Anti-inflammatory/Antioxidant Oral Nutrition Supplementation in COVID-19 (ONSCOVID19)

Anti-inflammatory/Antioxidant Oral Nutrition Supplementation on the Cytokine Storm and Progression of COVID-19: A Randomized Controlled Trial

COVID-19 pandemic threatens patients, societies and healthcare systems around the world. The host immunity determines the progress of the disease and its lethality. The associated cytokine storm mainly affects the lungs; leading to acute lung injury with variable degrees. Modulation of cytokine production using Immunonutrition is a novel concept that has been applied to other diseases. Using specific nutrients such as n3- fatty acids and antioxidant vitamins in extraordinary doses modulate the host immune response and ameliorate the cytokine storm associated with viral diseases such as COVID-19. In this proposal, we will conduct a prospective double-blinded controlled trial for 14 days on 30 SARS-CoV-2 positive cases. The participant will be randomly assigned to two groups (n=20/each); intervention (IG) and placebo (PG) groups. The IG group will be provided with an anti-inflammatory and antioxidant oral supplement (OS) on a daily basis, while the PG will be given an isocaloric placebo. Basal and weekly nutritional screening, as well as recording of anthropometric, clinical and biochemical parameters, will be done. The main biochemical parameters include serum ferritin level, cytokine storm parameters (interleukin-6, Tumor necrosis factor-α, and monocyte chemoattractant protein 1), C-reactive protein, total leukocyte count, differential lymphocytic count and neutrophil to lymphocyte ratio. It is expected that the anti-inflammatory-antioxidant OS might help in the reduction of the COVID-19 severity with more preservation of the nutritional status of infected cases.

Study Overview

• Status: Unknown
• Conditions: COVID-19
• Intervention / Treatment: Dietary supplement: Oral supplement enriched in antioxidants; Dietary supplement: cellulose-containing placebo capsules

Detailed Description

Subjects: A total of 40 participants will be enrolled in this double-blinded prospective, randomized controlled trial. All participants will sign a written consent after details of the study have been fully explained to them. Later on, they will be randomly allocated into two study groups; intervention group (IG, n=20) and placebo group (PG, n=20). Computer-generated random numbers will be used to randomize the participants into one of two intervention groups. The study protocol will be approved by the IRB committee in King Khalid University Hospital, King Saud University Medical city. This clinical trial will be registered in the clinicaltrials.gov registry.

Settings: All participants will be SARS-CoV-2 positive cases admitted to King Khalid University Hospital.

Study protocol: All study participants will be instructed to either consume one capsule of oral supplement enriched in antioxidants vitamins or placebo. The OS will be served in opaque capsules of the same size, shape and color and should be ingested in the morning under the supervision of a nurse. The OS should not be consumed before the time of a meal. The composition of one capsule of the intervention-OS includes: enriched in vitamin A, C, E, Selenium and Zinc. The composition of one capsule of the intervention-supplement includes: 1500 mcg vitamin A (as β-carotene), 250 mg Vitamin C, 90 mg vitamin E, 15 ug Selenium, and 7.5 mg Zinc. The composition of the placebo will have the same weight of cellulose, and zero concentrations of vitamin A, C, E, Selenium and zinc.

All participants will be assessed at the start and reassessed again after 1 week and after 14-days period. The assessment will include nutritional screening by Nutritional risk screening 2002 (NRS-2002), Subjective global assessment (SGA), and Global Leadership Initiative on Malnutrition (GLIM) criteria. Besides anthropometric measures, clinical Global Leadership Initiative on Malnutrition (GLIM). also, anthropometric measurements, clinical assessment, and biochemical data will be measured. Statistical analysis: The Statistical Package for the Social Sciences (SPSS) version 25 will be used for analysis. The descriptive statistics for continuous variables will be presented as mean ± standard deviation, while other categorical variables as percentages. The independent sample t-test will be used for comparison between the IG and PG groups. For repeated measures at multiple points of time will be tested by Friedman's two-way ANOVA. The Pearson correlation coefficient will be applied to correlate some relevant variables. All these tests were performed with 80% power and a 5% level of significance.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Mahmoud M.A. Abulmeaty, M.D., FACN; Phone Number: 00966548155983; Email: mabulmeaty@ksu.edu.sa

Study Locations

• Saudi Arabia
  • Riyadh, Saudi Arabia, 14214
    • Recruiting
    • Prince Mohamed BinAbdulaziz Hospital
    • Contact: Abdulla Abdulsalam, MD; Phone Number: 00966112616462; Email: research-dept@pmah.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed SARS-CoV-2 infection
• COVID-19 patient in stable condition (i.e., not requiring ICU admission).

