Clinical trial NCT04780061
Conditions: Covid19
Keywords: Natural Health Products NHP Dietary Supplements Vitamin C Vitamin D Vitamin K Zinc COVID-19 SARS-CoV-2
Sponsor: The Canadian College of Naturopathic Medicine
Start date: 2021-07-12; Completion date: 2022-07-07
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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).

Arms: arm 1: 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. arm 2: 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
Interventions: intervention 1: Vitamin D3 50,000 IU intervention 2: Vitamin C/Zinc intervention 3: Vitamin K2/D intervention 4: Microcrystalline Cellulose Capsule intervention 5: Medium Chain Triglyceride Oil
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: 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 intervention 4: Placebo equivalent of Vitamin C/Zinc and Vitamin D3. intervention 5: Placebo equivalent of Vitamin K2/D

Protocol documents:
Prot_SAP_000.pdf: 
Dietary supplements for COVID-19 
Version Date: September 3rd, 2021 
 
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Dietary supplements to Reduce Symptom Severity and Duration for people with 
SARS-CoV-2: A Randomized, Double-Blind, Placebo-Controlled Trial 
 
 
Protocol ID: 20210072-01H 
Supported By: The Ottawa Integrative Cancer Centre Foundation 
Sponsored By: The Ottawa Hospital Research Institute 
 
Principal Investigator: 
Dugald Seely, ND, MSc 
Founder & CEO, Centre for Health Innovation  
Executive Director of Research, Canadian College of Naturopathic Medicine 
Affiliate Investigator, Ottawa Hospital Research Institute 
Associate Professor, University of Ottawa 
 
 
Qualified Investigator: 
Kumanan Wilson, MD, MSc, FRCPC 
Internal Medicine, The Ottawa Hospital 
Scientist, Ottawa Hospital Research Institute 
 
 
Original Protocol: 2021-01-29 
Amendment 1: 2021-04-16 
Amendment 2: 2021-05-04 
Amendment 3: 2021-09-03 
 
 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Investigator’s Agreement: 
I confirm that I have reviewed and agree to the conditions delegated to me relating to the above-
mentioned protocol.  I acknowledge that I have read the protocol entitled ‘Dietary Supplements to Reduce 
Symptom Severity and Duration for people with SARS-CoV-2: A Randomized, Double Blind, Placebo-
Controlled Trial‘ (version date 2021-05-04) and agree to carry out its terms in accordance with the 
approved protocol, Part 4 of the Natural Health Products Regulations, Part C Division 5 of the Food and 
Drug Regulations and to follow ICH GCP guidelines for good clinical practice.  
 
 
_______________________ 
________________________________     __________________ 
Signature 
 
 
Qualified Investigator (please print)   
    Date 
 
_______________________ 
________________________________     __________________ 
Signature 
 
 
Principal Investigator (please print)   
    Date 
 
 
 
 
 
 
 
 
 


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Study Co-Investigators: 
Ellen Conte, ND 
Research Associate, Centre for Health Innovation & Canadian College of Naturopathic Medicine 
 
Mark Legacy, BSc 
Clinical Research Assistant III, Centre for Health Innovation & Ottawa Hospital Research Institute 
 
Athanasios Psihogios, ND 
 
Research Assistant, Centre for Health Innovation & Canadian College of Naturopathic Medicine 
 
Dean Fergusson, PhD 
 
Senior Scientist & Director, ClinEpi Program, Ottawa Hospital Research Institute 
 
Associate Professor, Departments of Medicine, Surgery, Epidemiology, and Community   
 
Medicine, University of Ottawa 
 
Tim Ramsay, PhD 
 
Scientific Director, Ottawa Methods Centre 
 
Scientist, Ottawa Hospital Research Institute 
 
Salmaan Kanji, BSc, PharmD 
 
Associate Scientist, ClinEpi Program, Ottawa Hospital Research Institute 
 
Clinical Pharmacy Specialist, Critical Care, The Ottawa Hospital 
 
John-Graydon Simmons, MD 
 
Resident, General Medicine, The Ottawa Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Correspondence: 
Centre for Health Innovation 
Dugald Seely, ND, MSc 
429 MacLaren Street, Ottawa ON K2P 0M7 
613-792-1222 ext. 2 
dseely@thechi.ca  
 
