Evaluation of the Daily Intake of 0.5 L of Water Saturated With Molecular Hydrogen for 21 Days in COVID-19 Patients Treated in Ambulatory Care

CURRENT STATE OF KNOWLEDGE ON PATHOLOGY :

SARS-CoV-2 is the causative agent of a new infectious respiratory disease called Covid-19
(for CoronaVirus Disease 2019) which is characterized primarily by potentially serious and
fatal lung damage. The seriousness of the clinical signs associated with this pathology
requires hospital admission of approximately 20% of patients, of which 5 to 10% will be
admitted to intensive care. The more severe forms, though seen mainly in people over 60 years
old, also occur in younger patients, most of whom are affected by comorbidities such as
hypertension (30%), diabetes (17 %) or cardiovascular pathologies (15%). The mortality due to
this infection varies according to the series between 2 and 14%. The most severe cases of
this pathology begin with dyspnea which rapidly worsens around the 7th to 10th day of the
disease into Acute Respiratory Distress Syndrome (ARDS) which requires the patient to be
mechanically ventilated in the intensive care unit. and is responsible for the majority of
deaths. ARDS is an active feature of severe forms of Sars-Cov-2 infection, directly linked to
the mortality of this infection. The clinico-radiological aspect is not specific to other
aetiologies of ARDS. Certain biological parameters suggest a massive and sudden release of
cytokines (interleukins IL-6, IL-8 and IL-10 mainly) secondary to a syndrome of macrophage
activation mainly at the pulmonary level. This cytokine storm is comparable to that of
secondary hemophagocytic lymphohistiocytosis which occurs in approximately 4% of sepsis and
is accompanied, in 50% of cases, by ARDS. The effect of this inflammatory cascade leads to an
uncontrolled influx and activation of polynuclear and macrophagic cells with hyperproduction
of oxygen-derived free radicals. These reactive species will damage the capillary alveolar
membrane with initially hyperpermeability, and secondarily with fibrosis and fibroblast
proliferation.

Several therapeutic trials aimed at reducing or controlling this immune storm are underway
(anti-IL-6 antibodies, anti-r IL6 antibodies, corticosteroids).

PROPOSED STRATEGY, PURPOSE AND NOVELTY OF THE STUDY :

There are many theoretical, preclinical and clinical arguments to suggest that the
administration of molecular hydrogen (H2) could, by the original anti-inflammatory effect of
H2, help to avoid the cytokine storm. These arguments justified the launch of clinical trials
proposing the inhalation of H2 (the investigators submitted to the French Ministry of Health
(ANSM) a protocol, which has just been accepted by the ANSM, providing for the inhalation of
H2 in patients Covid-19 at the start of oxygen therapy). As will be described in the next
section, inhalation delivers significantly more H2 than ingestion of water saturated with H2.
However, the inhalation of H2 involves a complex intervention, which in practice can only be
considered late, as it can only be implemented for the benefit of hospitalized patients,
typically in addition to oxygen therapy.

However, the arguments in favor of the potential interest of H2 in preventing the
consequences of the cytokine storm apply particularly at the very beginning of the pathology:
it would be very useful to be able to prevent not the consequences, but the occurrence of
this storm, which would imply a very early intervention. It is this thinking that motivates
this clinical trial.

The investigators hypothesis is that the early ingestion of water enriched in H2, through its
anti-inflammatory effect, could prevent the complications of Covid-19 in the short, medium
and long term. The investigators have found no evidence of any clinical study proposing to
explore this original route, which does not use a drug, but a product classified and marketed
as a dietary supplement.

