02; Completion date: 2019-08-13
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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).

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Hydrogen intervention 2: Minocycline intervention 3: Placebo Hydrogen intervention 4: Placebo Minocycline
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: 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. intervention 4: Normal saline solution or placebo capsule will be administered i.v. or p.o. respectively, in place of minocycline.

Protocol documents:
Prot_SAP_000.pdf: 
1
TITLE: Pilot study of the neuroprotective effects of hydrogen and minocycline in acute ischemic stroke 
(v14.9)
INVESTIGATORS
Principal Investigator: Kamil Stefanowski, MD
Co-Investigators: Dennis Choi, MD, PhD; Michael Guido, MD, Jason Mathew, DO; Alison Caruana, 
MD; Lauren DeNiro, MD; Yuehjien Gu, MD, Ethan Brandler, MD.
A. SPECIFIC AIMS
The aim of this pilot randomized control trial (RCT) is 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.
B. BACKGROUND AND SIGNIFICANCE
The cellular and molecular processes responsible for driving brain cell death after hypoxic-ischemic 
insults have been progressively delineated over the past 30 years, but the development of an inaugural 
neuroprotective agent capable of reducing human brain damage after stroke has remained elusive 
(Ginsberg, 2008; Tymianski, 2014). Many putative therapeutic countermeasures have been identified that 
show promising neuroprotective effects in rodent models of stroke, but none so far have shown efficacy 
in human clinical trials. A wave of candidate drugs was brought forward into Phase II and even Phase III 
clinical stroke trials by both large and small pharmaceutical companies in the 1990s, but with 
disappointing results. These failures have led to widespread abandonment of the stroke therapeutic area 
by industry, further accelerated in recent years by a progressive de-investment by pharmaceutical 
companies in the entire CNS sector (Choi et al, 2014).
Compounding this reduction in investigative bandwidth, there are growing reasons to suspect that the 
biology of hypoxic-ischemic brain injury might be refractory to single interventions. As more injury 
mechanisms proceeding in parallel have been identified, the possibility looms that even an intervention 
powerful enough to halt a major injury mechanism might exhibit limited benefit when applied alone, with 
brain cells still dying due to parallel pathophysiology. An analogous situation has emerged in other 
therapeutic areas, including cancer and infections such as by HIV.
There is currently little experience with testing combination treatments (multiple concurrent drugs) for 
efficacy in reducing stroke-induced brain damage. The number of possible drug combinations is 
dauntingly high, making a fully systematic approach to testing impractical even in experimental models. 
Furthermore, predictive limitations of rat stroke models for human stroke have become clear, leading 
even to a suggestion that baboon models be deployed instead (Kwiecien et al, 2014). The bandwidth of 
baboon stroke model testing is of course modest, and applicability to man also unproven. A more 
practical path forward given these issues may be to identify promising combinations based on underlying 
principles, known mechanisms of action and the demonstration of individual efficacy in rodent stroke 
models; and then to test these rationally selected combinations directly in small exploratory clinical trials 
powered only to detect marked therapeutic effects. Only combinations showing high promise in such 
grass roots exploratory testing would move forward into rigorous, multicenter clinical trials. Ultimately, 
the demonstration of success with any approach, whether commercializable or not, could provide a major 
boost for the stroke field, increasing industry engagement and the prospects of developing more effective 
therapies in the future.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


2
With these ideas in mind, we propose here to perform a clinical pilot study, exploring the ability of a 
novel combination (“H2M”) of a promising antioxidant agent, molecular hydrogen, with a widely used 
antibiotic, minocycline, to protect brain tissue from ischemia/reperfusion injury, and hence aid recovery 
after stroke. Minocycline is known to inhibit the activation of matrix metallo-proteinase-9 (MMP-9) and 
poly(ADP-ribose) polymerase (PARP), events hypothesized to contribute to the later pathogenesis of 
ischemic brain tissue damage. 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) and 
achieving some degree of therapeutic reperfusion. Both agents can be easily administered to subjects 
intravenously or orally. Additional background information relevant to our selection of these agents and 
doses is presented below in section D, Research Design and Methods.
C. PRELIMINARY STUDIES
The proposed study is a pilot study, so there are no directly applicable preliminary studies utilizing the 
proposed H2M combination therapy. Relevant prior work with H2 or minocycline is summarized below 
under D.1, Rationale/overview.
D. RESEARCH DESIGN AND METHODS
D.1. Rational/overview
Hydrogen 
While the chemical ability of molecular hydrogen (H2, a gas at temperatures above minus 252°C) to react 
with oxygen free radicals has been long known, recent studies have identified a remarkable and 
biologically favorable selectivity: H2 efficiently quenches toxic hydroxyl and peroxynitrite free radicals, 
but has little effect on superoxide, nitric oxide, or hydrogen peroxide. The former radicals are highly 
pathogenic, whereas the latter radicals play important roles in normal cellular signaling (Ohsawa et al, 
2007). H2 diffuses through tissues and penetrates cell membranes readily, even quenching hydroxyl 
radicals generated in cell nuclei (Ohsawa et al, 2007).
Furthermore, exposure to H2 is not associated with any known biological toxicity. Human exposure to 
molecular hydrogen occurs naturally as a trace gas in air (about 0.5 ppm), and can reach 7,500 ppm 
(0.75%) in a closed environment such as aboard a nuclear submarine during long underwater periods 
(Hagar 2003). A 2008 National Academies study group was charged with considering the effects of long 
term hydrogen inhalation in submariners, and concluded that it was devoid of known toxic activity, beside 
a risk of asphyxia at concentrations high enough to replace ambient oxygen. That group recommended 
setting occupational exposure standards based solely on consideration of explosivity, noting that a 
concentration of 4.1% H2 in air was level at which hydrogen first becomes flammable (Committee on 
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, 2008). 
Inhalation of 49% H2 (with 50% helium and 1% O2) in a gas mixture called hydreliox is used by human 
divers in deep diving.
Reactive oxygen species are postulated to be a downstream mediator of several acute neurodegenerative 
pathways including excitotoxicity (Choi, 1988; Coyle and Puttfarcken, 1993), and both excitotoxicity and 
free radical-induced cellular damage have been implicated in the pathophysiology of brain tissue damage 
after ischemic insults (Chan, 2001). Oxidative damage is specifically promoted by reperfusion after 
ischemia (e.g., after successful mechanical thrombectomy or use of tPA), as well as the availability of 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


3
iron after hemorrhage (due to Fenton chemistry). In a rat model of transient focal ischemia (90min MCA 
occlusion), administration of 2% H2 gas by inhalation during ischemia-reperfusion, or only during 
reperfusion, reduced infarction 1d later; behavioral deficit 7d later was also reduced (Ohsawa et al 2007). 
A range of other cytoprotective effects have been observed after H2 administration (by inhalation, or in 
fluids delivered IV or PO) in rodent models of disease (Ohta, 2011), including against ischemic hepatic 
injury (Fukuda et al 2007), ischemic myocardial infarction (Hayashida et al 2008), inflammatory injury to 
cardiac allografts (Noda et a 2012), radiation-induced lung damage (Terasaki et al 2011), and 6-OH-
dopamine-induced nigrostriatal degeneration (Fu et al, 2009). Besides direct scavenging effects, indirect 
mechanisms, e.g. activation of transcription factor Nrf2, have been suggested to contribute to observed 
protective effects in these animal models of organ injury.
Minocycline
Minocycline is a second generation tetracycline, shown to have neuroprotective and anti-inflammatory 
effects in a wide range of acute and chronic injury models. These unexpected tissue protective effects 
may in part stem from minocycline’s ability to inhibit matrix metalloproteinases (MMPs) including 
MMP-9, at standard antimicrobial doses. Brain MMP-9 cellular expression (multiple cell types) and 
release to the extracellular space is increased after ischemic insults, likely contributing to inflammation, 
cell death, and breakdown of the blood-brain barrier (Chaturvedi and Kaczmarek, 2014). tPA is known to 
activate MMP-9, a side effect that has been postulated to promote blood-brain barrier breakdown and 
limit tPA’s therapeutic benefit, so there may be special advantage in inhibiting MMP-9 in conjunction 
with tPA administration. Minocycline also has other potentially beneficial actions, including reducing 
apoptosis, inflammation, and the activity of PARP. PARP inhibition occurs at even lower concentrations 
(submicromolar) of minocycline than needed for MMP-9 inhibition (Alano et al., 2006), and may reduce 
several neuronal injury cascades, including zinc neurotoxicity (Sheline et al., 2003), a process the co-PI’s 
laboratory identified and implicated in the pathogenesis of late infarction after focal ischemic insults (Lee 
et al., 2002).
The first reported human trial of minocycline in stroke was a single blind RCT that allocated 152 patients 
6-24h after stroke onset to placebo or 200 mg minocycline PO qd x 5d. At day 9, the odds of handicap-
free survival (modified Rankin clinical outcome scale, mRS <= 2) was 91% in the minocycline group vs 
47% in the placebo group (Lampl et al., 2007). A second small (n=50) open label pilot trial was similarly 
positive (72% mRS <=2 in minocycline treated vs 37% control) (Srivastava et al., 2012). However a third 
single blind RCT (n=95) did not see a benefit with 100 mg minocycline every 12h for 5 doses 
intravenously (2.5d therapy, 66% mRS <=2 in the minocycline-treated group vs 70% in the control group) 
(Kohler et al., 2013). This last study cooled enthusiasm in the stroke field for use of minocycline as a 
stroke neuroprotectant treatment, but to our eye, its design deviated importantly from the earlier positive 
studies. It enrolled all comers including patients with minor strokes (NIHSS > 0) who would be expected 
to recovery to mRS <=2 naturally, whereas the Lampl and Padma studies excluded such minor strokes, 
requiring the NIHSS upon entry to be >5 or >4, respectively. Inclusion of minor strokes, together with 
steady improvement in standard care, could account for the much better placebo outcomes seen in the 
Kohler study compared to the Lampl and Padma studies. Furthermore, the Kohler study only 
administered minocycline for 2.5d, instead of the 5d therapy duration used in the Lampl and Padma 
studies. 
ClinicalTrials.gov lists a fourth RCT of minocycline in stroke (NeuMAST) that was conducted in 
Singapore between 2009-2012 (R. Singh, PI): https://clinicaltrials.gov/show/NCT00930020. This trial 
enrolled 139 patients and administered 200 mg minocycline or placebo 3-48 hr after stroke onset, and was 
stopped to futility. However, enrollment of patients again deviated importantly from that utilized in the 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