 
Ottawa Hospital Research Institute 
Kumanan Wilson, MD, MSc, FRCPC 
1053 Carling Avenue, Ottawa, ON K1Y 4E9 
613-737-8899 ext. 17921 
kwilson@toh.ca  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
1. Background…………………………………………………………..…………………………………………….................. 
6 
2. Objectives and Hypotheses………………….…………………………………………………………………………….. 
7 
2.1 Objectives………………………………………………………………………………………………………………………….. 
7 
2.2 Hypothesis……………………………………………………………………………………….................................. 
7 
3. Methods……………………………………………………………………………………………………………………………. 
8 
3.1 Study Design……………………………………………………………………………………………………………………. 
8 
3.2 Participants……………………………………………………….................................................................. 
8 
3.3 Inclusion/Exclusion Criteria………….………………………………………………………………………………….. 
8 
3.4 Interventions……………………………………………………………………………………………………………………… 
9 
3.5 Manufacturing & Distribution of Product……………………………………….................................... 
11 
3.6 Concomitant Medications and Stopping Rules…………………………………………………………………. 
12 
3.7 Outcome Measurements & Timeline ………………………………………………………………………………. 
12 
4. Study Conduct…………………………………………………………………………………………………………………… 
16 
4.1 Ethical Considerations & Study Oversight………………………………………………………………………… 
16 
4.2 Quality Control & Quality Assurance………………………………………………………………………………… 
16 
4.3 Screening & Recruitment…………………………………………………………………………………………………. 
17 
4.4 Informed Consent……………………………………………………………………………………………………………. 
18 
4.5 Randomization, Blinding, and Control……………………………………………………………………………… 
19 
4.6 Setting……………………………………………………………………………………………………………………………….. 
19 
5. Sample Size Determination & Power Calculation………………………………………………………………. 
19 
6. Data Collection, Analysis, and Management …………………………………………………………………….. 
20 
6.1 Data Collection…………………………………………………………………………………………………………………. 
20 
6.2 Data Analysis……………………………….………………………………………………………………………………….. 
20 
6.3 Data Management and Monitoring…………………………………………………………………………………… 
21 
7. Adverse Events and Safety ……………………………………………………………………………………………….. 
22 
7.1 Definitions………………………………………………………………………………………………………………………… 
22 
7.2 Collection and Reporting…………………………………………………………………………………………………… 
22 
7.3 Expected Adverse Events…………………………………………………………………………………………………… 
23 
8. Privacy and Confidentiality………………………………………………………………………………………………… 
24 
9. Dissemination and Knowledge Transfer……………………………………………………………………………… 
24 
10. Relevance and Impact………………………………………………………………………………………………………. 
24 
11. References………………………………………………………………………………………………………………………… 
26 
 
 
 


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1. Background  
 
Coronavirus Disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), has caused hospitalizations and deaths worldwide.1  COVID-19 causes mild 
to moderate flu-like symptoms in most people, but can cause severe disease including pneumonia, acute 
respiratory distress syndrome (ARDS), multi-organ failure, and death in high-risk individuals. As of January 
2020, over 98 million people have been diagnosed with COVID-19, 2.1 million deaths have occurred, and 
numbers continue to rise.1,2   
 
There are currently two vaccines approved for COVID-19 in Canada.3,4 Despite this, effective treatments 
are still needed for COVID-19. It is anticipated to take approximately one year for Canadians to be 
vaccinated,5 the long-term efficacy of the approved vaccines are not yet known as median follow-up for 
both vaccine trials was around two months6, the vaccines are not 100% effective,6 and there are 
challenges to herd immunity as not everyone will be immunized due to underlying conditions preventing 
effective immunity and vaccine hesitancy.7 Thus, there is an ongoing need for effective COVID-19 
treatments. Treatments for COVID-19 are currently limited. In Canada, the only approved treatment is 
Remdesivir,8 which is indicated for COVID-19 positive patients with pneumonia needing supplemental 
oxygen; however, results from studies of Remdesivir have been mixed.9,10 The main treatment for most 
hospitalized patients is supportive care including supplemental oxygen.11 To date, there are no approved 
treatments for non-hospitalized patients diagnosed with COVID-19. The majority of research on 
treatments for COVID-19 has focused on hospitalized patients, while community research, aside from 
vaccines, is largely observational. 
 
 
The use of natural health products (NHPs), including vitamins, minerals, and herbs, to treat COVID-19 
infections has received attention in both the academic community and the public.12,13 Various NHPs have 
undergone observational and clinical research for a wide variety of other upper respiratory tract infections 
(URTIs). These trials mainly focus on the treatment of URTI symptoms, including reducing their duration 
and severity. Some of the most heavily researched NHPs include andrographis,14,15 quercetin,16 vitamin 
C,17-19 vitamin D,20-22 and zinc,23 each with varying effectiveness. Naturally, these NHPs present candidates 
for the treatment of symptoms associated with COVID-19. While there has been observational evidence 
to support some NHPs for the treatment of COVID-19, such as vitamin D24,25 and vitamin K26, currently 
there are no published double-blind, placebo-controlled, randomized clinical trials studying NHPs and 
COVID-19 symptoms. Based on the above studies for COVID-19 and other similar URTIs, the nutrients 
vitamin C, vitamin D, vitamin K2, and zinc stand out as the most promising NHPs for the treatment of 
symptoms caused by COVID-19. 
 
