Effect of a Nutritional Support System to Reduce Complications in Patients With Covid-19 and Comorbidities in Stage III
Phase: NA
Conditions: COVID19, Diabetes Mellitus, Hypertension, Obesity, Overweight, Oxygen Saturation, Mortality, Inflammation
Sponsor: Anahuac University

 
 
 
 
ANAHUAC UNIVERSITY MEXICO-NORTE 
 
 
FACULTY OF HEALTH SCIENCES 
 
 
RESEARCH COORDINATION 
 
 
 
 
EFFECT OF A NUTRITIONAL SUPPORT SYSTEM TO 
INCREASE SURVIVAL AND REDUCE MORTALITY IN 
PATIENTS WITH COVID-19 IN STAGE III AND 
COMORBIDITIES —— A BLINDED RANDOMIZED 
CONTROLLED CLINICAL TRIAL 
 
Investigation Protocol 
 
 
 
 
Clinical Trials identifier: NCT04507867. 
Protocol identification number: 202036. 
CONBIOETICA-15-CEI-004-20160729. 
 
 
 
 
MEXICO CITY, JULY 2020 
 
 
 
 

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1. ABSTRACT 
The disease caused by SARS-CoV-2 has become a pandemic in which its evolution and 
complications depend on the immunological capacity of the host. In Mexico, the global 
lethality rate of the virus is 11.3% (1,2), with a mortality rate of 0.2795 per 1000 inhabitants 
(3). It is relevant to study therapies that allow the host to recover and reduce complications; to 
date, the virus has been characterized by an inflammatory cascade, increased by the 
overproduction of cytokines, the decrease of metalloenzymes and the rapid dissemination of 
the virus. There are several lines of treatment, however, nutrition is considered as a caloric 
contribution and not as part of the treatment. For this reason, this study will evaluate the 
evolution of patients with COVID-19 assisted by a nutritional support system (NSS) based on 
supplements such as omega 3, zinc, selenium, vitamin D, glutamine, arginine, magnesium, 
cobalamin, pyridoxine, thiamine, prebiotics, probiotics, foods such as Spirulina Maxima, 
brewer's yeast and the effect of this therapy in the reduction of complications and 
comorbidities. Research question: Will the nutritional support system reduce complications in 
stage III COVID-19 patients with comorbidities (type 2 DM, HAS, overweight/obesity with 
BMI <35) with a better benefit than that achieved with conventional nutritional therapy? 
Hypothesis: The nutritional support system will reduce complications in patients with COVID-
19 with stage III comorbidities. General Objective: To determine the effect of the use of a 
nutritional support system on complications in patients with COVID-19 and stage III 
comorbidities. Methodology: A controlled, blinded and randomized clinical trial will be 
conducted in patients with COVID-19, both sexes, older than 30 years old, hospitalized at 
Centro Médico ISSEMYM Toluca Arturo Montiel Rojas, who meet the inclusion criteria and 
are classified in stage III. Two groups will be evaluated: 1. Control group (CG) which will 
receive the normal diet implemented by the hospital and 2. Intervention group (IG) which will 
receive the normal diet implemented by the hospital together with the NSS. Blood chemistry 
of 46 elements, coagulation tests, blood biometry, % SpO2, homocysteine, 25-
hydroxycholecalciferol, clinical data and anthropometry will be evaluated at baseline and 
during their hospital stay. 
 
 
 
 