4
earlier positive studies, as beginning treatment up to 48 hr after stroke onset would limit impact on earlier 
injury processes. Furthermore, this trial used an elevated and perhaps unrealistic primary criterion for 
efficacy, mRS 0 or 1.
 
In our view, another look at minocycline as a stroke neuroprotectant is justified. We believe the proposed 
combination of minocycline with H2 has a better chance than minocycline alone for producing the 
dramatic neuroprotective effect needed to gain the large funding required to conduct a definitive stroke 
neuroprotection trial.
D.2. Research Site
Eligible subjects will be recruited at Stony Brook University Hospital. Follow up assessments will be 
conducted by telephone or in the SB Neurology outpatient clinic.
SUNY Stony Brook is the only Level 1 Trauma Center in Suffolk County (population 1.5 million) in 
eastern Long Island, and has a highly active clinical stroke service, recognized for the last few years by 
the American Heart Association with a “Gold-Plus” award for outstanding adherence to recommended 
care paths. The Stony Brook stroke team responds within minutes to patients presenting to SBUH with a 
stroke at any time day or night. In 2015, the SB stroke team evaluated 575 patients presenting to the 
emergency room (or already on SBUH inpatient services) with acute ischemic stroke; 46 of these received 
tPA at an outside hospital prior to transfer here, and 36 received tPA here; 39 received mechanical 
thrombectomy at SB. Of these 575 patients, 196 had a baseline admission NIHSS between 5 and 25.
D.3. Study Sample
Subjects admitted to SBUH with an acute ischemic stroke (or developing an acute ischemic stroke while 
already in the hospital for other reasons), who meet the inclusion/exclusion criteria in Table 1 below and 
provide consent (directly or through their legally authorized representative, LAR) will be recruited and 
randomized sequentially 1:1 to receive either H2M or placebo.
We will seek to enroll a total of 100 patients meeting enrollment criteria and randomized to H2M vs 
placebo arms. Subjects who receive mechanical thrombectomy (likely <10% of total) will be stratified 
separately. While they also may benefit from H2M, these patients not uncommonly exhibit a marked and 
rapid recession of stroke symptoms after successful mechanical thrombectomy, which could make 
detection of additional treatment benefit difficult (ceiling effect). We project a study duration of 2y with 
one interim analysis at 1y to look for futility.
D.4. Screening
When a patient presents to SBUH with a new onset stroke from outside, or when hospitalized as an 
inpatient, code BAT is called and the stroke team responds immediately. A stroke team member will 
review the patient’s medical record to evaluate whether he/she is eligible for the present study (Table 1). 
If eligible, the subject’s capacity to provide informed consent will be assessed by a stroke team clinician 
(attending, resident, fellow, nurse practitioner, or physician’s assistant). This clinician will determine if 
the subject understands: 1) that the study procedures constitute research, not standard treatment; 2) the 
risks and benefits of a study; 3) the alternatives that are available if they do not participate; and 4) that if 
they choose not to participate, that decision will be accepted without penalty, i.e., without jeopardizing 
clinical care. If the subject is capable of understanding the treatment and is interested in participating in 
the study, he/she will be asked to sign the consent form. In cases where the subject is unable to provide 
consent, the subject's legally authorized representative (LAR) will be asked to provide consent. If 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


5
possible, the subject will also be asked to indicate their assent on the consent form. A study staff will 
review the consent form, including the risks and potential benefit of the study medications, with the 
subject and/or his/her LAR. If no LAR is present in the hospital we will use a verbal consent by a LAR. A 
LAR/next of kin to verbally consent to research on behalf of the subject will be contacted by telephone. 
The person conducting the informed consent discussion will discuss the study with the LAR/next of kin 
and answer any questions they have. An email address will be requested, and the ICF will be sent (via 
email or mail) to the LAR/next of kin. If the LAR/next of kin agrees to participate they will print the 
document (either on paper or to PDF) and sign the document with either a pen or a stylus if they are able 
to do so. The signed document can be scanned, or if no scanner is available, a cell phone photograph can 
be taken of the document and returned as soon as possible after the consent process. The subject will be 
enrolled in the study after a signed consent form has been received. For Spanish-speaking patients, we 
will request an in-house Spanish interpreter to assist with oral presentation and serve as an impartial 
witness. The Spanish consent form will be signed by the subject/LAR. Patients who speak a language 
other than English or Spanish (<1% of SBUH patients) will not be enrolled in this study, as interpreters 
for other languages are not in-house at SBUH, and we do have the resources to make a range of other 
language interpreters available to us in person and on short notice. The subject and his/her LAR will be 
allowed to ask questions and discuss in private before deciding to sign the consent form. Subjects will be 
informed during the consenting process that they will bear responsibility for the costs of treating any AEs 
resulting from study medication.
Table 1: Inclusion/exclusion criteria
1.
Aged 18 years old or over
2.
Presenting to/at SBUH with acute ischemic stroke
3.
Baseline (at admission to study) National Institute of Health Stroke Scale (NIHSS) of ≥ 5
Inclusion 
criteria
4.
Administration of study medication possible within 24 hours of last known well
1.
2.
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 (<100x109platelets / 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
Exclusion 
criteria
11. Inability to safely tolerate the 850 ml fluid load (IV NS 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*
*These criteria will be judged by the attending physician.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


6
D.5. Procedures
D.5.a Study Procedures
This will be a double blinded, placebo-controlled trial. Subjects will be sequentially randomized in a 1:1 
ratio to receive H2M, or corresponding dual placebos, additional to all standard-of-care treatments. 
Enrollment goal is 100 subjects over 2 years.
For subjects meeting enrollment criteria and providing consent, treatment with H2M or placebo will start 
as soon as possible after arrival in the emergency department or SBUH, and assessment of vital signs, 
baseline NIHSS, and baseline modified Rankin Score (mRS). The subject will then be randomly assigned 
by the study coordinator to either the H2M treatment group or the placebo group. A blocked 
randomization list will be generated using this website: https://www.sealedenvelope.com/simple-
randomiser/v1/lists. The study coordinator will be in charge of using the generated list to assign treatment 
to subjects as they are enrolled. This study coordinator may have interaction with subjects when obtaining 
consent or during follow up, but he/she will not be assessing any study outcome. The study staff who will 
assess study outcomes will remain blinded to treatment assignment. Masking of active and placebo 
treatments will be preserved by creating IV bags, capsules, and containers that appear identical. 
For each subject we will use one of three routes of administration of hydrogen and minocycline 
depending on the subjects’ ability to tolerate oral administration:
1)
PO; we use this if subject can tolerate oral administration.
2)
Nasogastric intubation (NG); we use this for patients that are unable to swallow but able to have 
an NG tube placed.
3)
IV; we use this in patients that are unable to swallow and NG tube placement is clinically 
contraindicated.
If the subject passes the dysphagia test, we will switch from NG intubation or IV to PO for the next doses.
Minocycline (200 mg daily) will be given for 5 days, either as 200 mg in 100cc normal saline (NS; IV) 
over 60 min, or in capsules (per NG and PO). Hydrogen will be given TID x 3d, either as 250 ml of H2-
enriched water (per NG or PO), or as 250 ml of H2-enriched NS (IV over 20-60 min). The first dose of 
hydrogen will be given STAT and all other doses per SBUH TID schedule (8 am, 12,pm, 4 pm), but for 
convenience a dose may be given a few hours earlier or later, as no available information or expected 
mechanism of action indicates that dose timing would be critical for efficacy) x 3d. Subjects will be 
monitored for their duration of stay for adverse events. If the subject is discharged before study therapy is 
completed, the study coordinator will follow up with subjects via phone call to ask about adverse events 
during study treatment. 
To assess neurologic deficits and level of handicap, study staff blind to treatment assignment will assess 
the mRS (see below) on 1) day 45 ± 7 days via a phone call, and 2) day 90 ± 7 days at the subject’s 
routine follow up clinical visit (preferred) or by phone call. If the 90d follow-up can be performed in 
person at a clinic visit, the NIHSS will also be assessed at that time. For Spanish speaking subjects, the 
language line will be used for the assessments. 
Subjects can withdraw from the study at any time. Study staff will try to assess the mRS on the subject’s 
last phone call. 
Subjects who have undergone one MRI scan within the first 48 hours after stroke will be offered the 
opportunity to have a second unenhanced MRI scan at 80 to 100 days after stroke to assess the evolution 
of infarct volume. We will perform additional analysis for research purpose on the patients clinical MRI 
as comparison. The second MRI will be performed at the SB outpatient MRI facility. The first MRI scan 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


