Conditions: Parkinson Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
This study is a placebo-controlled, double-blind trial that will investigate the safety and tolerability of molecular hydrogen, a promising antioxidant agent, in patients with early-stage Parkinson's Disease. The medication will be administered orally as 8 ounces of hydrogen-enriched drinking water twice a day over the course of one year.

Detailed description:
This study will investigate the safety and tolerability of molecular hydrogen, a promising antioxidant agent, in patients with early-stage Parkinson's Disease. Subjects will be sequentially randomized in a 1:1 ratio to receive hydrogen-enriched water or the corresponding placebo twice a day, in addition to all standard-of-care treatments. Enrollment goal is 70 subjects. Duration of therapy is 52 weeks.

The primary outcome measures are safety and tolerability of hydrogen-enriched water. Secondary outcome measures include: progression of motor symptoms, health-related quality of life, progression of cognitive decline, and progression of symptom burden.

Arms:
arm 1: The ingredient in the tablet producing H2 is magnesium. Each tablet contains 80 mg magnesium, a safe level well below the recommended daily dietary allowance of 420 mg for men/ 320 mg for women. Dissolving one tablet in 250 mL of water will achieve a saturating H2 concentration of approximately 1.6 ppm. Twice a day subjects will dissolve a tablet into water and drink the effervescent water. arm 2: effervescent placebo tablets will also contain 80 mg magnesium but do not generate hydrogen-enriched water

Interventions: intervention 1: Hydrogen intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: each hydrogen tablet contains 80mg magnesium intervention 2: matching placebo tablet

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and 
Tolerability of Molecular Hydrogen in Patients with Parkinson’s Disease 
 
 
 
 
 
NCT03971617 
 
 
 
 
 
 
 
 
21 APRIL 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
TITLE: A Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the 
Safety and Tolerability of Molecular Hydrogen in Patients with Parkinson’s Disease 
 
VERSION: 21 APRIL 2020 
 
INVESTIGATORS 
 
Principal Investigator: Carine W. Maurer, M.D., Ph.D. 
Co-Investigators: Dennis Choi, M.D., Ph.D., Hanna Czarkowska, M.D., Guy Schwartz, M.D 
 
A. OBJECTIVES 
 
Primary Objective: To investigate the safety and tolerability of molecular hydrogen H2 in 
patients with Parkinson’s disease (PD).  
 
Secondary Objective: To investigate the efficacy of molecular hydrogen H2 in slowing the 
progression of symptoms in patients with PD. 
 
B. BACKGROUND AND SIGNIFICANCE 
 
PD is an increasingly prevalent neurodegenerative disorder. Current predictions estimate that the 
number of individuals with PD will double by 2040, increasing from 6.9 million in 2015 to 14.2 
million in 20401. Disease-modifying therapy that slows the rate of progression of 
neurodegeneration remains one of the greatest unmet therapeutic needs in PD.  
PD is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta 
(SNpc). Several lines of evidence suggest that oxidative stress plays a critical role in this process. 
Oxidative stress occurs when endogenous antioxidant systems become overwhelmed by the 
generation of reactive oxygen species (ROS), which occurs primarily at the level of the 
mitochondria. Mitochondrial dysfunction is recognized as being critical to PD pathogenesis, with 
several of the genes associated with recessively inherited PD, including parkin, PINK1 and 
Fbxo7, recognized as key players in the mitophagy of damaged mitochondria. Post-mortem 
studies have also provided strong evidence for oxidative damage in PD brains. Lipid 
peroxidation, the degradation of cell membrane components mediated by ROS, has been 
demonstrated to be increased in the SN of PD patients2. In addition, an altered ratio of reduced to 
oxidized glutathione (GSH/GSSG) has been detected in the SN of PD patients, consistent with a 
role for oxidative stress in the pathogenesis of nigral cell death.3  
Given the substantial evidence suggesting that oxidative stress may contribute to PD 
pathogenesis, antioxidant molecules have long been considered attractive as potential disease-
modifying agents. Clinical trials examining the role of antioxidants such as vitamin E, coenzyme 
Q104, and creatine5 as disease-modifying agents in PD have unfortunately failed to demonstrate 
efficacy of these agents in slowing disease progression. The failure of these agents, however, 
may have been secondary to significant limitations in antioxidant efficacy and access to cellular 
compartments where highly reactive, pathogenic radicals are generated. Despite these failures, 
targeting oxidative stress in PD remains a promising line of investigation. Recent data have in 
fact identified an inverse relationship between levels of the antioxidant urate and both PD risk6 


3 
 
and rate of disease progression7, 8. Given these promising epidemiological findings, a phase 2 
study demonstrating safety and tolerability of the urate precursor inosine has now been 
completed9, and a phase 3 trial testing whether inosine slows clinical decline in PD patients is 
currently underway.  
H2 is another recently emergent and potentially therapeutic antioxidant. H2 acts as a powerful yet 
selective antioxidant, efficiently penetrating bio-membranes to quench toxic free radicals 
including OH and ONOO- while having little effect on free radicals with important roles in 
normal cellular signaling such as O2-, NO, and H2O210. Work in PD rodent models using the 
neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-
OHDA) have demonstrated that H2-enriched water acts as both a highly effective antioxidant as 
well as a cytoprotective agent, downregulating markers of oxidative stress in dopaminergic 
neurons, attenuating dopaminergic neuronal loss, and improving parkinsonian features11, 12.  
 