To be able to demonstrate this effect, it is preferable to address a population in which the
prevalence of complications is high. The investigators have therefore chosen to target
patients over the age of 60 or 18 to 59 years old with at least one risk factor, in whom the
complication rate is of the order of 50%. To explore the effect of a very early
administration of H2, the investigators will limit themselves to patients at the very
beginning of the pathology, symptomatic for no more than 5 days with the realization of a
nasopharyngeal sample for COVID- 19, or asymptomatic contact subjects diagnosed with COVID +
by RT-PCR or antigen test, the contagion dating no more than 10 days, and who may remain at
home, without treatment or with routine care not requiring oxygen therapy. The patients in
the interventional arm will self-administer H2, by ingesting 2 x 250 mL for 21 days, i.e. 0.5
L of water enriched in H2 per day, which they will manufacture themselves by dissolving 80 mg
tablets of Mg metal (supplied by DrinkHRW, British Columbia, Canada): this was the method
which seemed to us to be the simplest and easiest to implement for self-administration at
home. Patients in the control group will receive an effervescent placebo tablet containing
the same dose of Mg, but in ionic form, unable to generate H2 on contact with water.

The primary endpoint will be a composite endpoint combining worsening of symptoms (dyspnea
and fatigue), putting on 02, hospitalizations and death occurring within 12 to 14 days
following a PCR COVID-19 + diagnosis.

CURRENT KNOWLEDGE ON THE EXPLORATIONS PROVIDED FOR BY THE PROTOCOL :

Molecular hydrogen (H2) acts on the final path of the complex inflammatory cascade leading to
the cytokine storm, by inhibiting the cellular action of reactive oxygen species.

Although the first study on the protective effects of hydrogen reported in the literature
dates back to the 1970s, it is an experimental study on the therapeutic effects of molecular
hydrogen in a model of cerebral infarction in rats which really constituted the starting
point for numerous experimental works in animals and humans. This study showed that hydrogen
enrichment (2-4%) of inspired air significantly decreases the volume of necrosis resulting
from experimental cerebral ischemia in rats. The authors' interpretation was that the
protective effect of molecular hydrogen was due to an antioxidant action linked to its
reducing properties and its ability to diffuse easily through cell membranes. However, other
studies quickly showed that the antioxidant and anti-free radical properties of hydrogen
alone are not sufficient to explain the anti-inflammatory and anti-apoptotic effects of
hydrogen administration. Thus, a study have shown that hydrogen inhibits the intracellular
signaling pathways of inflammation without involving anti-free radical effects.

In addition, inhalation of hydrogen (2.9%) also limits the activation of mast cells. Finally,
a study showed that two 60-minute sessions of inhalation of a gas mixture containing 2%
hydrogen made it possible to limit lesions and mortality of multiple organs in a model of
generalized inflammation in mice. The same authors have shown that inhalation of hydrogen
restores the PaO2 / FiO2 ratio, both in a mouse model of sepsis by cecal ligation and in a
model of lung disease induced by lipopolysaccharides (LPS). In view of the current data in
the literature, the application of a treatment with molecular hydrogen makes it possible to
trigger many potentially protective mechanisms in a hyperinflammatory context, such as sepsis
and very probably Covid-19, by trapping hydroxyl radicals and peroxynitrite, by limiting
inflammatory reactions by modulating intracellular transduction cascades and by modifying the
expression of certain genes. This has been confirmed and specified in the case of Covid-19 by
a very recent publication.

Several routes of administration have been used for hydrogen, they have been widely
implemented in the clinic. The most widely used today, both in animals and in clinical trials
in humans, are the ingestion of drinking water enriched in hydrogen and the inhalation of a
gas mixture containing up to 4% of hydrogen. The inhalation route allows for the
administration of much larger amounts of H2 than ingestion of H2 enriched water. In fact, as
Ohta reports, inhalation makes it possible to permanently maintain a high concentration of H2
in the liquid compartments, whereas, less than an hour after ingestion of water enriched in
H2, the concentration in the organism of molecular hydrogen returns to its baseline.