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2. THEORETICAL FRAMEWORK 
2.1 Theoretical background 
Coronaviruses are a group of RNA (ribonucleic acid) viruses that cause respiratory and 
digestive diseases, producing mild to severe symptoms such as acute respiratory distress 
syndrome and death. (4,5,6) SARS-CoV-2 virus can cause the disease called coronavirus 
disease 2019 (COVID-19), first manifested in Wuhan, China, in December 2019. (7,8) 
2.2 Epidemiology 
Worldwide, 11,874,226 confirmed cases and 545,481 deaths have been reported. In 
Mexico, 282,283 cases have been confirmed and 33,526 deaths. The global case fatality 
rate is 4.6%, in Mexico it is 11.3% with a mortality rate of 0.2795 per 1000 population 
(2,3,7). 
2.3 Stratification  
In a retrospective study conducted in January 2020 in Beijing, the classification of 
COVID-19 was described as: mild, severe, non-pneumonic and asymptomatic, depending 
on the clinical manifestations and radiological evidence of pneumonic process (7,8). The 
presence of comorbidities such as obesity, cardiovascular disease, arterial hypertension, 
type 2 diabetes mellitus and immune deficiency states have been associated with more 
severe disease (9,10). In Mexico, according to the interim algorithms for the care of 
COVID-19 are classified according to the time of evolution, signs and symptoms, the 
application of different clinical scales and laboratory findings in: stage I (early infection) 
outpatient management, stage II (pulmonary phase) medical review and evaluation for 
hospitalization; and stage III (hyperinflammatory phase, cytokine storm) the patient 
requires hospitalization in reconversion areas. (11) 
2.2 Transmission and Pathophysiology 
Transmission occurs through the air or through fomites; airborne spread is due to 
respiratory droplets reaching 1-2 m generated by talking, coughing and sneezing; the 
virus can remain viable for 24 to 72 hours on surfaces, which allows contagion by contact 
with these fomites and touching eyes, nose or mouth (9); SARS-CoV-2 enters human cells 

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through the respiratory tract by binding to angiotensin-converting enzyme 2 (ACE2), 
expressed in alveolar cells, cardiac myocytes, vascular endothelium and other cells 
(13,14,15). Infection occurs in 3 steps: binding to the receptor, conformational changes in 
glycoprotein S and proteolysis of cathepsin L within the endosomes. The virus, upon 
entering the host cell, releases the RNA genome into the cytoplasm, subsequently attaches 
to ribosomes and gives way to viral genome translation. SARS-CoV-2 can affect different 
cellular levels (16,17). ACE2 expressed in the epithelial cells of the esophagus and 
enterocytes in ileum and colon causes gastrointestinal colonization in patients infected by 
COVID-19. Viral infections are related to dysbiosis due to alterations in the intestinal 
microbiota, immunological defects or different pathologies that cause damage to the 
Peyer's plaques, decreasing the production of T17 lymphocytes, generating a state of 
immunosuppression. These effects are reversible after adequate probiotic colonization 
(gastrointestinal microbiota), as well as the supply and metabolism of different 
micronutrients such as vitamins D and A that modulate the function of neutrophils and 
participate in the differentiation of T lymphocytes to Th1 or Th17. Dysbiosis inhibits the 
synthesis of short-chain fatty acids, which influence intracellular and extracellular 
immunoregulatory signaling, altering gene transcription, promoting antibody synthesis, 
cell differentiation, among others, which has effects on distal organs such as the lungs, 
comprising the microbiota-intestine-lung axis. (18,19,20) 
2.3 Clinical manifestations 
The clinical manifestations of COVID-19 are nonspecific, may remain asymptomatic, mild 
clinical manifestations such as fever, cough, sore throat, fatigue, dyspnea, myalgia, headache, 
vomiting and diarrhea (14,20). Presentation and severity usually vary by age (> 65 years), 
comorbidities and compromised immune system. In these cases the patient may be at increased 
risk of developing organ dysfunction, including shock, acute respiratory distress syndrome 
(ARDS), acute cardiac injury, and acute kidney injury, resulting in a higher mortality rate (15). 
Symptoms of COVID-19 infection appear after an incubation period of 5-6 days, the time 
period between symptom onset and death ranges from 6 to 41 days, with a median of 14 days. 
The median time from symptom onset to dyspnea is 5 days, hospitalization 7 days and the onset 
of ARDS is 8 days. The need for admission to the Intensive Care Unit (ICU) in several 
published series is 25 - 30%. Different complications have been evidenced, which include (21): 