We propose to perform a clinical study to investigate the safety and tolerability of molecular 
hydrogen, a promising antioxidant agent, in PD. We intend to explore the efficacy of this agent 
in slowing disease progression as a secondary objective, with the goal of determining whether 
and how H2 should be pursued in subsequent phase 3 clinical trials.  
 
C. PRELIMINARY STUDIES 
A recent small pilot randomized double-blind placebo-controlled trial involving a total of 17 
patients with idiopathic PD treated with levodopa (Hoehn & Yahr stages I – IV; average disease 
duration of 6.5 and 7.2 years for active treatment and placebo arms, respectively) demonstrated 
that drinking 1000 mL/day of H2-enriched water for a total of 48 weeks was safe and well-
tolerated in this patient cohort, with no adverse events reported. Notably, patients in the active 
treatment arm demonstrated significant improvement in total scores on the Unified Parkinson’s 
Disease Rating Scale (UPDRS) when compared to placebo (-5.7 ± 8.4 vs. 4.1 ± 9.2 for active 
treatment vs. placebo, respectively). Changes in the motor subscale of the UPDRS (UPDRS-III), 
a secondary outcome measure, trended towards significance (-5.8 ± 7.2 vs. 2.3 ± 8.5 for active 
treatment vs. placebo, respectively; p = 0.074)13. Despite the promising results from this small 
pilot study, its design is inherently unable to differentiate between disease-modifying and 
symptomatic effect. Additionally, the recruited patients were relatively advanced in the course of 
their disease, when the pool of existing dopaminergic neurons was likely quite low, and the 
disease-modifying potential for the treatment therefore diminished. 
A follow-up randomized double-blind placebo-controlled multi-center trial to assess the efficacy 
of H2 in a larger sample of PD patients, including those not on levodopa, is currently underway.14 
Several aspects of the design of this ongoing study are concerning, however. Enrolled patients 
had an average disease duration of 6.8 ± 4.5 years at time of study onset, indicating that many of 
the study participants have a small pool of salvageable dopaminergic neurons. In addition, the 
H2-enriched water provided to patients in this study is distributed weekly in plastic bottles, 
through which H2 is able to rapidly diffuse over a period of minutes to hours. The H2 
concentration at the time of consumption is thus unclear.  
Here, we propose a double-blind placebo-controlled study to investigate the safety and 
tolerability, and to explore the efficacy, of H2-enriched water in a population of early-stage PD 


4 
 
patients. We seek to enroll a total of 70 patients with early-stage PD, and will make use of a 
practical method our department has considerable experience with in order to generate H2-
enriched water.  
D. RESEARCH DESIGN AND METHODS 
D1. Rationale/Overview 
 
The therapeutic potential of H2 stems from both its safety and ease of administration in humans 
as well as its selective mechanism of action.  
 
Importantly, exposure to H2 is not associated with any known biological toxicity. Molecular 
hydrogen occurs naturally as a trace gas in air at a concentration of about 0.5 ppm, and can reach 
a concentration of 7500 ppm (0.75%) in closed environments such as aboard nuclear submarines. 
In 2008, a National Academies study group exploring the long-term effects of hydrogen 
inhalation in submariners concluded that hydrogen did not have known toxic activity except at 
concentrations high enough to replace ambient oxygen. The group recommended setting 
occupational exposure standards based upon consideration of explosivity, noting that hydrogen 
becomes flammable in air at a concentration of 4.1% (Committee on Emergency and Continuous 
Exposure Guidance Levels for Selected Submarine Contaminants, 2008). H2 can be safely 
administered in numerous ways: inhaling H2 gas, drinking H2-enriched drinking water, injecting 
H2-dissolved saline, as well as using H2-enriched eye drop solution15. 
 
H2 readily diffuses through tissues and cell membranes, and acts as a powerful yet selective 
antioxidant10. Cytoprotective effects have been described after H2 administration in various 
rodent models of disease, including ischemic hepatic injury16, ischemic myocardial infarction17, 
and radiation-induced lung damage18. In mice subjected to chronic physical restraint stress, 
continuous ad libitum consumption of H2-enriched water suppressed the increase in oxidative 
stress markers and prevented the stress-induced decline in learning and memory induced by 
chronic restraint19. In rodent models of PD, ad libitum consumption of H2-enriched water 
downregulated markers of oxidative stress in dopaminergic neurons, attenuated dopaminergic 
neuronal loss, and improved parkinsonian features11, 12 While the primary target underlying 
cytoprotective effects in these models remains unclear, several possible mechanisms have been 
suggested, including direct scavenging of ROS as well as indirect effects on gene expression 
impacting downstream inflammatory and apoptotic factors15. 
 
In addition to these animal studies, several dozen clinical studies exploring the efficacy in H2 in 
treating human diseases ranging from rheumatoid arthritis to metabolic syndrome have been 
reported20. Randomized clinical trials in neurodegenerative conditions such as mild cognitive 
impairment in APOE4 carriers21 and PD13 have reported promising findings that merit further 
validation in larger, randomized, placebo-controlled clinical trials. 
 
