Dietary Supplements for COVID-19

Study Overview
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Brief Summary
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This is a double blind, placebo controlled, phase III randomized controlled trial evaluating the effects of the dietary supplements vitamin C, vitamin D, vitamin K, and zinc versus placebo on the overall health, symptom severity, and symptom duration of outpatients diagnosed with SARS-CoV-2.

Detailed Description
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This study proposed is a double-blind, placebo-controlled, phase III randomized controlled trial powered to detect meaningful differences in the overall health and symptom severity of people with COVID-19 between the treatment and control arms. Eligible participants will be randomly assigned, using a web randomization system, in a ratio of 1:1 to one of the following groups: (1) nutrient therapy with vitamin D, vitamin C, vitamin K2, and zinc or (2) placebo. Total trial duration will be 12 weeks. Nutrients or placebo will be given for a period of 21 days following enrolment and randomization. Total trial duration will be 12 weeks. Adverse events will be collected during the treatment phase plus one additional week (maximum 4 weeks). With respect to the primary outcome of participant-reported overall health, power calculations were conducted based on between-group differences at a single time point (21 days) and Cohen's guideline for a small effect size of 0.3. A sample size of 176 (88 per arm) provides 80% power to detect a difference at an α of 0.05. To account for an approximate 10-15% lost to follow-up we will enrol 200 participants (100 per arm).

Official Title
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Dietary Supplements to Reduce Symptom Severity and Duration in People With SARS-CoV-2: A Randomized, Double Blind, Placebo Controlled Clinical Trial

Conditions
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Covid19

Intervention / Treatment
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* Drug: Vitamin D3 50,000 IU
* Dietary Supplement: Vitamin C/Zinc
* Dietary Supplement: Vitamin K2/D
* Other: Microcrystalline Cellulose Capsule
* Other: Medium Chain Triglyceride Oil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥18) who test positive for SARS-CoV-2 in an outpatient setting Access to internet Exclusion Criteria: Symptom onset greater than 4 days prior to enrolment Supplementing regularly with >500 mg vitamin C, >1000 units vitamin D, >120 mcg vitamin K (any form), or >15 mg zinc taken daily within the past month Currently taking warfarin or an equivalent vitamin K antagonist anticoagulant End stage chronic kidney disease History of calcium oxalate kidney stones Active granulomatosis (sarcoidosis, tuberculosis, lymphoma) Known hypercalcemia or hypervitaminosis D Currently taking either of the following antibiotics: cephalexin, tetracyclines Participating in an investigational study or participation in an investigational study within the past 30 days Any reason which, under the discretion of the qualified investigator or delegate, would preclude the patient from participating.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Specific Product: Vitamin D3 50,000 IU Formulation: Capsule. Each capsule will contain 500 mg (50,000 units) cholecalciferol (vitamin D3) Dose: One capsule on day 1 of the intervention period Specific Product: Vitamin K2/D Formulation: Liquid. Each 0.0285 mL drop contains 30 mcg menaquinone-7 (MK-7, vitamin K2) and 3.125 mcg (125 units) cholecalciferol (vitamin D3). Dose: 0.114 mL (four drops) twice daily for 21 days totalling 240mcg MK-7 and 1,000 units cholecalciferol per day. Specific Product: Vitamin C/Zinc Formulation: Capsule. Each capsule will contain 666 mg ascorbic acid (vitamin C) and 8.3 mg of zinc acetate Dose: Three capsules three times daily for 21 days totalling 6 g ascorbic acid and 75 mg zinc acetate per day. | Drug: Vitamin D3 50,000 IU<br>* This is a loading dose of Vitamin D. Vitamin D (cholecalciferol [vitamin D3]) is a fat-soluble vitamin that is synthesized following ultraviolet radiation to the skin, naturally occurs in a few dietary sources and is available as a dietary supplement.<br>* Other names: Cholecalciferol;Dietary Supplement: Vitamin C/Zinc<br>* This is a combination of Vitamin C and Zinc. Vitamin C (ascorbic acid, ascorbate) is a water-soluble vitamin that naturally occurs in many foods and is sold as a dietary supplement. It is required for the functioning of several enzymes and is important for the immune system. Zinc is one of the most abundant essential trace elements in the human body and is required for the function of several hundred enzymes and transcription factors.<br>Dietary Supplement: Vitamin K2/D<br>* This is a combination of Vitamin K2 (menaquinone-7) and vitamin D. Vitamin K (menaquinone-7 [vitamin K2]) is a fat-soluble vitamin found in foods and sold as a dietary supplement. Vitamin K plays a large role in synthesizing coagulation factors in the blood, and vitamin K deficiency has been associated with uncontrolled bleeding. Vitamin K1 (phylloquinone) is an alternate form of vitamin K found in foods and supplements; however, vitamin K2 has a better absorption profile50 and additionally plays a role in bone metabolism controlling the binding of calcium, especially in older adults, where it attenuates the rate of bone loss<br>|
| Placebo Comparator: Control<br>Specific Product: Vitamin D3 50,000 IU Placebo Equivalent: microcrystalline cellulose capsule, 350 mg Specific Product: Vitamin K2/D Placebo Equivalent: Medium chain triglyceride oil Specific Product: Vitamin C/Zinc Placebo Equivalent: microcrystalline cellulose capsule, 350 mg | Other: Microcrystalline Cellulose Capsule<br>* Placebo equivalent of Vitamin C/Zinc and Vitamin D3.<br>Other: Medium Chain Triglyceride Oil<br>* Placebo equivalent of Vitamin K2/D<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant-reported overall health | Measured using the EuroQol Visual Assessment Scale (EQ-VAS). Scores each day range from 0 (worst health imaginable) and 100 (best health imaginable). | During the intervention period (Daily for 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of COVID-19 on the health status of participants | Measured using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire. Scores are converted into a unique health state. Health states are converted to an index value between 0 and 1, where 1 is considered the best possible health. | Baseline plus weeks 1, 2, 3, 4, 8, and 12 | 
| Symptom Severity of common COVID-19 symptoms | Measured using an internally-developed questionnaire. Includes fever, cough, shortness of breath, fatigue, headache, myalgia/arthralgia, nausea, vomiting, diarrhea, congestion, loss of taste, and loss of smell. Scores range from 0-3 for each symptom, totaling 0-42 for each day. 0 = no symptom, 1 = mild symptom, 2 = moderate symptom, 3 = severe symptom. | During the intervention period (Daily for 21 days) | 
| Total symptom duration | Measured as the time to a complete reduction of symptoms with no relapses (i.e., a 0 in all categories on the symptom questionnaire). | During the intervention period (21 days) | 
| Incidence of delayed return to usual health | Measured by the number of people experiencing ongoing symptomatic COVID-19 (symptoms persisting between 4 and 12 weeks) and the number of people experiencing post-COVID-19 syndrome (symptoms persisting longer than 12 weeks) | 12 weeks | 
| Frequency of Hospitalizations | Includes ER visits, acute care admissions, and ICU admissions | 12 weeks | 
| Hospital Length of Stay | Number of days in acute care or ICU | 12 weeks | 
| All-cause mortality |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHP, Natural Health Products, Dietary Supplements, Vitamin C, Vitamin D, Vitamin K, Zinc, COVID-19, SARS-CoV-2