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2.3.1 Pulmonary damage: in severe cases of COVID-19 there is a decreased ratio between 
arterial oxygen partial pressure and fractional inspired oxygen (PaO2: FiO2 ratio) with 
concomitant hypoxia and tachypnea. In addition, low CO2 levels have been observed as the 
mean partial pressure of carbon dioxide (PaCO2) level at 34 mmHg. In summary, hypoxia and 
hypercapnia are observed in severe cases. (22). IL-6 acts as a potent proinflammatory factor 
and has been implicated as a strong predictor of respiratory failure (23). 
2.3.2 Immune response: Damage by immune mechanisms is caused by the storm of cytokines, 
mainly inflammatory, which activate T lymphocytes, macrophages and endothelial cells, with 
the consequent vascular permeability, activation of the complement cascade and coagulation 
(24,25). In patients with severe COVID-19, there is a decrease in the absolute number of 
circulating CD4+ cells, CD8+ cells, B cells and NK cells; a decrease in monocytes, eosinophils 
and basophils has also been reported. (26) SARS-Cov-2 requires in a key way the association 
with S-adenosyl-L-methionine (SAM), with its nsp 14N7-Mtase regions. When SAM is 
transformed into S-adenosylhomocysteine (SAH) and this is in contact with SAH hydrolase 
(SAHH), homocysteine is obtained, which is an intermediate that stimulates oxidative stress 
and is recycled by remethylation and trans-sulfuration in humans. In a study published in the 
journal Nature Communications, the focus was on understanding the homocysteine-related 
regulatory mechanisms that stimulate the angiotensin II receptor type. Thus, SARS-CoV-2 
utilizes increased activation of ACE2 (27).   
2.3.3 Gastrointestinal symptoms: Studies have identified SARS-CoV-2 RNA (obtained by 
PCR) in stool samples from infected patients, and it was found that the ACE2 receptor is 
expressed in enterocytes, suggesting that it can infect and actively replicate in the 
gastrointestinal tract (evidenced by electron microscopy), which has implications for the 
management, transmission (fecal-oral) and control of COVID-19. Some patients reported 
symptoms such as diarrhea, vomiting, and abdominal pain during the course of the disease. 
(28) 
2.3.4 Nutritional status: Lymphopenia, which is a marker of malnutrition, is a poor prognostic 
factor in patients with COVID-19. Circulating albumin levels should not be considered as a 
nutritional marker in patients with active inflammatory response, since it was recently reported 
that low levels of prealbumin predict progression of ARDS (29). The acute phase response, 
induced by inflammation and infections, alters lipid metabolism, decreasing serum HDL and 
increasing triglycerides, which initially may help fight infection, but increases the risk of 

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atherosclerosis. Reducing inflammation has been shown to result in a return of the lipid profile 
to normal. (30,31) It has been shown that in patients with muscle wasting due to disease, the 
use of glutamine, arginine and HMB (beta hydroxy beta methylbutyric acid) can decrease 
muscle loss because they can promote the production and decrease in protein degradation. 
Since arginine improves cell size and protein synthesis and glutamine activates cell division. 
2.3.5 Thrombotic and thromboembolic complications: the main hemostatic complications 
include mild thrombocytopenia (<100. 000/µL) and increased D-dimer levels, which are 
associated with a high risk of requiring mechanical ventilation, admission to the ICU or death. 
Prolongation of prothrombin time (PT), thrombin time (TT), tendency of shortening of 
activated partial thromboplastin time (aPTT), increased INR (international normalized ratio) 
and high fibrinogen levels have also been associated. This predisposes to thrombotic events; 
whether these alterations are specific to SARS-CoV-2 or are a consequence of the cytokine 
storm that precipitates the onset of systemic inflammatory response syndrome (SIRS) as seen 
in other viral diseases remains unknown. Another consideration that has not been investigated 
is that hemostatic changes are related to liver dysfunction. (12) 
2.3.6 Kidney manifestations: The alterations associated to COVID-19 have been hematuria, 
acute kidney injury (AKI), the most common finding is proteinuria that goes from mild to 
moderate; it has also been evidenced that podocytes and tubular epithelial cells are infected. 
Diao et al. found that SARS-CoV-2 antigens agglomerate in renal epithelial tubules, i.e., the 
human kidney is directly infected causing renal dysfunction and collaborating with viral 
propagation in the body (32). It has been evidenced that acute renal injury is related to higher 
mortality. (33,34) 
2.3.7 Metabolic control: It is estimated that 20-50% of infected patients in the world have 
diabetes, as a consequence of chronic inflammatory levels such as obesity. Mexico ranks first 
in childhood obesity and second in adult obesity, which makes its population a population with 
a high potential for SARS-COVID-2 complications, with obesity being the most important risk 
factor regardless of age. The comorbidities of obesity are hypertension, diabetes and coronary 
heart disease, (35,36) conditions that together aggravate the cellular inflammatory state. 
Obesity, overweight and metabolic syndrome alter the innate immune response altering the 
first lines of defense, the elevation of IL-6 caused by obesity also participates in the 
pathogenesis of pulmonary diseases, asthma, respiratory distress and hepatic damage. 
Glycoproteins such as DPP4 (dipeptidyl peptidase 4) are found in epithelial cells of the 