 
 
D2. Research Site  


5 
 
Eligible participants will be recruited at the Stony Brook Movement Disorders Center, where 
several newly diagnosed PD patients are typically seen each week. The offices of the 
investigators and study coordinator are located at the Stony Brook University Health Sciences 
Center. The subjects will be seen at the Stony Brook Neurology Clinic or research sites affiliated 
with Stony Brook University.  
Stony Brook is the only academic medical center in Suffolk County, a large area with a 
population of 1.5 million people. We expect to be able to draw subjects from our region, 
including other nearby population centers in NY and CT. We intend to recruit non-Stony Brook 
subjects through the posting of the study on the website www.clinicaltrials.gov.  
D3. Study Sample 
 
Subjects with idiopathic PD who meet the inclusion/exclusion criteria in Table 1 below and 
provide consent will be recruited and randomized sequentially 1:1 to either receive H2 or 
placebo. 
 
We seek to enroll 70 eligible subjects diagnosed with idiopathic PD, as per UK Parkinson’s 
Disease Society Brain Bank criteria22. We project an active recruitment period of 3 years.  
D4. Study design 
 
This will be a double-blinded, placebo-controlled trial. Subjects will be sequentially randomized 
in a 1:1 ratio to receive H2-enriched water or the corresponding placebo, in addition to all 
standard-of-care treatments. Enrollment goal is 70 subjects.  
Subjects can withdraw from the study at any time. 
D5. Study procedures 
 
D5. a. Recruitment 
 
Investigators will review the medical records of their patients who are due for a visit at the Stony 
Brook Neurological Associates to identify eligible patients. Study coordinators will contact these 
patients before their visit to ascertain interest in participating in a clinical trial. If so, the study 
coordinator will send the patient the consent forms (via mail/fax/email), and review the forms 
with the patient over the phone. The patient will also have the opportunity to speak with Dr. 
Maurer or one of the co-investigators about the consent form at their visit. For potential study 
subjects who are under the care of another neurologist, the treating physician will first approach 
the patient to obtain the patient’s verbal consent for study staff to contact them about the study. 
Inclusion/exclusion criteria are listed in Table 1.  
D5. b. Screening visit  
 
A study staff member will complete the inclusion/exclusion checklist (Table 1) based on review 
of the patient’s medical records. The PI or co-investigator will review and sign the completed 
inclusion/exclusion checklist(s) after the patient is seen at the screening visit.  


6 
 
 
Table 1: Inclusion/exclusion criteria 
Inclusion 
criteria 
 Age 40 - 80 
 Diagnosis of idiopathic PD with bradykinesia plus one of the other 
cardinal signs (resting tremor, rigidity), as confirmed by a movement 
disorder specialist according to UK Parkinson’s Disease Society Brain 
Bank criteria22 
 Modified Hoehn & Yahr Stage < III 
 Diagnosis of PD made within past 3 years 
 Ability to provide informed consent 
 Strong enough familiarity with the English language to undergo careful 
assessment of cognition 
 Ability to complete questionnaires 
 Willingness to go off parkinsonian medication for 12 hours prior to 
baseline and 56-week assessments 
Exclusion 
criteria 
 Other major diseases of the central nervous system, including brain 
tumors, demyelinating disease, epilepsy, Alzheimer’s disease, 
inflammatory brain or vascular disease, traumatic encephalopathy 
 History of stroke 
 Use of antipsychotic neuroleptic medication within the last 6 months 
 Symptomatic (secondary) parkinsonism (ie. drug induced) 
 Atypical parkinsonian variants (ie. progressive supranuclear palsy, multi-
system atrophy, corticobasal syndrome) 
 Unstable medical or psychiatric illness that may compromise participation 
in the study 
 Known kidney disease  
 History of stereotactic brain surgery 
 Significant cognitive impairment  
 Inability to safely tolerate 500 mL fluid PO water daily associated with the 
study medication 
 Unable to avoid regular use of medications containing magnesium 
 Treatment with another investigational drug within the last 30 days that 
may interfere with the study medication 
 Inability to tolerate or comply with study procedures 
 Pregnancy or nursing. Females of childbearing potential* must have a 
negative urine pregnancy test result at screening, and use an effective 
method of contraception throughout the entire study period and for 30 
days after study drug discontinuation.     
* All females will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
known or suspected cause of amenorrhea) or have been sterilized surgically (i.e., bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy). 
 


7 
 
 
At the screening visit, the study staff will review the consent form with the patient, including the 
purpose of the study, the procedures to be followed, and the risks and benefits of participation. 
As part of the informed consent process, the subject will be counselled specifically about side 
effects to look out for, and will be told to contact the PI immediately to report the occurrence of 
side effects. The study doctor will meet with the patient to discuss any concerns or questions 
about the study. If the patient would like more time to make a decision, the baseline visit will be 
postponed until patient agrees to participate and signs the consent form. After the consent form 
has been signed, the patient will be given a copy of the signed consent form.  
Pregnancy test (as needed) will also be performed at the screening visit. 
D5. c. Baseline visit  
 
The baseline visit will occur no more than 4 weeks after the screening visit, and may occur on 
the same day as the screening visit if the patient is not taking dopaminergic medication. 
 