7
will be billed to the patient, but the second MRI will be provided to the patient for free unless clinically 
indicated. The patient will only be responsible for transportation costs to and from the MRI scan 
appointment. We do not expect to obtain this second MRI scan for all patients, but we would like to be 
able to obtain this data when circumstances permit. 
D.5.b Study Drug
The FDA has approved this study protocol with minocycline and molecular hydrogen (IND#131621).
D.5.b.i Hydrogen
Preparation 
The optimal route for administering H2 in the present study would be via gas inhalation, but the associated 
environmental risk of gas leakage, buildup, and explosion would have to be managed by hospital 
engineering. This could be accomplished using a tightly-fitted face mask and room ventilation, but for the 
purposes of this initial study we propose the logistically easier route of administration of pre-dissolved H2 
in IV or oral fluids. H2 can be dissolved in water at atmospheric pressure up to a saturating concentration 
of 0.8 mM (1.6 ppm), and tissue protection has been demonstrated in a variety of rat models utilizing 
either infusion of H2 -enhanced IV fluids or ad lib access to H2 –enhanced drinking water. 
We will use one of three methods for hydrogen preparation:
1)
H2 drinking water obtained by dissolving an over-the-counter (dietary supplement) magnesium-
containing tablet in tap water.
2)
Diffusion of hydrogen into IV bags (containing saline) by placing the IV bag in a chamber filled 
with water that is bubbled with pure H2 gas, obtained from a gas tank.
The drug administration route flow chart depicted below summarizes this process (Figure 1).
Figure 1: Study drug administration flow chart
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


8
Method 1 H2 drinking water obtained by dissolving an H2 magnesium tablet in tap water for 
enteral administration (PO or NG): as an alternative method to prepare H2 drinking water, we would 
use the hydrogen producing tablets from HRW 
(https://drinkhrw.com/shopping/sc_cart/sc_CatTy.asp?SectionID=1&treeUID=1040&guid=60614F5C-
6904-4E9A-959B-1448EB4BFCC6). These tablets are sold commercially under the general category of 
dietary supplements, for the purpose of enhancing the hydrogen dissolved in drinking water.
The ingredient in the HRW tablets producing H2 is magnesium. The tablets contain a safe level of 
magnesium (80 mg) well below recommended daily allowance (420 mg/d for men; 320 mg/d for women.
Dissolving one tablet in ~250ml of water will achieve a H2 concentration of approximately 0.9 to 1.6 
ppm. The tablet will be added to the water in an open glass/cup at bedside as the hydrogen dissipates 
quickly. As soon as the tablet is dissolved near-completely and rises to the surface the patient will be 
instructed to drink the water quickly all at once. For a matching placebo, we will use tablets with same 
size, same magnesium content and similar dissolve times provided by HRW Natural Health Products Inc.  
While the nurse may be able to tell the difference between the active study drug and placebo (different 
color), he/she will not be involved in the assessment at day 45 or 90. 
Figure 2: Nutrition label of hydrogen producing tablets from HRW.
The study coordinator will be responsible for preparing H2 –enhanced drinking water or IV fluid and 
untreated drinking water or IV fluid as placebo in HSC laboratory room 12-048 and maintaining the 
master list of treatment assignments. The study co-PI (DWC) has experience operating a cell biology 
laboratory and will ensure that all preparation surfaces are kept clean with no risk of cross contamination 
from other laboratory procedures (no concurrent procedures in the same space are currently anticipated). 
The Stony Brook Pharmacy will be responsible for preparing the H2 magnesium tablets and placebo. The 
route of administration and formulation for each dose per patient will be recorded. The study drug will be 
labeled with the patient's name, MRN, name of drug or matching placebo, preparation time, and 
expiration.
Method 2 H2 –enhanced fluids for IV administration: we will first obtain ordinary intact 250 ml IV 
bags of NS from Stony Brook Hospital supplies. For H2 to diffuse into an intact IV bag while keeping it 
dry in the water bath, the vendor-supplied thick plastic VIAFLEX overwrap will be replaced at time of 
use by a standard plasma overwrap (a thin plastic bag that is currently used by the SB Blood Bank to thaw 
frozen plasma in a water bath). According to Baxter Healthcare Corporation (see letter on IRBnet), the 
primary purpose of the VIAFLEX overwrap is to retard water evaporation from the inner IV bag over 
long storage, which is not an issue here. At room temperature and for 100-1000 ml bags, Baxter 
recommends that the VIAFLEX overwrap not be removed longer than 30d before use. The inner IV fluid 
bag is adequate to keep contents sterile and is normally handled with ungloved hands prior to clinical use.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


9
The IV fluid bag will be sealed water-tight inside the plasma overwrap bag using a heat sealer on the open 
edge; a test strip moisture indicator will also be placed inside the bag to detect any failure of the seal. The 
overwrapped IV bag will then be placed into a galvanized steel chamber filled with H2 water (obtained 
from the chained Pure Hydration system and Iontech IT-380 water treatment systems, see below). The H2 
water in the steel chamber will then be slowly bubbled with pure H2 gas (Ultra High Purity grade; Airgas) 
at a pressure of 10-15 psi over atmosphere to further increase dissolved H2 to saturation. This will be 
carried out inside of a standard laboratory exhaust hood so that escaping excess H2 gas will be safety 
vented to the outside (this procedure has been reviewed with SB EHS). A H2 gas monitor mounted near 
the ceiling and hood will assure that the exhaust hood is working properly and that H2 gas is not 
accumulating in the laboratory room. 
Consistent with data published by Nagatani et al (2013) and others (eg, Ishibashi et al, 2014), we have 
found that H2 gas is able to permeate the sealed plasma overwrap and intact IV fluid bag, elevating the 
level of dissolved H2 in the bag’s saline contents to about 0.9 ppm after 18-24 hours incubation, measured 
with a dissolved hydrogen meter (Sata Shouji ENH-1000, Kawasaki City, Japan; accuracy +/- 5 ppb). 
Since the IV bag remains dry and intact, there is no risk of introducing non-gaseous contaminants or 
infectious agents into its fluid contents by this procedure. We will nonetheless keep the water chamber 
scrupulously clean, scrubbing it out after each use (at least every week) with a spray of alcohol and then 
rinsing thoroughly with water. In addition, if the IV bag is not used within 1 week, it will be discarded. 
The Ultra High Purity H2 gas from Airgas is assessed at >99.999% pure. The CO + CO2 concentration in 
this gas is assessed at < 1ppm, so even directly breathing this gas mixture would not carry a risk of CO 
toxicity (current OHSA permissible exposure limit is 50 ppm). We record cleaning and hydrogen 
preparation in a cleaning log and H2 preparation log. We prepare extra quality control IV bags and on 
every day that we administer an IV bag to a subject, we measure the hydrogen concentration in the quality 
control IV bag that has been prepared simultaneously with the IV bag for the subject.
The study coordinator will check the moisture indicator before transporting it to the hospital floor for 
timely administration by the subject’s nurse. If moisture is detected inside the overwrap (via the moisture 
indicator), the IV bag will be discarded. For placebo use, the IV fluid bag and moisture indicator will be 
sealed in the plasma overwrap bag without exposure to water. At point of administration, H2 –enhanced 
and ordinary IV fluid (placebo) will be indistinguishable. The placebo IV bags will be discarded if they 
are not used within 30 days following Baxter’s instructions as stated above. 
Administration 
Subjects will start H2 treatment (concurrent with minocycline treatment, see below) as soon as possible 
after arrival at SB (see above). The outside window for enrollment will be 24h after onset of brain 
ischemia, as ascertained by the stroke team based on last known well. The study coordinator will provide 
the hydrogen-rich water in a stainless steel water bottle or the hydrogen-rich NS IV bag. In case of IV 
treatment, the subject’s nurse will open the plasma overwrap at bedside and administer IV fluid using the 
same procedures as a normal IV bag. The subject will receive 250cc H2 –enhanced water (if enteral) or 
NS (if IV, over 20-60 minutes) TID x 9 doses. If logistical issues preclude preparing a dose of H2 –
enhanced IV NS, or the attending physician would prefer to limit fluid delivery, a dose may be skipped, 
dropping administration for that day from TID to BID. As noted above and immediately below, available 
evidence and mechanistic arguments suggest that some flexibility around timing and dose of H2 delivery 
should not preclude efficacy. For subjects discharged from SBUH before the 3d H2 treatment ends, they 
will be instructed to continue drinking 250ml H2 –enhanced water TID. The study coordinator will 
provide the H2 magnesium tablets (or placebo) and a stainless steel water bottle for subjects to take with 
them. Subjects who cannot tolerate thin liquids can use commercial pre-thickened water or commercial 
thickener to get the water to the consistency they can tolerate (nectar-think or honey-thick). 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


