Clinical trial NCT05163743: Diet and COVID-19 Vaccination
Official title: COVID-19 Vaccination in Subjects With Obesity: Impact of Metabolic Health and the Role of a Ketogenic Diet
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Obesity
Keywords: Ketogenic Diet, COVID-19, VAT, Obesity
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2021-12-20
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Recently, obesity and excess visceral fat were shown to be major risk factors for the development of complications following Covid 19 infection. Recently, KDs have been suggested as possible weapons to tame the cytokine storm being described in those developing complications upon COVID-19 infection, and preclinical evidence strongly supports the hypothesis, with mouse models of COVID-19 infection in the elderly reporting strikingly better outcomes upon consumption of a KD. Short-term interventions that use low-calorie ketogenic diets may be prescribed for selected overweight or obese patients with type 2 diabetes or prediabetes.

No data is available on the impact of a ketogenic diet on immune modulation following vaccination. We herein aim at investigating whether obesity and unhealthy body composition are associated with poor seroconversion following the upcoming COVID-19 vaccine administration, and whether consumption of a KD before and between COVID-19 vaccine doses leads to better immune response in obese subjects. 24 obese patients will be assigned to follow a LCKD regimen for 5 weeks.

Detailed description: Recently, obesity and excess visceral fat were shown to be major risk factors for the development of complications following Covid 19 infection. Recently, KDs have been suggested as possible weapons to tame the cytokine storm being described in those developing complications upon COVID-19 infection, and preclinical evidence strongly supports the hypothesis, with mouse models of COVID-19 infection in the elderly reporting strikingly better outcomes upon consumption of a KD. Short-term interventions that use low-calorie ketogenic diets may be prescribed for selected overweight or obese patients with type 2 diabetes or prediabetes.

No data is available on the impact of a ketogenic diet on immune modulation following vaccination. We herein aim at investigating whether obesity and unhealthy body composition are associated with poor seroconversion following the upcoming COVID-19 vaccine administration, and whether consumption of a KD before and between COVID-19 vaccine doses leads to better immune response in obese subjects. 24 patients will be assigned to follow a low-calorie ketogenic diet (LCKD). Outcome measures will be antiSARS-CoV-2 antibodies, cell mediated response to SARS CoV-2, anthropometric parameters, vital signs, metabolic profile, and body composition. The patients will be assessed at baseline (T0) and every two weeks (T1, T2) as they receive both SARS Cov-2 vaccination doses up to 1 week after the second dose (T3) when they will be finally evaluated and carbohydrate reintroduction takes place. Patients will be given support and counselling to enhance their compliance. Anthropometric parameters such as body weight, blood pressure (systolic and diastolic), heart rate, waist and hip circumference will be measured at baseline (T0), every two weeks up to the end of the trial (T3).

Blood and urine chemistry Complete Blood Count (CBC), electrolytes (chloride, calcium, potassium, sodium, magnesium), fasting glucose, insulin, lipids (total and fractionated cholesterol and triglycerides) and proteins, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), plasma creatinine, blood urea nitrogen (BUN), alanine transferase (AST), aspartate transaminase (ALT), uric acid, beta hydroxy butyrate and estimated Glomerular Filtration Rate (using the Modification of Diet in Renal Disease study equation MDRD-eGFR) will be determined

AntiSARS-CoV-2 antibodies: antibodies will be quantified by enzyme-linked immunosorbent assay using the appropriate antigen at T3 and T4 in all arms. The cell mediated response to SARS CoV-2 will be analyzed by taking whole blood that will be stimulated with immune ligands.

Data obtained will be expressed as mean values ±Standard Deviation (SD) and finally processed to ascertain whether statistical differences among them can be demonstrated, using appropriate methods. In particular, the analysis of variance (ANOVA) at different times will be used for efficacy and safety data, such as weight reduction, changes in anthropometric measures, and variation of the metabolic parameters. P values \<0.05 will be considered statistically significant.