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respiratory tract, intestine, capillaries and myocardium, being important for angiogenesis, 
cardiovascular regulation and inflammation, an increased expression of DPP4 is associated 
with obesity and metabolic syndrome (37). Chronic inflammatory states develop peripheral 
leptin resistance causing dysregulation of insulin and glucose sensitivity (38). SARS-CoV-2 is 
thought to infect islet cells via the ACE2 receptor, impairing islet function and altering the 
balance of blood glucose metabolism (39). It has been seen that viral diseases can cause 
dyslipidemia, recent studies refer that the reduction of lipid levels is related to the severity of 
symptoms, the theories are: 1) SARS-CoV-2 can impair liver function, reducing LDL-c (low 
density lipoprotein concentration) biosynthesis; 2) acute inflammation alters lipid metabolism, 
mainly by TNF-a, IL-6 and IL-1b ; 3) lipids are sensitive to degradation by free radicals, which 
are elevated in host cells with viral infection; 4) altered vascular permeability can cause leakage 
of cholesterol molecules into tissues (alveolar spaces) and form exudates. (40) 
2.3.8 Hepatic: Liver injury is more common in severe cases of COVID-19, it may be directly 
caused by viral infection of liver cells, those patients with liver comorbidities showed abnormal 
levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the disease 
progressed. In addition, it has been proposed that ACE2 receptor expression is increased in 
cholangiocytes, suggesting that SARS-CoV-2 may cause destabilization of liver function 
through its direct binding to ACE2-positive cholangiocytes. Another factor that may be 
contributing to liver injury is cytokine storm and pneumonia-related hypoxia. (41) 
2.4 General treatment 
Treatment is supportive and symptomatic, depending on the severity of symptoms, although 
there is no specific treatment so far, most patients will require supplemental oxygen. 
Pharmacological treatment varies depending on the complications and the patient's clinical 
condition, including medications such as Ceftriaxone, Azithromycin, Oseltamivir and 
Ivermectin; together with the nutritional therapy recommended by the WHO, calculating the 
energy requirement per weight of 27 - 30 kcal/kg/day; protein requirement up to 1.5 g/kg/day 
in case of not having chronic renal failure; carbohydrate and lipid requirement with a range of 
30:70 in patients without respiratory failure and 50:50 in patients with respiratory failure. (42, 
43) 
2.5 Nutritional Support System (NSS) 