10
Dosage 
In the study of 6-OH-dopamine-induced nigrostriatal degeneration mentioned above, Fu et al (2009) 
found that 3ml of 50% saturated (0.8 ppm) H2 –enhanced water instilled into the rat stomach was roughly 
equivalent to inhaling 2% gas in raising blood levels to roughly 10 nM; free access to such H2 -enhanced 
drinking water was provided beginning 3d after surgery, and neuroprotection was observed at 2, 3, and 4 
week post-operative time points. Infusion of H2 -enhanced IV saline (5 ml/kg) given immediately after 
and 8h after cerebral hypoxia-ischemia reduced brain infarction in rat pups (Cai et al, 2008), and (at 6 
ml/kg x 2 doses) reduced L-arginine-induced acute pancreatitis in rats (Chen et al, 2010). These latter 
doses would correspond to 300-360 ml IV saline in a 60kg human, scaled by weight/water volume. 
Ishibashi et al (2014) performed a RCT of H2 -enhanced IV saline in 26 patients with active rheumatoid 
arthritis. They found that 500 ml daily x 5d of IV saline containing approximately 1 ppm of dissolved H2 
was sufficient to reduce the joint disease activity score immediately post first infusion, with benefits 
increased further by 4 weeks after treatment onset. They noted that circulating blood cells in the vein 
receiving IV infusion are exposed to H2 at local concentrations much higher than calculated blood 
equilibrium concentrations. These circulating immune cells participate in the pathogenesis of rheumatoid 
arthritis, and are also thought to participate in the pathogenesis of brain injury after ischemic insults.
For these reasons, we have selected a dosage target of 250 ml of H2 -enhanced IV saline or drinking water 
TID. Duration of therapy was set at 3d, balancing the desirability of limiting later phases of oxidative 
tissue damage with practicality, and recognizing the difficulty of maintaining this treatment once subjects 
are discharged from SBUH. 
D.5.b.ii Minocycline
Preparation 
The study coordinator will maintain the master list with the treatment assignments and fill out the order 
form for the Stony Brook Pharmacy. Stony Brook pharmacy will compound the minocycline-infused IV 
bag using minocycline for injection (MINOCIN IV). For placebo, untreated IV fluid bags will be used. 
The Stony Brook pharmacy will also compound minocycline and placebo into identical gelatin capsules 
for subjects who can tolerate oral medication. The route of administration and formulation for each dose 
per patient will be recorded. 
Administration 
Minocycline will be given at 200 mg qd x 5d, either via IV solution or in capsule form. NS 100cc will be 
administered over 60 minutes. For subjects discharged from SBUH before the 5d treatment ends, they 
will be instructed to continue taking 200 mg capsules PO qd. The capsules have to be swallowed whole. 
Patients who do not pass the swallow test are not likely to be discharged and will continue treatment via 
IV. 
Dosage 
Neuroprotective doses of minocycline in experimental studies are generally similar to antibiotic doses. 
Dose ranging in stroke patients (Fagan et al., 2010) showed that 3mg/kg was well-tolerated and sufficient 
to achieve neuroprotective plasma levels, as defined in rats subjected to transient focal ischemia (about 4 
mg/L = about 8 micromolar given MW 457; 12 mg/L had a slightly greater protective effect – (Xu et al., 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


11
2004)). For this reason, and because two prior positive clinical studies of minocycline in stroke patients 
utilized a single daily dose of 200 mg x 5d, we have selected 200 mg qd x 5d as our minocycline dosage 
level.
D.5.b.iii Compliance
Compliance will be monitored by the study coordinator and recorded in a log. For the subject’s inpatient 
stay, his/her nurse will make note of the administration and completion of each study drug dose in 
Powerchart. After discharge, the study coordinator will call the subject/caregiver to check compliance and 
for adverse effects.
D.5.c Outcome measures
Each subject’s neurological function will be evaluated at 45 and 90 days after stroke onset. The primary 
outcome measure will be the modified Rankin Scale (mRS), a global outcomes rating scale to assess level 
of functional independence for patients post-stroke with reference to pre-stroke activities, ranging from 0 
(no symptoms) to 6 (dead). 
Table 2: Modified Rankin Scale
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties and activities
2
Slight disability; unable to carry out all previous activities, but able to look after own affairs 
without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to attend to own 
bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care and attention
6
Dead
To limit subjectivity in mRS scoring, the simplified mRS questionnaire (sMRSq), a simple and validated 
questionnaire tool, will be used (Figure 3). It can be successfully administered via telephone, with 
telephone scores correlating well with in-person rating scores (Bruno et al., 2011). The smRSq will be 
administered in person at baseline, over the phone at day 45 ± 7 days, and in person or over the phone at 
day 90 ± 7 days. 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


12
Figure 3: Simplified Modified Rankin Scale Questionnaire
A secondary outcome measure will be the NIH Stroke Scale (NIHSS), a 15-item neurologic examination 
stroke scale used to evaluate the effect of stroke on several domains of neurological function: level of 
consciousness, language, attention, visual-fields, extraocular movement, motor strength, motor 
coordination, speech, and sensation. A trained observer rates the patent’s ability to answer questions and 
performs a limited neurological examination. Ratings for each item are scored with 3 to 5 grades, 0 being 
normal, with allowance for untestable items. The single patient assessment requires less than 10 minutes 
to complete. Item scores are summed to yield a total score. A total NIHSS of 0 is normal; 1-4 considered 
a minor stroke; 5-15 moderate; 16-20 moderate to severe; and 21-42 severe. The NIHSS will be 
administered at baseline and day 90 ± 7 days for subjects (a majority) who are able to be seen in-person in 
the neurology outpatient clinic for a follow-up visit.
An additional outcome measure for subjects who undergo the second MRI will be the change in volume 
of the infarct area, measured as the difference between the volume of diffusion restriction in the first 48 
hours and the T2 FLAIR infarct volume at 80 - 100 days after the stroke.
D.5.d Enrollment failure
Subject enrollment will be examined continuously. Our original goal was to enroll the targeted 100 
subjects within 2y of enrolling the first subject. In the first 15 months we enrolled 9 patients. To increase 
the number of eligible patients we changed the inclusion criteria to be able to include patients with 
National Institute of Health Stroke Scale (NIHSS) of 5-25 instead of 5-22.  Since last spring we have 
made the following adjustments to avoid missing any eligible patients: addition of personnel, enrollment 
during weekends, and addition of the option to administer hydrogen by nasogastric intubation. 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


