Table 2.

Clinical trials evaluating the effects of nutraceuticals in COVID-19 and KD.

Compound	Population/ Disease	Treatment	Study Design	Results Intervention vs. Control	Ref.
Curcumin	40 adults COVID-19	I = nano-curcumin capsules—160 mg/day/2 weeks	Triple-blind, placebo-controlled, RCT	↓ Transcription factor that controls Th1 cytokine and INF-g on day 7	[122]
	48 adults COVID-19	I = nano-curcumin capsules—160 mg/day/6 days	Double-blind, placebo-controlled, RCT	↓ Milder symptoms	[123]
	46 outpatients (adults) COVID-19	I = capsules with 500 mg of curcumin + 5 mg piperine	Double-blind, placebo-controlled, RCT	↓ Weakness	[124]
Omega-3 fatty acids	Adults with COVID-19	I = hydroxychloroquine + 2 g of DHA + EPA for 2 weeks C = hydroxychloroquine	Single-blind, controlled, RCT	↓ Body pain, fatigue, appetite, ESR, CRP	[125]
	128 adults Severe COVID-19	I = one capsule of 1000 mg/14 days	Double-blind, RCT	↑ Survival rate and higher levels of arterial pH, HCO3 ↓ BUN, Cr, and K	[126]
Palmitoylethanolamine (PEA)	Unvaccinated adults recently infected with COVID-19	I = 1.2 g of PEA daily C = placebo tablets daily/4 week	Double-blind, RCT	↓ P-selectin, IL-1β, and IL-2 concentrations	[127]
Quercetin	152 COVID-19 outpatients	I = 400 mg/daily/30 days C = without quercetin	Controlled, open- label, RCT	↓ Frequency and length of hospitalization, need for non-invasive oxygen, progression to ICU, and deaths	[128]
	42 COVID-19 outpatients	I = first 7 days with 600 mg/daily, following 7 days with 400 mg/daily C = standard care	Controlled, open- label, RCT	↓ LDH, ferritin, CRP, and D-dimer	[129]
Vitamin A	I = 91 adults Ctrl = 91 adults Infected with COVID-19	I = 25,000 IU/d oral vitamin A/10 days C = hydroxychloroquine	Triple-blind controlled trial	↓ Fever, body ache, weakness and fatigue, paraclinical symptoms, WBC count, and CRP	[130]
Vitamin A, B, C, D and E	I = 30 adults Ctrl = 30 adults COVID-19	25,000 IU daily of vitamins A, 600,000 IU once during the study of D, 300 IU twice daily of E, 500 mg four times daily of C, and one amp daily of B complex for 7 days	Single-blinded, RCT	↓ ESR, CRP, IL-6, TNF-a, and hospitalization time	[131]
Vitamin C	I = 39 children with acute KD Ctrl = 17 healthy children	I = intravenous infusion of 100 mL of 0.9% saline containing 3 g of vitamin C over 10 min C = placebo (100 mL 0.9% saline)	Placebo-controlled, RCT	↑ Percent change in diameter of the brachial artery induced by reactive hyperemia in 19 patients with a history of KD	[121]
	I = 31 adults Ctr = 31 adults COVID-19	I = 500 mg of vitamin C daily/14 days	RCT	↑ Mean survival duration	[132]
	30 adults with severe COVID-19 infection	I = single oral dose of 500,000 IU C = placebo	Open-label, RCT	No effects	[133]
Vitamin D3	218 adults mild-to-moderate COVID-19	I = single oral dose of 500,000 IU Ctrl = placebo	Multicenter, double-blind, sequential, placebo-controlled, RCT.	No effects	[134]
	207 patients ≥65 years COVID-19	I = single oral dose 400,000 IU C = standard-dose 50,000 IU	Multicenter, open-label, RCT	↓ Overall mortality at day 14. The effect was no longer observed after 28 days	[135]
	151 adults with COVID-19 and vitamin D deficiency (serum < 25 nmol/L)	I = high-dose booster (≥280,000 IU) up to 7 weeks	Retrospective	↓ Risk of COVID-19 mortality	[136]
	200 adults With moderate to severe COVID-19	I = single oral dose 200,000 IU Ctrl = Placebo	Post hoc analysis of multicenter, double-blind, placebo-controlled, RCT	No effect in cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19	[137]
	240 adults mild-to-moderate COVID-1	I = single oral dose of 200,000 IU C = placebo	Multicenter, double-blind, placebo-controlled, RCT	No effects	[138]
	95 adults COVID-19	I = 50,000 IU per month, or 80,000 IU or 100,000 IU or 200,000 IU/2–3 months, n = 66), or daily supplementation with 800 IU (n = 1). C= without vitamin D supplements (n = 28)	Intervention study	↑ 3-month survival in older COVID-19 patients	[139]
	129 workers COVID-19	I = 50,000 IU/week for 2 weeks, followed by 5000 IU/day for the rest of the study C = 2000/day	Intervention study	Asymptomatic SARS-CoV-2	[140]
	129 adults COVID-19	I = 100,000 IU (50,000 IU at first day and eight days of hospitalization) C = without vitamin D3	Randomized, open-label, single-center study	↓ Time of hospitalization, CRP (at day 9) frequencies of CD38++CD27 transitional and CD27-CD38+ mature naive B cells ↑ Neutrophil and lymphocyte count and CD27-CD38-levels in DN B cells	[141]
	50 adults COVID-19	I = 25,000 IU/daily/4 days, followed by 25,000 IU/week/6 weeks C = placebo	Double-blind, placebo-controlled, RCT	↓ Hospital stay and need for supplemental oxygen	[142]
	86 adults COVID-19	I = 10,000 IU/day/14 days C = 2000 IU/day/14 days	Multicenter, single-blind, prospective, RCT	↑ Anti-inflammatory cytokine IL-10, levels of CD4+ T cells ↓ Hospital stays	[143]
	106 adults COVID-19 and circulating 25(OH)D3 concentration of <30 ng/mL	I = 25 μg daily (3000 to 6000 IU per day) up to 30 and 60 days C = placebo	Multicenter, double-blind, placebo-controlled, RCT.	Correct vitamin D deficiency/insufficiency in patients with COVID-19 ↑ Blood lymphocyte percentage	[144]
	69 adults Mild to moderated COVID-19	I = 5000 IU/day/14 days C = 1000 IU/day/14 days	Multicenter, RTC	↓ Time to recovery for cough and gustatory sensory loss among patients with suboptimal vitamin D status	[145]
	321 recruited subjects for preventive treatment of COVID-19	I = 4000 IU VD/daily/30 d C = placebo/daily/30 d	Double-blind, parallel, RTC	↓ The risk of acquiring SARS-CoV-2 ↑ Serum levels of 25-hydroxyvitamin D3, independently of vitamin D deficiency	[146]
	30 old patients’ recovery after COVID-19 infection	I = 2000 IU/day/for 6 weeks C = placebo	Pilot study, double-blind trial	↑ Serum creatine kinase levels returned to optimal values	[147]
Vitamin D3 magnesium and vitamin B12	73 adults with COVID-19 without oxygen support	I = 1000 IU/d + magnesium 150 mg/d + vitamin B12,500 mcg/d	Cohort study	↓ The proportion of patients with clinical deterioration requiring oxygen support, intensive care support, or both	[148]

Up arrows indicate an increase, or down arrows a decrease, in the specified characteristics of the intervention group when compared to the control group. Abbreviations: BUN = blood urea nitrogen; C = control or compared group; I = intervention; RTC, randomized controlled trial.