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Nutritional status influences the outcome of patients with COVID-19, but so far there is no 
information on the impact of early nutritional support in patients with COVID-19 before ICU 
(28). Zhang and Liu recently developed a list of nutrients with potential anticoronavirus effects 
based on in vitro and clinical studies. However, none of the literature available so far has 
discussed how to adapt currently available guidelines for nutritional therapy during illness to 
the specific clinical scenario of COVID-19 (13). 
2.6 Evidence for specific nutrients 
Probiotics are beneficial in the prevention of acute upper respiratory tract infection, helping to 
counteract dysbiosis in patients with COVID-19. Specifically, Saccharomyces Boulardii, also 
increases IgA levels in the intestine reducing the proinflammatory response, (44). On the other 
hand, beta-glucans from the cell wall of brewer's yeast (Saccharomyces Cerevisiae) stimulate 
the immune system, especially those related to inflammatory responses (leukocytes and 
epithelial cells) and the reticuloendothelial system (45). Nutrients may favor the immune 
response with respect to the common characteristics currently presented in patients with 
COVID-19 (16). The SARS-CoV-2 viral genome encodes for the nsp12 protein, which harbors 
RNA-dependent RNA polymerase (RdRP) activity. It has been shown that vitamin B12 
(methylcobalamin) can bind to the active site of the nsp12 protein, preventing association with 
RNA and thereby inhibiting the RdRP activity of nsp12 (46). On the other hand, administration 
2-500 μM of Zinc significantly inhibits influenza replication in vitro, through inhibition of 
RNA-dependent RNA polymerase (RdRp), with a similar effect occurring with SARS-CoV, 
where binding and elongation of the RdRp template is inhibited (47). In addition, C-
phycocyanin, an extract found in Spirulina maxima, acts by blocking hemagglutination of virus 
particles to inhibit influenza virus strains and may help prevent morbidity in airway diseases 
(48). Protein D1, derived from Omega 3, reduces virus replication of some strains of influenza 
viruses, so omega 3 is also considered an important nutrient when considering a feeding scheme 
with antiviral action (49). Arginine and resveratrol are able to decrease apoptosis induced by 
MERS-CoV and inhibit infection caused by it, prolonging cell survival after infection (50). 
These antiviral mechanisms are due to the fact that resveratrol activates the ERK 1/2 signaling 
pathway and promotes cell proliferation by enhancing SIR1 signaling, both of which are related 
to cell survival and DNA repair in response to DNA damage (51). The release of 
proinflammatory cytokines such as TNFα, IL-6, IL-8 and IFN (interferon Alpha, Beta and 
Gamma) correlates with disease severity. Administration of vitamin D especially in its active 
form 1, 25, dihydroxycholecalciferol [1, 25 (OH) 2D3], causes modulation in the immune 

8 
system and antiviral activity by reducing the expression of proinflammatory cytokines (TNFα, 
IL-6, IL-8) and increasing the expression of anti-inflammatory cytokines (IL 4, IL 10) by 
macrophages through regulation by vitamin C (52). Khare et al (53) observed that treatment of 
human lung epithelial cells with 100 or 30 nM of 1α, 25 (OH) cholecalciferol before or after 
H1N1 exposure significantly decreased TNFα, IFNβ and IFNγ levels and IL-8 and IL-6 levels. 
Vitamin D deficiency (plasma 25 (OH) D levels <50 nmol / L) has been identified in patients 
with acute respiratory distress syndrome (ARDS) (54). 
25-hydroxycholecalciferol is a stable marker of vitamin D status that can be measured in blood. 
This vitamin immunomodulates the innate and adaptive immune system, which is useful 
against the cytokine storm caused by SARS-Cov-2, since its active metabolites modify NF-κB 
signaling in macrophages, reduces the synthesis of proinflammatory mediators (TNFα, IL -6 
and MCP-1) and decreases the recruitment of monocytes and macrophages, lowering overall 
tissue inflammation, in addition, it has been documented to have an antifibrotic effect in lung 
tissue. (55,56, annex 4). Omega 3, derived in the formation of docosahexaenoic acid (DHA), 
reduces extremely high inflammatory parameters, since it regulates lymphocyte proliferation, 
cytokine production and neutrophil chemotaxis (57). Folates mediate the production of 
proinflammatory cytokines and the immune response mediated by Th-1 cytokines. Therefore, 
their deficiency decreases the antibody response to various antigens, including the blastogenic 
response of T lymphocytes to certain mitogens, and the capacity of CD8 T lymphocyte cells 
(58). There is evidence that magnesium plays a key role in the immune response as a cofactor 
for immunoglobulin synthesis, (48) as well as a relationship between magnesium deficiency 
and increases in proinflammatory cytokines (59). It is known that intracellular free glutamine 
in skeletal muscle is markedly reduced in the stress response to surgery, trauma and 
inflammatory states; thus, reduced plasma glutamine values have been detected in hospitalized 
patients with emphysema, COPD and evidence of muscle wasting (60). SARS-CoV-2 enters 
the cell through its surface proteins; however, this protein must be divided into 2 domains, 
where furin intervenes. It has been shown that folic acid inhibits furin activity, preventing the 
virus from entering the cell. (61) 
3. JUSTIFICATION 
COVID-19 is a disease that spreads rapidly and has a high mortality rate, which has caused the 
collapse of health systems; therefore, it is important to implement a comprehensive treatment 
to avoid complications of the disease, reduce the length of hospital stay and provide a rapid 
recovery. Treatment costs can vary from $500,000 Mexican pesos per admission to $1,512,000 