The following data will be collected at the baseline visit. 
 
Table 2. Baseline data 
Data 
Detail 
General health status 
Physical examination findings 
Neurological examination findings 
Concomitant medications (including review of use 
of over the counter and prescription medications 
containing magnesium) 
Height, weight, orthostatic vital signs* 
PD symptom burden  
Total Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) score (parts I – IV) 
Health-related quality of life 
Parkinson’s Disease Questionnaire-39 (PDQ-39) 
PD stage 
Modified Hoehn & Yahr staging 
Cognitive status 
Montreal Cognitive Assessment (MoCA) 
Emotional status 
Geriatric Depression Scale – short form (GDS-15) 
Uric acid  
Blood draw 
 
If subjects are taking parkinsonian medication, we will ask them to be off this medication for at 
least 12 hours prior to their baseline visit in order to perform assessment of their motor 
symptoms (MDS-UPDRS part III) and PD stage (Modified Hoehn & Yahr) in the practically 
defined “off” medication state. This is a standard procedure for this type of study23. Subjects 
must be willing to undergo this washout procedure to participate in the study. Assessment of 
cognitive status will also be performed in the practically defined “off” medication state. After 
motor assessment and PD staging is performed in the “off” state, patient will be instructed to 
take his/her parkinsonian medication in the office.  The motor subscale (MDS-UPDRS part III) 
will then be performed, and PD stage (Modified Hoehn & Yahr) will be assessed, in the best 


8 
 
“on” state (best response to morning dose of antiparkinsonian drug) 30-60 minutes after 
medication has been taken.  
 
* Orthostatic vital signs will be obtained by measuring vital signs after 5 minutes supine and 
after 2 minutes standing.  We will obtain 3 sets of orthostatic vital signs at least 15-20 minutes 
apart.  The average of the 3 orthostatic vital signs measurements will be used for comparison to 
all post-treatment measurements.  
  
Subjects will be instructed to avoid the regular use of over the counter antacids, laxatives, and 
cathartics that contain magnesium while taking study medication. 
 
Serum uric acid level will be drawn at the baseline visit given evidence suggesting that there may 
be an inverse relationship between levels of uric acid and rate of PD progression7, 8.  Uric acid 
level is for research purposes only. 
 
The PI or co-investigator will once again review the inclusion/exclusion checklist at the time of 
the baseline visit. 
 
 
D5. d. Treatment assignment & administration 
 
For subjects meeting enrollment criteria and providing consent, treatment with H2-enriched water 
or placebo will begin after the baseline visit. The subject will be randomly assigned to either the 
active treatment or the placebo group. A blocked randomization list will be generated using the 
following website: https://www.sealedenvelope.com/simple-randomiser/v1/lists. The research 
pharmacist will be responsible for using the generated list to assign treatment to subjects as they 
are enrolled. The study staff assessing study outcomes will remain blinded to treatment 
assignment. The study doctor will dispense study drug to the subject. Masking of active and 
placebo treatment will be maintained by bottling tablets in containers that appear identical.  
The medication will be administered orally as 250 mL BID of H2-enriched or placebo drinking 
water. Subjects will be instructed to adhere to a q6h – q10h schedule, but for convenience a dose 
may be taken a few hours earlier or later, as there is no expected mechanism of action indicating 
that dose timing would be critical for efficacy. 
 
D5. e. Follow-up visits 
Follow-up visits will be scheduled to occur at weeks 8, 24, 40, 52, and 56 (± 4 weeks). Adverse 
effects will be monitored to assess safety and tolerability in this patient population. The study 
doctor will dispense study drug to patient at weeks 8, 24, and 40. The subject will be counseled 
to call the investigator immediately to report the occurrence of any adverse events. Subjects will 
be instructed to return bottles with unused tablets at each follow-up visit. Tablet counts will be 
performed by the research pharmacist to monitor patient compliance.  
As a temporary measure to allow for continuity of this study during the COVID-19 pandemic, 
follow-up visits will be conducted remotely via telephone and/or secure videoconferencing using 