13
We hope that these adjustments will improve enrollment rate to the point that a reasonable extension of 
time will enable completion of original study goals; or at least, enrollment of enough patients that a 
preliminary analysis of study data is worthwhile.  Such a preliminary analysis may enable us to compete 
for outside grant support, permitting hiring of additional study coordinator(s) and increasing enrollment 
duty cycle during the week, or partnership with another medical center.  In any case, prior to end of the 
originally proposed 2y enrollment period, we will either terminate the study, or submit an appropriate 
amendment request to the IRB.
E. STATISTICS
This is an exploratory study. It will be powered only to detect a large superiority of H2M treatment 
compared to placebo on the primary outcome measure, which will be a favorable functional outcome as 
assessed by mRS, 90d after the stroke.
Favorable outcome will be defined using a sliding dichotomy, an approach sometimes designated 
“responder analysis”. 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. This approach, in use by the Stroke Hyperglycemia Insulin Network Effort (SHINE) 
trial (Bruno et al, 2014) requires subjects with milder strokes to achieve a higher level of recovery 90d 
after treatment than subjects with more severe strokes, to reach the study’s favorable outcome endpoint. 
Many previous stroke therapy trials have used a simpler, straight 90d mRS 0-2 definition of favorable 
outcome, but this simpler approach runs the risk of a ceiling effect when patients with mild strokes 
naturally achieve a good functional recovery. This problem may have occurred in the Kohler et al (2013) 
study which enrolled patients with mild strokes (NIHSS >0), used a mRS 0-2 definition of favorable 
outcome, and observed a high rate of favorable outcome in both placebo and minocycline arms (66-70%).
The primary study population will be subjects presenting with acute ischemic stroke who are treated 
medically, with or without tPA. As noted above, this population constitutes the large majority of acute 
ischemic stroke patients at SBUH. A small number (<10%) of acute stroke patients, with strokes caused 
by an accessible large artery thrombus, are taken to surgery for mechanical thrombectomy, usually 
additional to administration of tPA. Mechanical thrombectomy not uncommonly produces marked and 
rapid alleviation of stroke symptoms, challenging detection of additional benefit due to an experimental 
therapy. But there is still room for improvement – mechanical thrombectomy typically does not eliminate 
cerebral infarction entirely, and as noted above, H2M therapy is predicted to specifically reduce the 
reperfusion injury induced by thrombectomy. We will enroll these surgical patients if they meet 
inclusion/exclusion criteria, but stratify them separately from the primary target population of subjects 
receiving medical therapy only.
Statistical analyses will be performed according to intention-to-treat using the Pearson chi-square statistic. 
Subjects lost to follow up will be considered to have an unfavorable outcome. No correction for 
additional exploratory analyses will be performed. Final statistical analyses will be performed under the 
guidance of an expert statistical consultant.
Power
Using the large effect size for minocycline seen in the original Lampl et al study (2007), with 47% 
favorable outcome in the placebo arm and 91% in the treatment arm, study size estimate yields a total 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


14
sample size of 44 (22 in each arm) needed to detect therapeutic effect (reject null hypothesis) in a 
comparison between two independent proportions at p < 0.05 and with a power of 0.90, using a two-tailed 
test. Using the large effect size seen in the Srivastava et al (2012) study, with 37% favorable outcome in 
placebo arm and 72% favorable outcome in treatment arm yields total sample size requirement of 82 for p 
< 0.05 / power 0.90, with sample size requirement falling to 62 for power 0.80.
Futility
A single interim analysis will be carried out once 45 primary study subjects have been enrolled (medical 
therapy only) to see if the study should be stopped for futility or harm, using the same Pearson chi-square 
statistic and the guidance of an expert statistician. Given pre-specification of this single interim test and 
enrollment point, it should have limited impact upon the power of the final analysis (O’Brien and 
Fleming, 1979).
FUNDING STATUS, DETAILS
This is an investigator-initiated pilot study that will be funded at launch from the investigators own 
uncommitted research funds, possibly with some help from the Department of Neurology. The 
investigators may seek outside funding once they have established their ability to conduct the study, and 
certainly will seek outside funding if interim study results are encouraging.
F. HUMAN SUBJECTS RESEARCH PROTECTION FROM RISK
F.1 Risk to Subjects
Based on known biology, we do not anticipate clinically significant adverse effects associated with the 
proposed brief administration of H2. Several published studies have administered H2-enhanced drinking 
water or IV saline to human subjects without observing any serious treatment-associated AEs. Nakao et al 
(2010) administered a higher, more sustained dose of H2-enhanced drinking water (1.5-2L qd x 8 weeks) 
to 20 subjects with potential metabolic syndrome. They observed a small decrease in high density 
lipoprotein cholesterol considered therapeutically promising, but no abnormalities in weight, blood 
pressure, hematological parameters, or routine clinical chemistry values. No serious adverse events were 
noted. 4 subjects had mild AEs (1 with headache, 1 with heartburn, 3 with loose stools) but no definitive 
relationship to treatment could be established in such a small study lacking a control arm.
In the study of Ishibashi et al (2014) noted above, H2 -enhanced IV saline (500 ml qd x 5d, approximately 
1 ppm H2) was given to 20 normal volunteers in a separate safety test. No clinical AEs or changes in 
routine hematology or blood chemistry were observed. Nagatani et al (2013) specifically carried out an 
open label exploratory safety study of H2 –enhanced IV fluid in 38 patients with acute stroke, given 
together with another anti-oxidant, edaravone. If tPA was administered (11 patients), H2 was given 
concurrently. They immersed regular plastic IV fluid bags in a water tank in which water was hydrolyzed 
to produce H2; the IV fluid reached about 1 ppm via diffusion through the plastic bags. 200ml of H2 –
enhanced IV fluid was given q12h. 2 patients (5%) had possible adverse effects, consisting of diarrhea in 
one, and late cardiac failure in another 90 days later, but it would not be unusual to see similar 
occurrences in stroke patients administered placebo. No acute deterioration in laboratory tests or EKGs 
were observed, and no patients treated with tPA developed symptomatic intracranial hemorrhage. The 
investigators concluded that their data did not reveal any safety concerns with administration of IV H2 to 
acute stroke patients.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


15
One US company, MitoGene, has recently begun to sell pouches of H2 –enhanced drinking water on the 
US market (http://htwo.com/about/). In recent correspondence with the FDA, MitoGene indicated their 
view that H2 –enhanced drinking water met criteria to be classified as GRAS. While the FDA has not 
made a decision on this issue, they indicated in a response letter that they had no questions at this time 
(see attached).
The proposed administration of 850 ml qd of saline IV or water PO to subjects who have just sustained an 
acute ischemic stroke should not pose significant risk. While administration of water can transiently 
increase brain swelling, this volume is less than needed to keep a patient hydrated and much less than 
typically administered to acute stroke patients at SB (75cc/hr IV NS = 1800 cc qd). Of course the volume 
of maintenance IV fluids will be adjusted to take study medication fluid load into account. Furthermore, 
any subject whose attending physician is concerned about study medication-associated fluid load is 
excluded from study. Patients with acute ischemic stroke at SBUH are closely monitored by a stroke care 
team expert in managing fluid status, blood pressure, and brain swelling.
Similarly, we do not expect much risk from administration of minocycline in this study. Minocycline 
administered as an antibacterial agent at the proposed dose has an extensive safety record and is also 
available for pediatric use. There is no reason to believe that concurrent administration of H2 will interact 
negatively with minocycline. 
The most important contraindications to minocycline use in adults are allergic hypersensitivity, renal 
failure (increased azotemia and systemic accumulation of drug leading to liver toxicity), hepatic failure, 
and pregnancy (teratogenesis). These are all exclusion criteria. Patients with infections requiring 
antibiotic therapy that minocycline could interfere with are also excluded. Pseudotumor cerebri is a rare 
complication of longer term use (weeks-months) of tetracycline drugs, typically resolving when drug is 
discontinued. It is unlikely to develop during 5d administration, but any prior history of this disorder is 
another exclusion criterion.
Reported minor adverse effects in a small number of individuals that typically resolve when drug is 
stopped include photosensitivity / exaggerated sunburn reaction, pruritus, arthralgia, light-headedness, 
dizziness, vertigo and tinnitus. We will make subjects aware of the possibility of these adverse effects and 
stop study medication if any of these symptoms occur and prove troublesome within the framework of 5d 
administration.
Subjects who are unable to swallow will undergo nasogastric intubation for administration of study drug, 
if not clinically contra-indicated. Nasogastric intubation is typically a routine part of care of stroke 
patients who have difficulty swallowing, but may be performed earlier in the hospital course in patients 
enrolled into the study. The potential risks of nasogastric intubation include discomfort, and injury of the 
tissue inside of the nose, sinuses, throat, esophagus, or stomach. Rare risks include internal bleeding, 
abdominal cramping, abdominal swelling, diarrhea, nausea, vomiting, regurgitation of medicine, and 
aspiration.
The potential risks of IV drug administration include discomfort, bruising, and pain at the site of 
injection. Rare risks include inflammation of the vein used for injection, phlebitis, metabolic disturbances, 
and injury. Very rarely will there be severe reaction, anaphylaxis, cardiac arrest, or death.
MRI is a routine part of the stroke workup, and generally considered safe. Patients who have 
contraindications for MRI (e.g. patients with pacemakers or metallic implants) would not get an MRI in 
the acute stroke period, and thus would automatically not qualify for the second MRI. A second MRI scan 
would involve discomfort similar to the first MRI scan. Some patients experience a claustrophobic 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