Eligibility criteria: * BMI ≥35.0 kg/m2 with comorbidities or BMI≥40
* Stable body weight (less than 5 kg self-reported change during the previous 3 months)
* Informed consent obtained before any trial-related activity takes place Exclusion criteria
* Stage 3-5 CKD (GFR\<60 ml/min)
* Type 1 diabetes
* Uncontrolled type 2 diabetes
* Previous infection with SARS CoV-2
* Immunodeficiency or immunomodulating treatment
* Treatment with anti-obesity medications or other medications potentially affecting body weight or SGLT2 inhibitors
* Pregnancy and lactation
* Previous gout episodes
* Cardio and cerebrovascular accidents in the preceding 12 months

Primary outcomes:
measure: AntiSARS-CoV-2 antibodies
timeFrame: 5 weeks
measure: Cell mediated response to SARS CoV-2
timeFrame: 5 weeks
Secondary outcomes:
measure: Body weight
timeFrame: 5 weeks
measure: Waist Circumference
timeFrame: 5 weeks
measure: Triglycerides, glucose, insulin, ESR, CRP, ferritin
timeFrame: 5 weeks
Other outcomes:
Locations:
city: Roma
country: Italy
facility: Sapienza University of Rome
Study officials:
affiliation: University of Roma La Sapienza
name: Lucio Gnessi, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Watanabe M, Risi R, De Giorgi F, Tuccinardi D, Mariani S, Basciani S, Lubrano C, Lenzi A, Gnessi L. Obesity treatment within the Italian national healthcare system tertiary care centers: what can we learn? Eat Weight Disord. 2021 Apr;26(3):771-778. doi: 10.1007/s40519-020-00936-1. Epub 2020 May 25.
citation: Mariani S, Fiore D, Varone L, Basciani S, Persichetti A, Watanabe M, Saponara M, Spera G, Moretti C, Gnessi L. Obstructive sleep apnea and bone mineral density in obese patients. Diabetes Metab Syndr Obes. 2012;5:395-401. doi: 10.2147/DMSO.S37761. Epub 2012 Nov 7.
citation: Lonardo A, Mantovani A, Lugari S, Targher G. Epidemiology and pathophysiology of the association between NAFLD and metabolically healthy or metabolically unhealthy obesity. Ann Hepatol. 2020 Jul-Aug;19(4):359-366. doi: 10.1016/j.aohep.2020.03.001. Epub 2020 Mar 21.
citation: Dwivedi AK, Dubey P, Cistola DP, Reddy SY. Association Between Obesity and Cardiovascular Outcomes: Updated Evidence from Meta-analysis Studies. Curr Cardiol Rep. 2020 Mar 12;22(4):25. doi: 10.1007/s11886-020-1273-y.
citation: Okamura T, Hashimoto Y, Hamaguchi M, Obora A, Kojima T, Fukui M. Ectopic fat obesity presents the greatest risk for incident type 2 diabetes: a population-based longitudinal study. Int J Obes (Lond). 2019 Jan;43(1):139-148. doi: 10.1038/s41366-018-0076-3. Epub 2018 May 1.
citation: Palermo A, Tuccinardi D, Defeudis G, Watanabe M, D'Onofrio L, Lauria Pantano A, Napoli N, Pozzilli P, Manfrini S. BMI and BMD: The Potential Interplay between Obesity and Bone Fragility. Int J Environ Res Public Health. 2016 May 28;13(6):544. doi: 10.3390/ijerph13060544.
citation: Arboleda S, Vargas M, Losada S, Pinto A. Review of obesity and periodontitis: an epidemiological view. Br Dent J. 2019 Aug;227(3):235-239. doi: 10.1038/s41415-019-0611-1.
citation: Watanabe M, Caruso D, Tuccinardi D, Risi R, Zerunian M, Polici M, Pucciarelli F, Tarallo M, Strigari L, Manfrini S, Mariani S, Basciani S, Lubrano C, Laghi A, Gnessi L. Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19. Metabolism. 2020 Oct;111:154319. doi: 10.1016/j.metabol.2020.154319. Epub 2020 Jul 23.
citation: Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell L, Chernyak Y, Tobin KA, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020 May 22;369:m1966. doi: 10.1136/bmj.m1966.