Exclusion Criteria:

• Tube feeding or parenteral nutrition.
• Pregnant or lactating women
• Admission to ICU > 24 hours
• participation in another study including any forms of supplementation or disease specific ONS.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; the intervention groups will receive daily oral antioxidant supplement enriched in vitamin A, C, E, Selenium and Zinc. The composition of one capsule of the intervention-supplement includes: 1500 mcg vitamin A (as β-carotene), 250 mg Vitamin C, 90 mg vitamin E, 15 ug Selenium, and 7.5 mg Zinc.	Dietary supplement: Oral supplement enriched in antioxidants; the intervention group will receive a commercially available antioxidant supplement, which will be given to patients with COVID-19 in the morning after breakfast.
Placebo Comparator: Placebo; Placebo group will receive daily intervention in form of cellulose-containing gelatin capsules with the same color and shape.	Dietary supplement: cellulose-containing placebo capsules; The placebo group will receive an oral supplement at the same time in the same shape/size/color.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline score of Nutrition risk screening-2002 (NRS-2002) at end of the trial	Changes in scores of the NRS-2002 for patients with COVID-19 at the end of the study, from 0 to 7 scores, with those scores < 3 means no risk of malnutrition and >= 3 means malnutrition.	up to 3 months
Change from baseline Serum ferritin level at end of the trial	Change in serum ferritin at the end of the trial as ferritin is considered as a COVID-19 fatality predictor.	up to 3 months
Change from baseline serum Interleukin-6 concentration at end of the trial	Change in IL-6 at the end of the trial as it represent the cytokine storm and it is considered as a COVID-19 fatality predictor	up to 3 months
Change from baseline serum C-reactive protein concentration at end of the trial	Change in C-reactive protein in the serum at the end of the trial which reflect the acute phase	up to 3 months
Change from baseline serum Tumor necrosis factor-α concentration at end of the trial	Change in the TNF a in the serum at the end of study as it represent severity of the cytokine storm	up to 3 months
Change from baseline serum monocyte chemoattractant protein 1 (MCP-1) at end of the trial	plasma MCP-1 represent severity of the cytokine storm	up to 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline Weight at end of the trial	Body weight in Kg	up to 3 months
Height	stature in cm	up to 1 month
Change from baseline BMI at end of the trial	Claculation of BMI according to weight / square Height	up to 3 months
Change from baseline mid arm circumference at end of the trial	changes of MAC in cm	up to 3 months
Change from baseline triceps skin-fold thickness at end of the trial	changes of TSF in mm	up to 3 months
Change from baseline MAMA at end of the trial	). The mid-arm muscle area (MAMA) will be calculated according to the following equation: {MAMA= (MAC - π x TSF)2 / 4π}.	Up to 3 months
Change from baseline percentage of peripheral O2 saturation at end of the trial	changes in the percentage of peripheral O2 saturation by an oximeter	up to 3 months
Change from baseline degree of body temperature at end of the trial	changes in the degree of body temperature by infrared thermometer	up to 3 months
Change from baseline count the total leukocyte at end of the trial	change in the count from complete blood counts	up to 3 months
Change from baseline differential lymphocytic count at end of the trial	change in the count from complete blood counts	up to 3 months
Change from baseline Neutrophil count at end of the trial	change in the count from complete blood counts	up to 3 months
Change from baseline neutrophil to lymphocyte ratio at end of the trial	change in the rations calculated by division of the neutrophil count by the lymphocyte count	up to 3 months