9 
 
the Microsoft Teams application. The following modifications will be made to follow-up visits 
during this time period: 
1. The study medication will be mailed to the subject instead of given to them in person. 
The study coordinator will pick up the medication from the research pharmacy at least 4 
days prior to the follow-up visit and bring it to the Stony Brook Post Office and have it 
shipped via Priority Mail.  The study coordinator will email the subject the day that the 
medication goes out by mail to let them know to look for it and will request that the 
subject email or call to confirm once they have received it. The study coordinator will 
call two days after the medication has been shipped to confirm it was received if the 
subject has not called by then. 
2. Instead of bringing the old container of study medication to the follow-up visit, subjects 
will be instructed to count the number of tablets in the container the morning of their 
follow-up visit (after taking the morning dose for that day) and reporting that number to 
the researcher during their follow-up visit. They will also be instructed to bring the 
container to their next in-person visit. 
3. Patients will not receive a physical examination or neurological examination.  While 
these examinations do provide some meaningful information, they are not necessary for 
the primary and secondary outcomes of the study.   
4. A modified version of the motor portion of the Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS III) will be performed remotely with the exception of rigidity testing and 
postural instability testing which both require hands-on assessment by the rater. The 
modified UPDRS (mUPDRS) has demonstrated evidence of validity and reliability.24 
5. A modified version of the Montreal Cognitive Assessment (MoCA) will be administered.  
Performing the MoCA remotely via telemedicine has been shown to be feasible in 
movement disorders populations.25 
6. Survey based assessments (MDS-UPDRS I, II, IV, GDS-15, and PDQ-39) will be 
administered online via RedCap. 
7. Height and weight will be measured by the subject, if they have the ability to do so, and 
reported during their visit. A notation will be added to the dataset indicating that these 
were measured by the subject since these measures may not be consistent with those that 
would have been obtained at the clinical research center.    
8. Instructions for measuring orthostatic vital signs will be provided to subjects prior to the 
follow-up visit.  If they have a means for measuring blood pressure they will take these 
measurements and report them at their visit. A notation will be added to the dataset 
indicating that these were measured by the subject since these measures may not be 
consistent with those that would have been obtained at the clinical research center.  
9. The research coordinator will call subjects weekly to inquire about adverse events 
beginning the week after the remote visit has taken place as a safeguard given the 
inability to conduct a physical and neurological exam and to have the research nurse 
measure orthostatic vital signs. Weekly calls will continue until the next in-person visit 
has taken place. 
10. If restrictions due to COVID-19 are lifted within 4 weeks of the remote visit, an in-person 
visit will be scheduled and the physical examination, neurological examination, MDS-
UPDRS III, Hoehn and Yahr Staging, and orthostatic vital signs will be taken during this 
visit. 


10 
 
11. Subjects will be sent a new consent form and have the changes reviewed by phone. They 
will be asked to sign the consent form and return via email or paper mail. Once received, 
the form will be signed by the study team member obtaining consent and sent back to the 
subject. 
The following data will be collected at follow-up visits at weeks 8, 24, 40 and 52. 
Table 3. Follow-up data at weeks 8, 24, 40 and 52 
Data 
Detail 
General health status Physical examination findingsa 
Neurological examination findingsa 
Concomitant medications 
Height, weight, orthostatic vital signsb 
PD motor symptoms 
MDS-UPDRS part IIIc 
The following modifications will be made for visits taking place remotely, as will be required during the COVID-19 
pandemic: 
aThese measurements will not take place for visits taking place remotely 
bThese measures will be taken by the subject, if they have the capacity to do so, for visits taking place remotely 
cA modified version of this measure will be administered for visits taking place remotely 
 
Orthostatic vital signs will be obtained by measuring vital signs after 5 minutes supine and after 
2 minutes standing. 
 
The following data will be collected at the follow-up visit at week 56. 
Table 4. Follow-up data at week 56 
Data 
Detail 
General health status Physical examination findingsa 
Neurological examination findingsa 
Concomitant medications 
Height, weight, orthostatic vital signsb 
PD symptom burden 
MDS-UPDRS score (parts I, IId, IIIc, IV) 
Health-related 
quality of life 
Parkinson’s Disease Questionnaire-39 (PDQ-39)d 
PD stage 
Modified Hoehn & Yahr staging 
Cognitive status 
Montreal Cognitive Assessment (MoCA)c 
Emotional status 
Geriatric Depression Scale – short form (GDS-15)d 
The following modifications will be made for visits taking place remotely, as will be required during the COVID-19 
pandemic: 
aThese measurements will not take place for visits taking place remotely 
bThese measures will be taken by the subject, if they have the capacity to do so, for visits taking place remotely 
cA modified version of this measure (mUPDRS) will be administered for visits taking place remotely 
dThese measures will be administered online via RedCap for visits taking place remotely  
In a similar manner to the baseline visit, if subjects are on parkinsonian medication, assessment 
of motor symptoms (UPDRS-part III) and PD stage (Modified Hoehn & Yahr) at week 56 will 


11 
 
be performed in the practically defined “off” and “on” medication states. Assessment of 
cognitive status will be performed in the practically defined “off” medication state.  
 
Orthostatic vital signs will be obtained by measuring vital signs after 5 minutes supine and after 
2 minutes standing. 
 
 
D5. f. Follow-up phone calls 
After the screening/baseline visit, the study coordinator will follow-up with the patient by phone 
at weeks 4, 16, 32, and 48. During the phone calls, the study coordinator will ask the subject 
about any adverse effects from the study drug. The subject will be reminded to call the 
investigator to report any adverse events. Subjects will also be asked if they have been compliant 
with taking the study medication as instructed. 
After the last visit, the study coordinator will follow-up with the subject one last time by phone. 
The purpose of this phone call will be to ascertain the subject’s medical status, to determine 
whether any ongoing adverse events present at the last clinic visit have resolved, and to inquire if 
any other adverse events have occurred since the last visit.  
D5. g. Early Termination 
Subjects will have the right to voluntarily discontinue study treatment and study visits at any 
time and for any reason.  
Occurrence of severe adverse events attributed to study participation will result in immediate 
withdrawal from the study and termination of study medication. Subjects who are not compliant 
with taking the study medication as instructed will also be withdrawn early from the study.  
Subjects who discontinue the study drug prior to week 52 will be seen for a final visit as soon as 
possible after study drug discontinuation.  
Table 5. Study Overview 
Assessments 
Screening 
visit 
Baseline 
visit 
(Week 0) 
Phone 
contact 
(Weeks 
4, 16, 
32, 48) 
Follow-
up 
(Weeks 
8, 24, 
40, 52) 
Final visit/ 
Early 
termination 
(Week 56) 
Phone 
contact 
(Week 58) 
Informed Consent 
x 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
x 
 