9 
pesos, considering an average hospital stay of 12 days (5). It has been seen that 26.4% of 
hospitalized patients recovered and were discharged from the hospital, and 46.4% improved 
and were reclassified. 13.4% have died (6). There are several lines of treatment, but nutrition 
is only considered within the caloric intake. In this study a nutritional therapy called NSS will 
be evaluated, trying to reduce complications in patients with COVID-19, as well as reduction 
of hospital stay days, disease progression, percentage of progression to mechanical ventilation 
and mortality. This study will provide scientific evidence to establish new strategies to improve 
the clinical evolution of patients with COVID-19 worldwide. This study is feasible given that 
it has the material and human resources to be carried out and is pertinent given that it seeks to 
contribute to the study of new nutritional therapies to reduce complications and mortality in 
patients with COVID-19.   
4. STATEMENT OF THE PROBLEM 
To date, cases of COVID-19 have been reported in 212 countries. It is currently known that 
COVID-19 mainly affects the respiratory system, although it is not the only one; it can cause 
mild to severe symptoms such as pneumonia, multiple organ failure or even death. It has a case 
fatality rate of 11.3% in Mexico. No pharmacological treatment has proven to be totally 
effective, therefore, the main treatment is symptomatic and supportive (62). Conditions such 
as age (>65 years), presence of comorbidities such as overweight or obesity, chronic pulmonary 
diseases (asthma, COPD), cardiovascular diseases, systemic arterial hypertension (SAH), 
diabetes (DM type 2) and immune deficiency states have been associated with more severe 
disease progression. New evidence suggests a possible regulatory role of specific nutrients in 
the pathogenesis and development of COVID-19 complications, but so far no nutritional 
support system has been integrated as part of the therapeutics. This proposal seeks to help 
patients reduce the appearance of complications and avoid their admission to the ICU. Recent 
research supports that certain nutrients favor the immune response with respect to the common 
characteristics that are currently being presented in patients with COVID-19. The present study 
proposes an evidence-based nutritional support scheme for the comprehensive management of 
patients with COVID-19. It is expected that this system will act synergistically with the current 
treatment and improve the evolution of the patients. 
5. RESEARCH QUESTION 
Will the nutritional support system reduce complications in patients with COVID-19 and 
comorbidities (type 2 DM, HAS, overweight/obesity with BMI <35) in stage III, with a better 
benefit than that achieved with conventional nutritional treatment? 
6. HYPOTHESIS 