citation: Watanabe M, Risi R, Tuccinardi D, Baquero CJ, Manfrini S, Gnessi L. Obesity and SARS-CoV-2: A population to safeguard. Diabetes Metab Res Rev. 2020 Oct;36(7):e3325. doi: 10.1002/dmrr.3325. Epub 2020 Jun 11.
citation: McLarnon A. Obesity: influenza immunity impaired in obesity. Nat Rev Endocrinol. 2011 Nov 15;8(1):3. doi: 10.1038/nrendo.2011.199. No abstract available.
citation: Andersen CJ, Murphy KE, Fernandez ML. Impact of Obesity and Metabolic Syndrome on Immunity. Adv Nutr. 2016 Jan 15;7(1):66-75. doi: 10.3945/an.115.010207. Print 2016 Jan.
citation: Painter SD, Ovsyannikova IG, Poland GA. The weight of obesity on the human immune response to vaccination. Vaccine. 2015 Aug 26;33(36):4422-9. doi: 10.1016/j.vaccine.2015.06.101. Epub 2015 Jul 8.
citation: Neidich SD, Green WD, Rebeles J, Karlsson EA, Schultz-Cherry S, Noah TL, Chakladar S, Hudgens MG, Weir SS, Beck MA. Increased risk of influenza among vaccinated adults who are obese. Int J Obes (Lond). 2017 Sep;41(9):1324-1330. doi: 10.1038/ijo.2017.131. Epub 2017 Jun 6.
citation: Gardner CD, Trepanowski JF, Del Gobbo LC, Hauser ME, Rigdon J, Ioannidis JPA, Desai M, King AC. Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial. JAMA. 2018 Feb 20;319(7):667-679. doi: 10.1001/jama.2018.0245.
citation: Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I, Golan R, Fraser D, Bolotin A, Vardi H, Tangi-Rozental O, Zuk-Ramot R, Sarusi B, Brickner D, Schwartz Z, Sheiner E, Marko R, Katorza E, Thiery J, Fiedler GM, Bluher M, Stumvoll M, Stampfer MJ; Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008 Jul 17;359(3):229-41. doi: 10.1056/NEJMoa0708681.
citation: Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011 Feb;17(2):179-88. doi: 10.1038/nm.2279. Epub 2011 Jan 9.
citation: Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015 Mar;21(3):263-9. doi: 10.1038/nm.3804. Epub 2015 Feb 16.
citation: Ang QY, Alexander M, Newman JC, Tian Y, Cai J, Upadhyay V, Turnbaugh JA, Verdin E, Hall KD, Leibel RL, Ravussin E, Rosenbaum M, Patterson AD, Turnbaugh PJ. Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells. Cell. 2020 Jun 11;181(6):1263-1275.e16. doi: 10.1016/j.cell.2020.04.027. Epub 2020 May 20.
citation: Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, Suarez J, Michalsen A, Cross AH, Morgan TE, Wei M, Paul F, Bock M, Longo VD. A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep. 2016 Jun 7;15(10):2136-2146. doi: 10.1016/j.celrep.2016.05.009. Epub 2016 May 26.
citation: Yasuda K, Takeuchi Y, Hirota K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol. 2019 May;41(3):283-297. doi: 10.1007/s00281-019-00733-8. Epub 2019 Mar 19.
citation: Sukkar SG, Bassetti M. Induction of ketosis as a potential therapeutic option to limit hyperglycemia and prevent cytokine storm in COVID-19. Nutrition. 2020 Nov-Dec;79-80:110967. doi: 10.1016/j.nut.2020.110967. Epub 2020 Aug 10.
citation: Bradshaw PC, Seeds WA, Miller AC, Mahajan VR, Curtis WM. COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm. Oxid Med Cell Longev. 2020 Sep 9;2020:6401341. doi: 10.1155/2020/6401341. eCollection 2020.
citation: Ryu S, Shchukina I, Youm YH, Qing H, Hilliard BK, Dlugos T, Zhang X, Yasumoto Y, Booth CJ, Fernandez-Hernando C, Suarez Y, Khanna KM, Horvath TL, Dietrich MO, Artyomov MN, Wang A, Dixit VD. Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model. bioRxiv [Preprint]. 2020 Sep 12:2020.09.11.294363. doi: 10.1101/2020.09.11.294363.