Collaborators and Investigators

• Sponsor: King Saud University

Publications and helpful links

General Publications

• Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
• Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-848. doi: 10.1007/s00134-020-05991-x. Epub 2020 Mar 3. No abstract available. Erratum In: Intensive Care Med. 2020 Apr 6;:
• Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2022 Oct 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/
• Calder PC. Immunonutrition in surgical and critically ill patients. Br J Nutr. 2007 Oct;98 Suppl 1:S133-9. doi: 10.1017/S0007114507832909.
• Abulmeaty MM, Almajwal AM, Almadani NK, Aldosari MS, Alnajim AA, Ali SB, Hassan HM, Elkatawy HA. Anthropometric and central obesity indices as predictors of long-term cardiometabolic risk among Saudi young and middle-aged men and women. Saudi Med J. 2017 Apr;38(4):372-380. doi: 10.15537/smj.2017.4.18758.
• Grimm H, Calder PC. Immunonutrition. Br J Nutr. 2002 Jan;87 Suppl 1:S1. doi: 10.1079/bjn2001450. No abstract available.
• Das SK, Chisti MJ, Sarker MHR, Das J, Ahmed S, Shahunja KM, Nahar S, Gibbons N, Ahmed T, Faruque ASG, Rahman M, J Fuchs G 3rd, Al Mamun A, John Baker P. Long-term impact of changing childhood malnutrition on rotavirus diarrhoea: Two decades of adjusted association with climate and socio-demographic factors from urban Bangladesh. PLoS One. 2017 Sep 6;12(9):e0179418. doi: 10.1371/journal.pone.0179418. eCollection 2017.
• Harada K, Minami H, Ferdous T, Kato Y, Umeda H, Horinaga D, Uchida K, Park SC, Hanazawa H, Takahashi S, Ohota M, Matsumoto H, Maruta J, Kakutani H, Aritomi S, Shibuya K, Mishima K. The Elental(R) elemental diet for chemoradiotherapy-induced oral mucositis: A prospective study in patients with oral squamous cell carcinoma. Mol Clin Oncol. 2019 Jan;10(1):159-167. doi: 10.3892/mco.2018.1769. Epub 2018 Nov 16.
• Kim H. Glutamine as an immunonutrient. Yonsei Med J. 2011 Nov;52(6):892-7. doi: 10.3349/ymj.2011.52.6.892.
• Kondrup J, Allison SP, Elia M, Vellas B, Plauth M; Educational and Clinical Practice Committee, European Society of Parenteral and Enteral Nutrition (ESPEN). ESPEN guidelines for nutrition screening 2002. Clin Nutr. 2003 Aug;22(4):415-21. doi: 10.1016/s0261-5614(03)00098-0.
• McCowen KC, Bistrian BR. Immunonutrition: problematic or problem solving? Am J Clin Nutr. 2003 Apr;77(4):764-70. doi: 10.1093/ajcn/77.4.764.
• Mariette C. Immunonutrition. J Visc Surg. 2015 Aug;152 Suppl 1:S14-7. doi: 10.1016/S1878-7886(15)30005-9. Erratum In: J Visc Surg. 2016 Feb;153(1):83.
• McCarthy MS, Martindale RG. Immunonutrition in Critical Illness: What Is the Role? Nutr Clin Pract. 2018 Jun;33(3):348-358. doi: 10.1002/ncp.10102.
• Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012 Mar;76(1):16-32. doi: 10.1128/MMBR.05015-11.
• Teo BW, Toh QC, Chan XW, Xu H, Li JL, Lee EJ. Assessment of muscle mass and its association with protein intake in a multi-ethnic Asian population: relevance in chronic kidney disease. Asia Pac J Clin Nutr. 2014;23(4):619-25. doi: 10.6133/apjcn.2014.23.4.01.

Helpful Links

• Immunonutrition: Interactions of Diet, Genetics, and Inflammation - Google Books. In Immunonutrition: Interactions of Diet, Genetics, and Inflammation
• COVID-19: consider cytokine storm syndromes and immunosuppression

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): December 30, 2020

Study Registration Dates

• First Submitted: March 23, 2020
• First Submitted That Met QC Criteria: March 24, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): September 22, 2020
• Last Update Submitted That Met QC Criteria: September 18, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: COVID-19; Cytokine storm; Antioxidant ONS
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants
• Other Study ID Numbers: ONS_COVID-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: all IPD that underlie results in a publication will be shared
• IPD Sharing Time Frame: starting 6 months after publication.
• IPD Sharing Access Criteria: Access will be available for any researcher interested in this type of research on considerable consent.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No