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].