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The nutritional support system will reduce complications in patients with COVID-19 and 
comorbidities (type 2 DM, HAS, overweight/obese with BMI <35) in stage III, with a better 
benefit than that achieved with conventional nutritional treatment. 
7. GENERAL OBJECTIVE 
To determine the effect of the use of a nutritional support system on complications in patients 
with COVID-19 and comorbidities (type 2 DM, HAS, overweight/obesity with BMI <35) in 
stage III, compared with conventional nutritional treatment.  
7.1. SPECIFIC OBJECTIVES 
1. To correlate biochemical and inflammatory factors with the evolution of the study groups. 
2. To correlate body composition with the clinical evolution of the patients.  
3. To evaluate the days of hospital stay, disease progression, percentage of progression to 
ventilator and mortality as predictive indexes of patient improvement. 
4. To stratify in groups by age ranges (30-39, 40-49, 50-59 and >60 years). 
8. METHODOLOGY 
8.1 Type of study and overall design: Blinded, randomized controlled clinical trial. 
8.2 Study Universe.  
Patients diagnosed with COVID-19 by PCR test, who are attended at Centro Medico 
ISSEMYM Toluca Arturo Montiel Rojas, located at Paseo Tollocan, Av. Baja Velocidad km 
575, Barrio de Sta Clara, Toluca de Lerdo, State of Mexico; both sexes, with presence of 
comorbidities and in stage III. 
8.3 Selection and sample size: the sample size will be calculated using the formula: n = 
𝑧2𝑝𝑞
𝑒2  , 
where: 95% confidence level (z = 1.96), p = 0.975, q = 0.025, with a margin of error of 5% (e 
= 0.05), obtaining 38 patients per group for the sample. 
8.4 Inclusion and exclusion criteria 

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Inclusion criteria: 1. Patients admitted to the Centro Medico ISSEMYM Toluca Arturo Montiel 
Rojas, diagnosed with COVID-19. 2. Patients in need of supplemental O2 with nasal prongs or 
mask-reservoir due to satO2 <90% and respiratory distress. 3. With concomitant diseases such 
as cardiovascular disease, diabetes mellitus 2, hypertension, overweight or obesity BMI <35. 
4. 5. Over 30 years of age. 6. Tolerant of oral feeding. 7. Signed informed consent letter. 
Non-inclusion criteria: 1. Who requires mechanical ventilatory support. 2. 2. Present 
neurological or neurodevelopmental disorders. Severe gastroesophageal reflux and/or 
dysphagia. 4. 4. Patients with any type of surgery performed in a period of less than 3 months. 
5. Allergies to any ingredient of the study treatment. 6. Who present acute malnutrition. 7. 
Patients who require admission to the Intensive Care Unit. 8. Who has criteria of sepsis or 
septic shock. 9. Glomerular filtration rate less than 60ml/min/1.73m2. 
Criteria for elimination: 1. Treatment failure. 2. Admission to ICU for any reason. 3. Patients 
who do not tolerate the oral route. 4. Reactions to treatment that compromise the health of the 
patients. 
Sampling and allocation: Consecutive cases. Systematic randomized allocation by means of a 
sequence of random numbers constructed with the Excel program divided into two groups. 
8.4 Procedure  
Once the participants have been selected, the patients and/or family members will be 
interviewed to explain the protocol and to obtain the signatures of the informed consent letters 
(Annex 1). Confirmatory test for COVID-19 by PCR, which should confirm the diagnosis in 
order for the study to continue.   Complete clinical and dietary history. Complete blood count: 
leukocytes, neutrophils, eosinophils, basophils, lymphocytes, monocytes, erythrocytes, red 
blood cell count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean 
hemoglobin concentration (MHC), mean corpuscular hemoglobin concentration (MCHC), 
platelets and mean platelet volume (MPV). 4. Blood chemistry (glucose, urea, urea nitrogen 
(BUN), creatinine, BUN/creatinine ratio, uric acid, calcium, phosphorus, sodium, potassium, 
chloride, magnesium, glomerular filtration rate (GFR), triglycerides, total cholesterol, low 
density lipoproteins (LDL), high density lipoprotein (HDL), very low density lipoprotein 
(VLDL), total lipids, total, direct and indirect bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), lactate 
dehydrogenase (LDH), total proteins and albumin. 5. D-dimer (see section 2.3.6). 6. 