16
sensation, and the scan can be noisy. Adverse events for MRI scans are very rare. If metallic objects are 
not removed prior to the scan, second degree burns may occur, and are the most commonly reported 
patient problem. Other reported problems include injuries from magnetic objects being brought too close 
and drawn toward the MRI scanner, crushed and pinched fingers from the patient table, patient falls, 
dizziness, tingling sensation and hearing loss or a ringing in the ear (tinnitus). A clinical MR imaging 
facility typically has numerous safeguards in place to prevent the above injuries and adverse events.
F.2 Adequacy of Protection Against Risks
The risks of the H2M therapy proposed here are small and thus dwarfed by the significant risks of death 
or major morbidity associated naturally with acute ischemic stroke. Patients with acute stroke at SBUH 
are very closely monitored by the stroke team, which includes neurologists, neurosurgeons, and 
radiologists with subspecialty expertise in the care of stroke patients. The PI and Data Safety Monitoring 
Committee will monitor safety and risks throughout the study. See section H for more details. 
Signed informed consent will be obtained from each subject. A copy of the consent form countersigned 
by study staff will be given to the subject. 
The PI and all key personnel involved in the study will have completed the Collaborative IRB training 
initiative and HIPAA training. The PI will be responsible to report adverse events experienced by study 
subjects to the IRB according to IRB guidelines.  
Confidentiality will be maintained, as all subject research data will be coded with subject ID number and 
initials. The paper files will be kept in a secure, locked area. The electronic database used during the trial 
will be secured with a password and saved on a secured shared drive only accessible to key personnel. 
Subject results will never be discussed in any form in the presence of other subjects in the study or with 
non-laboratory personnel. A subject will be referred to by his/her randomization ID number wherever 
possible. Subjects’ names will not be used in manuscripts or presentations about this research. 
F.3 Potential Benefits of Proposed Research to the Subject and Others
F.4 Importance of the Knowledge to be Gained
The proposed H2M therapy may protect the subject’s brain from injury pathways triggered by brain 
ischemia and/or reperfusion, thus reducing the brain damage and disability that ultimately results, and 
facilitating functional recovery. Even if the study is negative, observations made during the study may aid 
future refinements in H2M therapy or the development of other therapies for ischemic stroke. As stroke is 
the 2nd leading cause of death or adult disability globally, more effective treatments for acute stroke are 
much needed.
G. DATA SAFETY MONITORING PLAN
G.1 Adverse events monitoring
The Data Safety Monitoring Committee (DSM) will consist of three experienced physicians who are not 
study investigators or members of the acute stroke team, and who will be unblinded to treatment. The 
chair of the DSM will be Dr. Patricia Coyle, Professor and Vice Chair for Clinical Affairs in Neurology. 
Other members of the DSM will be Dr. Guy Schwartz, Assistant Professor of Neurology, and Dr. 
Agnieszka Kowalska, Co-Director of the Neuro-Oncology Center. Assisted by study staff, who will 
ensure that study data are accurate and complete, the DSM will assess protocol compliance by auditing 
protocol documentation. The DSM will check that inclusion/exclusion criteria are followed, adverse 
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


17
events are reported, and protocol amendments are approved in advance by the IRB. If in the DSM's 
judgment a pattern of unexpected and clinically serious adverse events emerges, or if protocol compliance 
is inadequate, the Committee will terminate the study. The DSM will proactively conduct full reviews of 
safety data after the first 5 and then 15 patients have been enrolled; proactive reviews will then take place 
annualy. 
Any unfavorable and unintended symptom, sign (including a clinically significant abnormal laboratory 
finding) or disease that is temporally associated with a study will be considered a study AE. The study 
staff will carefully monitor each subject throughout the study for possible AEs, and document such in an 
AE log. Minimum information recorded for each AE includes type of event, duration (start and end 
dates), severity, seriousness, causality to study drug, action taken, and outcome. The PI or one of the Co-
Is will grade the severity of AEs based on the DHHS/NIH Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0. Baseline stroke symptoms and signs documented prior to initiation of study 
medication will not be considered AEs, but any adverse change in these stroke symptoms and signs will 
be recorded as AEs for review by the unblinded DSM; those symptoms and signs judged by the PI or Co-
Is to be expected given the usual course of stroke under current management will be noted in the AE log 
as unlikely to be caused by study drug. Hemorrhage into bland infarction, with associated clinical decline, 
occurs naturally in a small percentage of ischemic stroke patients, and a higher percentage of patients who 
receive tPA or mechanical thrombectomy. The DSM will specifically watch rates of hemorrhagic 
conversion, although we have no a priori reason to think that study medication will enhance this rate. The 
PI will proactively bring to DSM attention any serious AEs judged possibly associated with study 
medication.
Subjects will be monitored by the stroke team for AEs from the time they sign consent until completion 
of their participation in the study. We expect most drug AEs to surface during their inpatient stay when 
they are receiving both H2 and minocycline, as the likelihood of a troublesome AE surfacing during the 
last day or two of oral minocycline therapy, or after drug discontinuation, is low. Subjects and any LARs 
will be made aware of the specific AEs known to be associated with H2M treatment (listed above) and 
will be instructed to discontinue minocycline and contact study staff immediately if they experience any 
troublesome AEs. Study staff will also proactively inquire about the occurrence of any AEs after 
discharge, at the follow up phone call 45d after stroke onset, and at the follow up phone call or clinic visit 
90d after stroke onset.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


18
Table 3: Schedule for safety monitoring and assessments
Assessments
Frequency
Water chamber will be cleaned with spray of 
alcohol and rinsed thoroughly with water
After each use or at least 
once a week
Moisture indicator in overwrap will be checked
Before each administration
H2 IV fluid
Hydrogen concentration of a quality control IV 
bag will be measured
Every day IV bags are used 
for subjects
H2 tablet and placebo
Stony Brook pharmacy will compound this 
following USP 797 guidelines.
At each preparation
Minocycline IV fluid
Stony Brook pharmacy will compound this 
following USP 797 guidelines.
At each preparation
Minocycline capsule 
and placebo
Stony Brook pharmacy will compound this 
following USP 795 guidelines.
At each preparation
Study safety
The Data Safety Monitoring committee will 
review adverse events and protocol compliance
After the first 5 and then 15 
patients enrolled; proactive 
reviews will then take place 
annually
 
G.2 Data safety
All paper study data will be kept in a secured, locked area. All identifiable electronic study data will be 
password-protected and saved in a secure shared drive on the Stony Brook server only accessible by study 
staff. The study coordinator will check the data for accuracy. Variable ranges and types will be assessed 
to ensure they are accurate. Missing data will be identified and obtained (if possible) in a timely fashion. 
Study staff will take steps to make sure all the information obtained is kept private. The subjects' name 
will not be used wherever possible. Study staff will use codes instead. The electronic data will be banked 
on the same secure server after the study ends. The study staff may submit a new proposal to obtain 
approval from the IRB to use this data.
H. LITERATURE CITED
Alano, C. C., T. M. Kauppinen, A. V. Valls & R. A. Swanson (2006) Minocycline inhibits poly(ADP-
ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci U S A, 103, 9685-90.
Bruno, A., Akinwuntan, A. E., Lin, C., Close, B., Davis, K., Baute, V., Aryal, T., Brooks, D., Hess, D. C., 
Switzer, J. A., Nichols, F. T. (2011) Simplified Modified Rankin Scale Questionnaire: 
Reproducibility Over the Telephone and Validation With Quality of Life. Stroke, 42:2276-2279.
Bruno, A., Durkalski, V. L., Hall, C. E., Juneja, R., Barsan, W. G., Janis, S., Meurer, W.J., Fansier, A., & 
Johnston, K. C. (2014). The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial 
protocol: A randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia 
management in acute stroke. International Journal of Stroke, 9(2), 246–251.
Chaturvedi, M., & Kaczmarek, L. (2014). MMP-9 inhibition: A therapeutic strategy in ischemic stroke. 
Molecular Neurobiology, 49(1), 563–573.
Cai, J., Z. Kang, W. W. Liu, X. Luo, S. Qiang, J. H. Zhang, S. Ohta, X. Sun, W. Xu, H. Tao & R. Li 
(2008) Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci 
Lett, 441, 167-72.
Chan, P. H. (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb 
Blood Flow Metab, 21, 2-14.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


