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 : 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. Double-blind, Randomized, Comparative Study

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....

Medienart:	Klinische Studie

Erscheinungsjahr:	2022
Erschienen:	2022

Enthalten in:	ClinicalTrials.gov - (2022) vom: 05. Apr. Zur Gesamtaufnahme - year:2022

Sprache:	Englisch

Links:	Volltext [kostenfrei]

Themen:	610 COVID-19 Medical Condition: SARS-CoV-2, Covid19, AMBULATORY CARE Recruitment Status: Active, not recruiting Study Type: Interventional

Anmerkungen:	Source: Link to the current ClinicalTrials.gov record., First posted: January 20, 2021, Last downloaded: ClinicalTrials.gov processed this data on April 18, 2022, Last updated: April 20, 2022

Study ID:

NCT04716985 2020-A03137-32

Veröffentlichungen zur Studie:

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PPN (Katalog-ID):	CTG003644278