12 
Coagulation times, bleeding time and prothrombin time. (See section 2.3.6). 7. Fibrinogen. 
(Serum electrolytes: sodium, potassium, magnesium, and chlorine.  (See section 2.3.7 and 
2.3.8). 9. Serum homocysteine levels. (See section 2.3.3). Serum levels of 25 
hydroxycholecalciferol. (See section 2.6). 11. Taking of tricipital fold and arm circumference, 
% muscle mass, % fat, BMI, weight, height. 12. Assignment to the research group in a random 
way, which will have the following characteristics: A) QA: calculate the Basal Energy 
Expenditure (BEE) per 1.5 of stress factor by means of the Harris Benedict equation. The 
distribution of macronutrients will be 50% for carbohydrates, 30% for lipids and 20% for 
proteins. The food will be established according to what is established in the nutrition 
department of the Centro Médico ISSEMYM Toluca Arturo Montiel Rojas. B) GI: calculate 
the Basal Energy Expenditure (BEE) plus the stress factor using the Harris Benedict equation. 
The distribution of macronutrients will be 50% for carbohydrates, 30% for lipids and 20% for 
proteins. The food will be established according to what is established in the nutrition 
department of the Centro Médico ISSEMYM Toluca Arturo Montiel Rojas, together with the 
following supplementation: 1. Neurobion injectable solution of 10 mg, 1 every 24 hrs for 5 
days IM. 2. One sachet of NSS-1 in the morning and one sachet in the afternoon mixed with 
400 ml of water each, containing: Spirulina Maxima 2. 5 g, folic acid 5 mg, Glutamine 5g, 
Cyanomax Ultra (10 grams of powder), ascorbic acid 1 g, zinc 20 mg, selenium 100 mcg, 
cholecalciferol 2000 IU, resveratrol 200 mg, concentrated omega 3 fatty acids (10 grams of 
powder), L-Arginine 1.5 g, and magnesium 400 mg. During the entire procedure. 3. 500 mg 
of Saccharomyces Bourllardii, administered with 1 capsule of 250 mg during breakfast and 
lunch, for the first 6 days. 
The energy balance of the supplements will be considered within the designated caloric balance 
for this group. The follow-up will be performed daily for 21 days or earlier, if they are 
discharged from hospital due to improvement in evolution or require access to the ICU, at 
which time the patient concludes the study. The following points will be supervised: 1. 
Application and consumption of the NSS supplementation as appropriate. 2. Recording of all 
the information in the records. 3. Food diaries of each patient. 4. Laboratory studies: QS every 
other day, BH every 3rd day, coagulation times every 3rd day, D-dimer and fibrinogen every 
3rd day, serum electrolytes every other day, serum homocysteine every other day and serum 
25 hydroxycholecalciferol levels every other day. 5. SpO2 %, heart rate, respiratory rate. 6. 
Clinical evaluation and record of bowel movements. 7. Taking of tricipital fold and arm 

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circumference, % muscle mass, % fat, BMI, weight, height every two days. 8. Days of hospital 
stay. 
9. ETHICAL CONSIDERATIONS 
The present clinical trial complies with the guidelines stipulated in the regulations of the 
General Health Law on Research, article 17 of which considers it a minimum risk research. 
According to what is established in articles 36 and 37 of this Law, the consent must be 
obligatorily in writing by means of a letter of informed consent and a letter of agreement (annex 
1). This letter will be signed voluntarily by the patient. The study does not affect the living, 
moral or physical conditions of the study subjects. It does not violate the basic principles of the 
Declaration of Helsinki, the Nuremberg Code and the NOM-012-SSA3-2012 about scientific 
research in humans, it also adheres to the international Ethical Guidelines for biomedical 
research involving human subjects. 
10. FUNDING 
In order to carry out this research it is necessary to have working and protection equipment, 
which has an estimated cost of $348,082.50 pesos MN. The supplementation of the NSS has 
an approximate total cost of $976,320.00 pesos MN. The evaluation and diagnostic methods 
will be the same as those routinely performed at the hospital.  This project, once authorized, 
will be submitted to the Universidad Anahuac Mexico Norte for institutional budgeting and 
will receive support from the private sector. 
11. BIBLIOGRAPHIC REFERENCES  
1. 
OMS. Situation Report-113 al 12 de mayo de 2020. Disponible en: https ://www.who.int/docs/default-
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