19
Chen, H., Y. P. Sun, Y. Li, W. W. Liu, H. G. Xiang, L. Y. Fan, Q. Sun, X. Y. Xu, J. M. Cai, C. P. Ruan, 
N. Su, R. L. Yan, X. J. Sun & Q. Wang (2010) Hydrogen-rich saline ameliorates the severity of l-
arginine-induced acute pancreatitis in rats. Biochem Biophys Res Commun, 393, 308-13.
Choi, D. W. (1988). Glutamate neurotoxicity and diseases of the nervous system. Neuron, 1(8), 623–634.
Choi, D. W., R. Armitage, L. S. Brady, T. Coetzee, W. Fisher, S. Hyman, A. Pande, S. Paul, W. Potter, B. 
Roin & T. Sherer (2014) Medicines for the mind: policy-based "pull" incentives for creating 
breakthrough CNS drugs. Neuron, 84, 554-63.
Committee on Emergency and Continuous Exposure Guidance Levels for Selected Submarine 
Contaminants, Committee on Toxicology & N. R. Council. 2008. Emergency and Continuous 
Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: 
The National Academies Press.
Coyle, J. T. & P. Puttfarcken (1993) Oxidative stress, glutamate, and neurodegenerative disorders. 
Science, 262, 689-95.
Fagan, S. C., J. L. Waller, F. T. Nichols, D. J. Edwards, L. C. Pettigrew, W. M. Clark, C. E. Hall, J. A. 
Switzer, A. Ergul & D. C. Hess (2010) Minocycline to improve neurologic outcome in stroke 
(MINOS): a dose-finding study. Stroke, 41, 2283-7.
Fu, Y., M. Ito, Y. Fujita, M. Ito, M. Ichihara, A. Masuda, Y. Suzuki, S. Maesawa, Y. Kajita, M. 
Hirayama, I. Ohsawa, S. Ohta & K. Ohno (2009) Molecular hydrogen is protective against 6-
hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease. 
Neuroscience Letters, 453, 81-85.
Fukuda, K. I., S. Asoh, M. Ishikawa, Y. Yamamoto, I. Ohsawa & S. Ohta (2007) Inhalation of hydrogen 
gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. 
Biochemical and Biophysical Research Communications, 361, 670-674.
Ginsberg, M. D. (2008) Neuroprotection for ischemic stroke: past, present and future. 
Neuropharmacology, 55, 363-89.
Hagar, R. 2003. Submarine Atmosphere Control and Monitoring Brief for the COT Committee. In First 
Meeting on Emergency and Continuous Exposure Guidance Levels for Selected Submarine 
Contaminants. Washington, DC.
Hayashida, K., M. Sano, I. Ohsawa, K. Shinmura, K. Tamaki, K. Kimura, J. Endo, T. Katayama, A. 
Kawamura, S. Kohsaka, S. Makino, S. Ohta, S. Ogawa & K. Fukuda (2008) Inhalation of 
hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. 
Biochemical and Biophysical Research Communications, 373, 30-35.
Ishibashi, T., Sato, B., Shibata, S., Sakai, T., Hara, Y., Naritomi, Y., Koyanagi, S., Hara, H. & Nagao, T. 
(2014). Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: A 
randomized, double-blind, placebo-controlled pilot study. International Immunopharmacology, 
21(2), 468–473. 
Kohler, E., D. A. Prentice, T. R. Bates, G. J. Hankey, A. Claxton, J. van Heerden & D. Blacker (2013) 
Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. 
Stroke, 44, 2493-9.
Kwiecien, T. D., C. Sy & Y. Ding (2014) Rodent models of ischemic stroke lack translational relevance... 
are baboon models the answer? Neurol Res, 36, 417-22.
Lampl, Y., M. Boaz, R. Gilad, M. Lorberboym, R. Dabby, A. Rapoport, M. Anca-Hershkowitz & M. 
Sadeh (2007) Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. 
Neurology, 69, 1404-10.
Lee, J. M., G. J. Zipfel, K. H. Park, Y. Y. He, C. Y. Hsu & D. W. Choi (2002) Zinc translocation 
accelerates infarction after mild transient focal ischemia. Neuroscience, 115, 871-8.
Nagatani, K., H. Nawashiro, S. Takeuchi, S. Tomura, N. Otani, H. Osada, K. Wada, H. Katoh, N. Tsuzuki 
& K. Mori (2013) Safety of intravenous administration of hydrogen-enriched fluid in patients 
with acute cerebral ischemia: initial clinical studies. Med Gas Res, 3, 13.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


20
Nakao, A., Toyoda, Y., Sharma, P., Evans, M., & Guthrie, N. (2010). Effectiveness of hydrogen rich 
water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot 
study. Journal of Clinical Biochemistry and Nutrition, 46(2), 140–9
Noda, K., Y. Tanaka, N. Shigemura, T. Kawamura, Y. N. Wang, K. Masutani, X. J. Sun, Y. Toyoda, C. 
A. Bermudez & A. Nakao (2012) Hydrogen-supplemented drinking water protects cardiac 
allografts from inflammation-associated deterioration. Transplant International, 25, 1213-1222.
O’Brien, P. C., & Fleming, T. R. (1979). A multiple testing procedure for clinical trials. Biometrics, 
35(3), 549–56.
Ohsawa, I., M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. 
Katayama, S. Asoh & S. Ohta (2007) Hydrogen acts as a therapeutic antioxidant by selectively 
reducing cytotoxic oxygen radicals. Nat Med, 13, 688-94.
Ohta, S. (2011) Recent progress toward hydrogen medicine: potential of molecular hydrogen for 
preventive and therapeutic applications. Curr Pharm Des, 17, 2241-52.
Padma Srivastava, M. V., A. Bhasin, R. Bhatia, A. Garg, S. Gaikwad, K. Prasad, M. B. Singh & M. 
Tripathi (2012) Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-
controlled trial. Neurol India, 60, 23-8.
Sheline, C. T., H. Wang, A. L. Cai, V. L. Dawson & D. W. Choi (2003) Involvement of poly ADP ribosyl 
polymerase-1 in acute but not chronic zinc toxicity. Eur J Neurosci, 18, 1402-9.
Terasaki, Y., I. Ohsawa, M. Terasaki, M. Takahashi, S. Kunugi, D. D. Kang, H. Urushiyama, S. 
Amenomori, M. Kaneko-Togashi, N. Kuwahara, A. Ishikawa, N. Kamimura, S. Ohta & Y. 
Fukuda (2011) Hydrogen therapy attenuates irradiation-induced lung damage by reducing 
oxidative stress. American Journal of Physiology-Lung Cellular and Molecular Physiology, 301, 
L415-L426.
Tymianski, M. (2014) STROKE IN 2013 Disappointments and advances in acute stroke intervention. 
Nature Reviews Neurology, 10, 66-68.
Xu, L., S. C. Fagan, J. L. Waller, D. Edwards, C. V. Borlongan, J. Zheng, W. D. Hill, G. Feuerstein & D. 
C. Hess (2004) Low dose intravenous minocycline is neuroprotective after middle cerebral artery 
occlusion-reperfusion in rats. BMC Neurol, 4, 7.
Approved: 10/27/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)

ICF_001.pdf: 
Page 1
RESEARCH CONSENT FORM
Project Title: Pilot study of the neuroprotective effects of hydrogen and minocycline in 
acute ischemic stroke
Principal Investigator: Kamil Stefanowski, MD
Co-Investigators: Dennis Choi, MD, PhD; Michael Guido, MD, Jason Mathew, DO; 
MD; Alison Caruana, MD; Lauren DeNiro, MD; Yuehjien Gu, MD; Ethan Brandler, MD
Department: Neurology, Emergency Medicine
You are being asked to be a volunteer in a research study. 
You are encouraged to take your time in making your decision. You may want to 
discuss this study with your friends and family.
PURPOSE 
The purpose of this study is: 
To test the effect of two drugs (hydrogen and minocycline, given together) on 
recovery after an acute stroke 
Adult patients with symptoms of acute stroke in the past 24 hours can be in the 
study.
While there are a few drugs that can directly reduce brain damage after stroke in lab 
animals (neuroprotective drugs), no such drug has yet worked in humans.  We hope 
that the combination of hydrogen and minocycline will be effective as 
neuroprotective drugs in human stroke.
Hydrogen can protect brain cells from damage by stroke in animals. Hydrogen is 
present in low amounts in normal air. Hydrogen is considered experimental in this 
study as it is not approved by the US Food and Drug Administration (FDA) for use as 
a drug.
Minocycline is a widely used antibiotic drug that can also protect brain cells from 
damage by stroke in animals. Minocycline is experimental in this study as it is not 
approved by the FDA to treat stroke.  
We aim to enroll 100 subjects from Stony Brook University in this study. 
Approved: 12/19/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


Page 2
PROCEDURES 
If you decide to be in this study, your part will involve: 
Your baseline brain function and vital signs will be obtained from your medical 
record.
You will be assigned by chance to either the treatment group to receive the real 
drug, or the placebo group. There is an equal chance of being in either group like 
flipping a coin. The placebo group will receive an inactive substance that looks like 
the real drug. 
Hydrogen will be given 2-3 times a day for 3 days, dissolved in drinking water or 
intravenous (IV) fluid. If you are found to be unable to swallow, a tube can be 
inserted through your nose to your stomach (called a “nasogastric tube”).  This is 
part of routine care for many patients after a stroke. The tube provides a route to 
administer fluids, nutrition, and medicines. We can administer the hydrogen water 
through the tube. If you cannot have a nasogastric tube inserted, the hydrogen water 
will be administered IV. If you can swallow but cannot tolerate thin liquids, you can 
use pre-thickened water like Hormel Thick & Easy or thickener.
Minocycline will be given once a day for 5 days, by IV fluid or capsules. 
If you are discharged before completing the treatment, you will be given the study 
medications to take with you. Study staff will call to see if you are able to finish the 
treatment. 
Study staff will call you on study day 45 and day 90 to ask a few questions about 
your brain function. The phone call will take 10 minutes. If you have a clinic visit at 
day 90, the questions will be asked in person. 
After the study, your data will be saved on a secure Stony Brook server which can 
only be accessed by study staff. In the future, the study staff may submit a new 
proposal to obtain approval from the Stony Brook Institutional Review Board to use 
this data.