 
 
 
 


12 
 
Medical history 
 
x 
 
x 
x 
 
Physical examination 
 
x 
 
xa 
xa 
 
Neurological 
examination 
 
x 
 
xa 
xa 
 
Height, weight, 
orthostatic vital signs 
 
x 
 
xb 
xb 
 
MDS-UPDRS, parts 
I, II, IV 
 
x 
 
 
Xc 
 
MDS-UPDRS, part 
III (obtained in “off” 
and “on” states) 
 
x 
 
 
Xd 
 
MDS-UPDRS, part 
III (obtained in “on” 
state) 
 
 
 
Xd 
 
 
Modified Hoehn & 
Yahr (obtained in 
“off” and “on” states) 
 
x 
 
 
X  
 
PDQ-39 
 
x 
 
 
Xc 
 
Pregnancy test             
(if needed) 
x 
 
 
 
 
 
GDS-15 
 
x 
 
 
Xc 
 
MoCA  (obtained in 
“off” state) 
 
x 
 
 
Xd 
 
Adverse event 
review 
 
 
x 
x 
x 
x 
Randomization 
 
x 
 
 
 
 
Record concomitant 
medications 
 
x 
x 
x 
x 
x 
Study drug 
dispensation 
 
X  
 
xe  
 
 
Tablet count 
 
 
 
X  
 
 


13 
 
Blood draw 
 
X  
 
 
 
 
The following modifications will be made for visits taking place remotely, as will be required during the COVID-19 
pandemic: 
aThese measurements will not take place for visits taking place remotely 
bThese measures will be taken by the subject, if they have the capacity to do so, for visits taking place remotely 
cThese measures will be administered online via RedCap for visits taking place remotely 
dA modified version of this assessment will be administered for visits taking place remotely 
e Does not include week 52; for visits taking place remotely, the study medication will be mailed to the subject prior 
to the visit. 
Subjects can withdraw from the study at any time. 
D6. Study Drug 
Preparation 
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 number of rat models using either 
infusion of H2-enhanced IV fluids or ad lib access to H2-enriched drinking water.  
To prepare H2-enriched drinking water, we will use H2 tablets obtained from the company ‘drink 
HRW’. Drink HRW manufactures effervescent H2 magnesium tablets for the purposes of 
creating hydrogen-enriched drinking water.  Drink HRW was selected because their tablets 
reliably produce the intended concentration of hydrogen in the water and remain at a viable 
concentration long enough for subjects to consume the water.  The rapid dispersion of hydrogen 
is a formidable challenge in the production of hydrogen-enriched water, thus tablets were 
selected in which we could be assured subjects are receiving the desired amount of molecular 
hydrogen. Hydrogen water has been “generally recognized as safe” (GRAS) by the Food and 
Drug Administration (FDA) (GRN 520 available at 
https://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices&id=520&sort=GRN_No&order
=DESC&startrow=1&type=basic&search=520. Drink HRW’s effervescent H2 magnesium 
tablets have been granted “New Dietary Ingredient” status by the FDA (NDI 1104; 
https://www.regulations.gov/document?D=FDA-2018-S-0023-0162). 
The tablets used in this study are sold commercially under the general category of dietary 
supplements, for the purpose of enhancing the hydrogen dissolved in drinking water 
(https://drinkhrw.com/shopping/sc_cart/sc_CatTy.asp?SectionID=1&treeUID=1040&guid=6061
4F5C-6904-4E9A-959B-1448EB4BFCC6). The ingredient in the tablet producing H2 is 
magnesium. Each tablet contains 80 mg magnesium, a safe level well below the recommended 
daily dietary allowance of 420 mg for men/ 320 mg for women. Dissolving one tablet in 250 mL 
of water will achieve a saturating H2 concentration of approximately 1.6 ppm. Twice a day 
subjects will dissolve a tablet into water and drink the effervescent water. 


14 
 
 
 Figure: Nutrition label of drink HRW H2 magnesium tablets 
For a matching placebo, we will use effervescent tablets obtained from the company ‘drink 
HRW’. These effervescent placebo tablets also contain 80mg magnesium per tablet, but do not 
generate H2-enriched water. The Stony Brook Pharmacy will be responsible for bottling the H2 
tablets and placebo tablets in such a way that study staff and subjects remain blinded. 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, Subject identification number, expiration, and the term 
“Parkinson’s study drug - SBUH”.  
 Administration 
At the time of the baseline visit, subjects will be provided with H2 tablets (or placebo tablets) to 
take home with them.  Subjects will be instructed to twice a day dissolve one tablet in 250 mL (8 
ounces) of drinking water and then drink the entire glass of effervescent water.  Subjects who 
cannot tolerate thin liquids can use commercial pre-thickened water or commercial thickener to 
achieve the tolerated consistency (ie. nectar-thick or honey-thick). 
Subjects will be instructed to adhere to a roughly q6h – q10h schedule, but for convenience a 
dose may be taken a few hours earlier or later, as there is no expected mechanism of action 
indicating that dose timing would be critical for efficacy.  
Subjects who are taking routine dietary magnesium supplementation will be advised to suspend 
this supplementation for the duration of the study, given the presence of magnesium in the H2 
tablets and placebo. 
Justification of Dosage 
Fu and colleagues found that ad libitum administration of 50% saturated H2-enriched drinking 
water reduced nigral dopaminergic cell loss in a rat PD model11. Furthermore, a recent small 
pilot trial involving a total of 17 patients with idiopathic PD demonstrated that drinking 1000 


