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

Through its anti-inflammatory role, molecular hydrogen could have a beneficial effect in preventing the runaway inflammatory reactions that lead to complications of Covid-19.

This hypothesis is supported by numerous preclinical and theoretical arguments, as well as by some Chinese clinical studies (the Chinese guidelines for the management of Covid-19 recommend the inhalation of hydrogen), a recommendation whose interest has just been confirmed by a publication describing the very positive results of a clinical study in China.

Through its anti-inflammatory role, molecular hydrogen could have a beneficial effect in preventing the runaway inflammatory reactions that lead to complications of Covid-19.

The ingestion of water saturated with molecular hydrogen has been the subject of several clinical studies in other indications than Covid-19, and no side effects of this ingestion have been reported. A recent publication recommends initiating clinical trials using a hydrogen fortified beverage.

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 \[Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7), National Health Commission \& State Administration of Traditional Chinese Medicine. March 3, 2020\].

Eligibility Criteria:
Inclusion Criteria:

* Age 18 to 59 years old or over 60 years old.
* If patient 18 to 59 years old, presence of at least one risk factor :

  * Hypertension under treatment (all stages)
  * Obesity (BMI ≥30 kg / m2)
  * Diabetes under treatment (all types)
  * Stable ischemic heart disease (all stages)
  * Atrial fibrillation
  * Stable heart failure (all stages)
  * History of stroke
  * Stage 3 chronic renal failure (30 ≤ estimated GFR \<60 mL / min / 1.73 m²)
  * COPD (all stages, including chronic respiratory failure under long-term oxygen therapy)
  * Solid tumors or malignant hemopathies that are progressive or whose diagnosis is less than 5 years old
  * Immunodeficiency:
* of therapeutic origin (solid organ transplantation or transplant of hematopoietic stem cells, anticancer chemotherapy, immunosuppressive treatment, corticosteroid therapy\> 15 mg / day equivalent to prednisone price for at least 2 months);
* or HIV infection and last known CD4 count \<200 / mm3

  * History of pulmonary embolism and / or proximal deep vein thrombosis
  * Asthma under inhaled corticosteroid therapy
  * Paired sleep apnea syndrome
  * Peripheral arterial disease of the lower limbs stage II and above
  * Another risk factor presented, according to the list defined by the French High Council of Public Health
  * OR Presence of at least 3 comorbidities, according to the Rapid Responses to COVID-19 from the French High Council of Public Health.
* Patient with nasopharyngeal swab (antigenic test, RT-PCR, or other HAS-validated swabs to come) :

  * In case of positive test (antigenic test, RT-PCR, Other), patient with at least 1 symptom at the time of testing:
  * In case of negative antigenic or other test or ongoing or uninterpretable RT-PCR test, the patient must present at least 3 of the 11 symptoms of COVID-19 dating back no more than 4 days as defined below and notion of contact (with a certain or probable COVID+ patient) dating back less than 10 days:

Fever \> 37,5°C since 3 days Cough Sore throat/cold Headache Anosmia, dysgeusia Myalgias, arthralgias, bone pain Respiratory difficulties (feeling of dyspnea at rest) Chest pain (sternal) Digestive complaints (diarrhea, nausea, vomiting) Tachycardia (palpitation) Conjunctivitis (red eyes)

* No seriousness signs during the consultation and for at least 72 hours.
* Patient able to understand the procedure and follow it and have tools for a video-consultation.
* Affiliation to the social security system.
* Voluntary to participate to the study, informed consent form signed after appropriate information

Exclusion Criteria:

* The absence of attending or referring physician
* Any sign of seriousness incompatible with home care.
* Severe chronic kidney failure or dialysis (i.e. DFGe \<30).
* drink cure Contraindication (500 ml/d for 21 days).
* Contraindication to any drug in the study, including a known allergy, especially magnesium.
* Uncontrolled and clinically significant heart disease, whether its origin (arrhythmias, angina, uncompensated congestive heart failure).
* Subject participating to an other clinical study interventional.
* Person deprived of liberty or under legal guardianship.
* No one in the same household who participated in this study.
* Patient refusing hospitalization.
* Persons subject to sections L1121-7 and L1121-8 of the CSP (minor, person deprived of liberty by judicial or administrative decision, person subject to a legal protection measure) or not able to communicate his consent verbally.