RISKS / DISCOMFORTS
The following risks/discomforts may occur as a result of you being in this study:
We do not expect any major side effects from hydrogen. Mild side effects reported in 
earlier small studies were headache, heartburn, and loose stools. 
Minocycline has been taken by many people and is usually safe.  However, any drug 
can produce side effects in an individual.  Uncommon side effects of minocycline 
include sensitivity to sunburn, skin itching, joint aching, light-headedness, dizziness, 
ringing in ears, or an allergic reaction.  When side effects occur, they usually stop 
when the drug is stopped.   
 Enrolling in this study may lead to somewhat earlier insertion of the nasogastric 
tube. The potential risks of nasogastric intubation include discomfort, and injury of 
the tissue inside of the nose, sinuses, throat, esophagus, or stomach. Rare risks 
Approved: 12/19/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


Page 3
include internal bleeding, abdominal cramping, abdominal swelling, diarrhea, 
nausea, vomiting, regurgitation of medicine, and aspiration.
The potential risks of IV drug delivery include discomfort, bruising, and pain at the 
site of injection. Rare risks include inflammation of the vein used for injection, 
phlebitis, metabolic disturbances, and injury. Very rarely will there be severe 
reaction, anaphylaxis, cardiac arrest, or death. 
Being a part of this study while pregnant may expose the unborn child to risks 
that are not justified, given the purpose of the study. Therefore, pregnant 
females will be excluded from the study. If you are a female who can become 
pregnant, a pregnancy test must be done and must be negative before you can 
enter this study. If you are sexually active, you or your partner must agree to 
use appropriate contraceptive measures while you are taking study drug. 
These measures include: 
Abstinence 
Barrier methods (such as condom or diaphragm) used with a spermicide, 
or 
an intrauterine device (IUD). 
Birth control pill is not recommended as the study drug (minocycline) may 
cause it to be less effective. If you do become pregnant while taking study 
drug, you must inform your study staff immediately.
Since this is a research study, not all risks may be known at this time.  There may be 
unforeseen risks associated with study participation.
Approved: 12/19/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


Page 4
BENEFITS
The following benefits may occur as a result of being in this study, but this cannot be 
guaranteed:
The study drug may protect your brain from damage and thus improve your 
recovery. 
This study will help researchers develop better treatments for stroke. 
PAYMENT TO YOU  
You will not be paid for your participation. 
CONFIDENTIALITY  
We will take steps to help make sure that all the information we get about you is kept 
confidential. Your name will not be used wherever possible. We will use a code instead. 
All the study data that we get from you will be kept locked up. The code will be locked 
up too. If any papers and talks are given about this research, your name will not be 
used. 
We want to make sure that this study is being done correctly and that your rights and 
welfare are being protected. For this reason, we will share the data we get from you in 
this study with the study team, Stony Brook University's Committee on Research 
Involving Human Subjects, applicable Institutional officials, and certain federal offices, 
including the Office for Human Research Protections (OHRP), and, where applicable, 
the Food and Drug Administration (FDA). However, if you tell us you are going to hurt 
yourself, hurt someone else, or if we believe the safety of a child is at risk, we will have 
to report this. 
In a lawsuit, a judge can make us give him the information we collected about you. 
While you are in this study we will get data about your health from your medical record. 
We will also get health data from the results of the tests you will have done in this study. 
You have a right to privacy but the data we get about your health in this study can be 
shared with the people referenced above (the study team, those who work for Stony 
Brook University's Committee on Research Involving Human Subjects, applicable 
institutional officials, and federal offices such as OHRP, FDA) as well as: 
your medical doctor 
A board that reviews the safety of the study on an on-going basis. 
Your health data are shared to make sure the study is being done correctly, costs are 
charged correctly, and to make sure your rights and safety are protected. Not all of 
these people are required by law to protect your health data. They might share it with 
others without your permission. 
Approved: 12/19/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


Page 5
Some of the health information we get from you in this study cannot be shared with you 
until the end of the study. 
You have the right to stop allowing us to use or give out your health data. You can do 
this at any time by writing to Dr. Stefanowski (Department of Neurology, 101 Nicholls 
Road, Health Sciences Center T12-020, Stony Brook, NY 11794-8121). If you do this, 
we will stop collecting any new health data from you, except if we need to keep an eye 
on a bad side effect you were having in the study. We will use any data we collected 
before you wrote your letter. When you sign the consent form at the end, it means: 
That you have read this section. 
That you will allow the use and reporting of your health data as described above. 
You have received a form from the University Hospital. It is called the Notice of 
Privacy Practices form. 
Clinical Trial Registry 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time”.
COSTS TO YOU  
The study drugs will be given to you without cost. There are no other costs to you or your 
insurance company for medications or treatment given in this study. 
ALTERNATIVES 
Your alternative to being in this study is simply not to participate.
IN CASE OF INJURY 
If you are injured as a result of being in this study, please contact Dr. Stefanowski at 
631-444-2599. The services of Stony Brook University Hospital will be open to you in 
case of such injury. However, you and/or your insurance company will be responsible 
for payment of any resulting treatment and/or hospital stay.
CONSEQUENCES OF WITHDRAWING 
You may choose to withdraw from the study at any time. There are no risks associated 
with withdrawing from the study.
REMOVAL FROM STUDY 
Approved: 12/19/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


Page 6
Your participation in the study may be stopped by study staff at any time. You will be 
removed from the study if: you become pregnant; your medical condition or current 
medications change; the study staff deem that it is in your best interests to withdraw 
from the study; or you do not follow study procedures. 
YOUR RIGHTS AS A RESEARCH SUBJECT  
Your participation in this study is voluntary. You do not have to be in this study if you 
don't want to be.
You have the right to change your mind and leave the study at any time without 
giving any reason, and without penalty.
Any new information that may make you change your mind about being in this study 
will be given to you.
You will get a copy of this consent form to keep.
You do not lose any of your legal rights by signing this consent form.
QUESTIONS ABOUT THE STUDY OR YOUR RIGHTS AS A RESEARCH SUBJECT   
If you have any questions, concerns, or complaints about the study, you may contact 
Dr. Stefanowski at 631-444-2599. Address: Department of Neurology, 101 Nicholls 
Road, Health Sciences Center T12-020, Stony Brook, NY 11794-8121.
If you have any questions about your rights as a research subject or if you would like 
to obtain information or offer input, you may contact Ms. Lu-Ann Kozlowski, 
Committee on Research Involving Human Subjects, (631) 632-9036, OR by e-mail, 
lu-ann.kozlowski@stonybrook.edu.   
Visit Stony Brook University’s Community Outreach page, 
http://www.stonybrook.edu/research/orc/community.shtml for more information about 
participating in research, frequently asked questions, and an opportunity to provide 
feedback, comments, or ask questions related to your experience as a research 
subject.
Approved: 12/19/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)


Page 7
If you sign below, it means that you have read (or have had read to you) the information 
given in this consent form, and you would like to be a volunteer in this study.
 Subject able to provide consent 
      ________________________________          ______________________________
      Subject Name                                                   Signature                           Date
      ________________________________          ______________________________
      Name of person obtaining consent                   Signature                           Date
 Subject unable to provide consent 
      _______________________________          
      Subject name   
      _______________________________         _______________________________ 
      Legally authorized representative (LAR)        Signature                            Date
      name 
      
      _____________________________          
      Relationship to Subject
      ________________________________       _______________________________
      Name of person obtaining consent                Signature                            Date
"My signature below attests to the fact that I am a qualified professional and I have 
interviewed (name of patient) on ______ (date). I have determined that s/he does_____ 
does not_____ have the capacity to consent to participation in this research activity, in that 
s/he is____ is not____ capable of appreciating a) that the activity described in this consent 
document constitutes research, not standard treatment, b) the risks and benefits of this 
study c) the alternatives that are available if s/he chooses not to participate, and d) that the 
decision to not participate will be accepted without penalty, i.e., without jeopardizing his/her 
clinical care." 
________________________________          _________________________________
Professional Providing Attestation                    Signature of Professional               Date
Name (Printed)                                                  providing Attestation
Approved: 12/19/2022
Expiration Date: 10/26/2023
Stony Brook University Human Subjects Committee (IRB)