15 
 
mL/day of H2-enriched water was well-tolerated in PD patients, with possible positive effect on 
motor symptoms14. 
For these reasons, we have selected a dosage target of 250 mL BID of H2-enriched drinking 
water. Duration of therapy is set at 52 weeks. 
D7a. Primary Outcome Measures 
1. Safety: To investigate the safety of H2-enriched water in PD patients. Safety is defined as 
the absence of serious adverse events (SAEs) warranting termination of the treatment arm 
or the trial, as determined by the Data and Safety Monitor. 
  
2. Tolerability: To investigate the tolerability of H2-enriched water in PD patients. 
Tolerability is defined as the extent to which the treatment group can continue without 
prolonged treatment suspension (>24 consecutive days or >36 cumulative days) due to 
adverse events (AEs), as assessed 24 and 52 weeks after receiving the study drug. 
The criteria for monitoring safety and tolerability have been modeled after previous phase II 
clinical trials of antioxidant use in early stage PD patients9.   
D7b. Secondary Outcome Measures 
1. Motor Symptoms: To investigate the effect of H2-enriched water on the progression of 
motor symptoms in PD patients. Progression of motor symptoms will be assessed by 
change in the motor subscale of the MDS-Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS-III) from baseline to week 56. This will be assessed in the “off” state. 
 
2. Quality of life: To investigate the effect of H2-enriched water on health-related quality of 
life in PD patients. Health-related quality of life will be assessed by change in the PDQ-
39 from baseline to week 56. 
 
3. Cognitive Function: To investigate the effect of H2-enriched water on the progression of 
cognitive decline in PD patients. Cognitive function will be assessed using the Montreal 
Cognitive Assessment (MoCA) scale at baseline and week 56. This will be assessed in 
the “off” state. 
 
4. PD Symptom Burden: To investigate the effect of H2-enriched water on the progression 
of symptom burden in PD patients. Progression of symptom burden will be assessed by 
change in the Total MDS-UPDRS from baseline to week 56. 
D8. Enrollment Failure 
Subject enrollment will be examined continuously. Our goal is to enroll the targeted 70 subjects 
within 3 years of enrolling the first subject. If enrollment rate by the end of 18 months is not on 


16 
 
track towards approaching this goal, and no prospects for enhancing enrollment are on the 
horizon (for example, through partnership with another medical center or network), we will 
terminate the study and analyze outcomes based upon subjects enrolled at that point. If 
enrollment is proceeding well, but a reasonable extension of time is needed to complete 
enrollment of the targeted 70 subjects, we will submit an appropriate amendment request to the 
IRB prior to the end of the 3 year time frame.  
E. STATISTICS 
 
The primary objective of this study will be to assess the safety and tolerability of H2-enriched 
water in patients with PD. Safety will be assessed by comparing time to first SAE by log-rank 
tests. As noted above, safety is defined as the absence of serious adverse events (SAEs) 
warranting termination of the treatment arm or the trial, as determined by the Data and Safety 
Monitor. Tolerability will be defined as the extent to which the treatment group can continue 
without prolonged treatment suspension (>24 consecutive days or >36 cumulative days) due to 
adverse events (AEs), as assessed 24 and 52 weeks after receiving the study drug. The study is 
reasonably powered to detect the emergence of an SAE; of note, there were no adverse events or 
drop-outs in the active treatment arm of a prior pilot study including 9 patients on active 
treatment with H2-enriched water13.     
   
We also plan to perform an exploratory analysis looking for evidence of benefit against disease 
progression in PD using the secondary outcome measures described above (see D7b). In order to 
obtain meaningful results towards this end, we have therefore powered the study to detect a 
superiority of treatment with H2-enriched water compared to placebo in slowing PD disease 
progression. A prior pilot study demonstrated changes in the motor subscale of the UPDRS 
(UPDRS-III) that trended towards significance when comparing active treatment with H2-
enriched water to placebo (-5.7 ± 8.4 vs. 4.1 ± 9.2 for active treatment vs. placebo, respectively). 
Power calculation using this data suggests that a sample size of 60 will be sufficient to detect a 
between-group difference with a 2-sided α = 0.01 and power = 90%. We plan on a sample size of 
70 to account for drop-outs who voluntarily discontinue study treatment and study visits, and are 
therefore lost to follow-up. 
 
F. FUNDING STATUS, DETAILS 
This is an investigator-initiated study that will be funded at launch from the investigators’ own 
uncommitted research funds, possibly with assistance from the Department of Neurology. The 
investigators may seek outside funding if interim results are encouraging. 
 