The preparation of water enriched with H2 can be done in several ways, and consumers have
access to it in the context of "general public" products, excluding health products,
considered as well-being products or as food supplements. Multiple CE marked water
electrolysis devices are available on the French market, they can easily be implemented at
home by interested consumers (see for example http://www.alkavoda.com/product/hydrogen-
water-generator / or https://www.lifeionizers.com/products/alkaline-water-ionizers/).
Hydrogenated water can also be produced industrially by electrolysis, and distributed in the
form of flexible aluminum bags (see for example https://susosuwater.com/products/packages).
Finally, the consumer can produce his hydrogenated water himself, by dissolving a tablet of
magnesium metal in a cup (see for example https://drinkhrw.com/, which will provide us with
the 80 mg tablets of Mg metal). Mg metal reacts spontaneously with water, according to the
reaction Mg + 2H20 -> Mg (OH) 2 + H2. This last approach allows to have a hydrogen
supersaturation for about 10 minutes, then the H2 concentration returns to the saturation
limit (800 micromoles / L), with a half-life of one hour thereafter. The investigators will
therefore recommend that the patient dissolve one Mg tablet in 250 mL of water twice a day,
to drink as much water as possible (ideally at least 200 mL) immediately after dissolving
this tablet (approximately 90 mL/s), and the rest as soon as possible, while remaining within
the limits of an ingestion deemed comfortable by the patient.

No side effects of the administration of H2 could be demonstrated by the numerous preclinical
and clinical studies. Some studies have even been carried out with high pressure gas mixtures
(60 bars) containing 49% H2, which corresponds to a considerably greater administration of H2
than inhalation of mixtures with 4% H2 at atmospheric pressure, and therefore even more than
what can be administered by ingestion (this was during deep diving experiments, the mixture
was used to prevent decompression sickness and arterial thrombi. There are traces at
https://clinicaltrials.gov/ of 20 clinical trials involving inhalation or ingestion of
hydrogen, but there are more globally, as research in this area is much more active in Japan
, not all of the trials of which are listed on this site, and more recently in China, where
two trials on the benefit of inhalation of H2 in Covid-19 by an original method have been
launched, one of which is still in progress. A first publication highlights the protective
effect against the complications of Covid by inhaling a mixture containing 66% H2. Regarding
the ingestion of water enriched in H2, Ohta lists numerous clinical trials. The investigators
carried out a literature review themselves, which found a total of 410 patients included in
clinical trials involving the ingestion of water enriched in H2. Among the recent trials
whose methodology is similar to that which the investigators are considering, the
investigators note a Japanese double-blind randomized trial including 178 patients with
Parkinson's disease, patients in the interventional arm received 1 L of H2-saturated water
for 48 weeks: no side effects has been noted. Finally, note the recent mini-review which
concludes that the ingestion of water supersaturated with H2 (and also containing citrulline)
is of potential interest in COVID-19.

Finally, it should be noted that the FDA has published a note classifying hydrogen-enriched
water as GRAS (Generally Regarded As Safe), see
http://www.rexresearch.com/bghealth/ucm409796.pdf and more specifically published a note
accepting the tablets designed by DrinkHRW as "New Dietary Ingredient", specifying the
conditions of use that the investigators will implement in this project.

Since the discovery of the first cases of Covid-19 in China, different strategies have been
adopted to contain the inflammatory response of patients through antioxidant approaches. In
this context, at least three pilot studies
[https://www.cebm.net/covid-19/registered-trials-and-analysis/] and one multicenter clinical
study [https://clinicaltrials.gov/ct2/show / NCT04336462? Cond = hydrogen + covid + 19 & draw
= 2 & rank = 1] have been launched in China since January 2020, using the reducing properties
of molecular hydrogen. The first results of these studies have been very encouraging, to such
an extent that the Chinese health authorities have included hydrogen therapy in the
guidelines on the management of patients hospitalized with moderate Covid-19 [Diagnosis and
Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7), National Health
Commission & State Administration of Traditional Chinese Medicine. March 3, 2020].