G. HUMAN SUBJECTS RESEARCH PROTECTION FROM RISK 
G 1. Risk to Subjects 


17 
 
Based on prior studies, we do not anticipate clinically significant adverse effects associated with 
the administration of H2-enriched water. Several published studies have administered H2-
enriched drinking water or IV saline to human subjects without observing any serious treatment-
associated adverse events. Nakao and colleagues administered 1.5 – 2 L of H2-enriched water 
daily for a total of 8 weeks to 20 subjects with potential metabolic syndrome. They observed a 
small decrease in high density lipoprotein, but no abnormalities in weight, blood pressure, 
hematological parameters or routine clinical chemistry values26. No serious adverse events were 
noted. Four subjects exhibited mild AEs (1 headache, 1 heartburn, 3 loose stools), but no 
definitive relationship to treatment could be established. Ishibashi and colleagues administered 
H2-enriched IV saline (500 mL qday x 5 days, approximately 1.6 ppm H2) to 20 normal 
volunteers to assess safety; researchers reported lack of clinical AEs, and lack of abnormalities 
detected on routine hematology and blood chemistry27.  
The proposed administration of 250 mL BID of PO water to subjects with Parkinson’s disease 
should not pose significant risk. This volume is less than needed to keep a patient hydrated. Any 
subject whose attending physician is concerned about study medication-associated fluid overload 
would be excluded from the study, as per the exclusion criteria.  
The risks associated with the blood draw included in this study include temporary pain and 
bruising there the needle enters the skin, possible fainting, and small chance of infection.  
We will ask subjects on parkinsonian medication to refrain from taking their parkinsonian 
medication for 12 hours prior to the baseline and 56-week visits. This is not expected to 
contribute any significant risk, as hundreds of studies have been conducted using this procedure. 
Subjects will sign on the consent form that they understand this procedure and are comfortable 
with it. 
G 2. Adequacy of Protection against Risks 
Although the risks of the H2 therapy proposed here are more than minimal, they should not pose 
significant risk. The PI and Data Safety Monitor will monitor safety and risks throughout the 
study (see section G 1).  
Signed informed consent will be obtained from each subject. A copy of the consent form 
countersigned by study staff will be provided 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 for reporting adverse events 
experienced by study subjects to the IRB according to IRB guidelines.  
Confidentiality will be maintained. All subject research data will be coded with subject ID 
number. Paper files will be kept in a secure, locked area. The electronic database used during the 
study will be secured with a password and saved on a secured shared drive only accessible to key 


18 
 
personnel. Subject results will never be discussed in any form in the presence of other subjects in 
the study, or with non-laboratory personnel. Subjects’ names will not be used in manuscripts or 
presentations about this research. 
G3. Potential Benefits of Proposed Research to the Subject and Others 
The proposed therapy may slow the progression of Parkinson’s disease, a common 
neurodegenerative disorder for which disease-modifying treatment is not currently available.  
Even if the study is negative, observations made during the study may aid the development of 
future neuroprotective trials.  
H. DATA SAFETY MONITORING PLAN 
 
H 1. Adverse events monitoring 
Dr. Patricia Coyle, who is unaffiliated with the current study, has volunteered to serve as our 
data safety monitor (DSM). Dr. Coyle is Professor and Vice Chair (Clinical Affairs) in the 
Department of Neurology here at Stony Brook.  Dr. Coyle will be unblinded to treatment.   
Assisted by study staff, she will periodically review the protocol documentation and safety data.  
The first review will occur after the first 5 subjects have been enrolled and on study drug for >6 
weeks. Additional reviews will then take place quarterly.  Among the important goals of the 
reviews will be to ensure that adverse events are reported, protocol amendments are filed with 
the IRB, inclusion/exclusion criteria are followed. If in the DSM’s judgement a pattern of 
unexpected and clinically serious adverse events emerges, or if protocol compliance is 
inadequate, the study will be terminated. 
 
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 
parkinsonian symptoms and signs documented prior to initiation of study medication will not be 
considered AEs. The PI will proactively bring to DSM attention any serious AEs judged possibly 
associated with study medication. Any unexpected fatal or life-threatening suspected adverse 
reactions will be reported to the FDA within 7 calendar days. 
 
Table 6: Schedule for safety monitoring and assessments 
 
 
Assessments 
Frequency 


19 
 
H2 tablet and 
placebo 
Stony Brook pharmacy will bottle tablets 
following USP 797 guidelines 
At each preparation 
Study safety 
The Data Safety Monitor will review adverse 
events and protocol compliance 
At the first 5 patients enrolled and 
on study drug > 6 weeks; 
proactive reviews will then take 
place quarterly 
 
H 2. Data safety 
 
All paper study data will be kept in secure, locked cabinets. All identifiable electronic study data 
will be password-protected and saved in Redcap and/or in a secure shared drive on the Stony 
Brook server only accessible by study staff. The study coordinator will check the data for 
accuracy. Missing data will be identified and obtained (if possible) in a timely fashion. Study 
staff will take steps to ensure that all information obtained is kept private. The subjects’ names 
will not be used whenever possible. Study staff will instead use study codes lacking PHI. 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.  
 
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