This project is timely as several other organizations and researchers are looking into these and other NHPs 
for COVID-related treatments.27-32 With no proven treatments available for managing COVID-19 
symptoms in the community, the burden on the healthcare system remains high. If a collective positive 
result is seen, these NHPs could provide an inexpensive, safe treatment for COVID-19 symptoms in the 


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community and decrease the burden on the healthcare system through reduced hospitalizations and 
decreased length of stay while in hospital.  
 
2. Objectives and Hypotheses 
 
2.1. Objectives 
 
The overarching goal of the project is to determine if supplementation with dietary nutrients (specifically 
vitamin D, vitamin C, vitamin K2, and zinc) improves overall health by decreasing symptom severity and 
duration for outpatients diagnosed with SARS-CoV-2.  
  
2.1.1. Primary Objective 
 
The primary objective will be the difference in participant-reported overall health in each arm. 
  
2.1.2. Secondary Objectives 
 
Secondary objectives include: 
 
1. Effect of COVID-19 on the health status of participants 
2. Symptom severity of COVID-19 symptoms, including: fever, cough, shortness of breath, fatigue, 
headache, myalgia/arthralgia (body aches), nausea, vomiting, diarrhea, shakes/chills, congestion, and 
loss of taste and smell 
3. Total symptom duration  
4. Incidence of delayed return to usual health   
5. Frequency of hospitalizations, including: ER visits, acute care admissions, and ICU admissions 
6. Hospital length of stay 
7. All-cause mortality 
 
2.2. Hypothesis 
 
We hypothesize that supplementation with vitamin D, vitamin C, vitamin K2, and zinc will increase 
participant-reported overall health and health status in outpatients diagnosed with SARS-CoV-2 compared 
to a placebo. We also hypothesize the intervention will reduce the severity and duration of common 
COVID-19 symptoms experienced in a community setting.  
 
 
 
 
 


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3. Methods 
 
3.1. Study Design 
 
This study 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. The length of the intervention period (21 
days) encompasses the most common period within which recovery occurs. The median duration of time 
to symptom resolution is 4-8 days from testing and yet a substantial number of people (26-47%) do not 
return to their usual state of health within 14-21 days.33 Available guideline recommendations support a 
prolonged follow up period in order to assess patients experiencing ongoing symptomatic COVID-19 (signs 
and symptoms for 4-12 weeks) and those with post-COVID-19 syndrome (signs and symptoms >12 
weeks).34  
 
3.2. Participants 
 
Potential participants will be identified by clinical nursing staff at The Ottawa Hospital (TOH) who are 
responsible for contacting anyone who tests positive for COVID-19 at a testing centre associated with 
TOH. Specific screening and recruitment procedures are described in section 4.3. 
 
3.3. Inclusion/Exclusion Criteria 
 
3.3.1. Inclusion criteria:  
 
1. Adults (≥18) who test positive for SARS-CoV-2 by reverse transcriptase polymerase chain reaction 
(RT-PCR) in an outpatient setting 
2. Access to internet 
 
3.3.2. Exclusion criteria 
 
1. Symptom onset greater than 7 days prior to enrolment 
2. 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 
3. Currently taking warfarin or an equivalent vitamin K antagonist anticoagulant 
4. End stage chronic kidney disease 
5. History of calcium oxalate kidney stones 
6. Active granulomatosis (sarcoidosis, tuberculosis, lymphoma) 
7. Known hypercalcemia or hypervitaminosis D 


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8. Currently taking either of the following antibiotics: cephalexin, tetracyclines 
9. Known allergy to any investigational product, silicon dioxide, cellulose, or medium chain triglyceride 
oil 
10. Participating in an investigational study or participation in an investigational study within the past 30 
days 
11. Any reason which, under the discretion of the qualified investigator or delegate, would preclude the 
patient from participating. 
 
3.4. Interventions  
 
The interventions for this study will consist of dietary supplements for participants in the treatment arm 
and a placebo for those in the control arm. Three vitamins and one mineral will be included in the 
intervention for those in the treatment arm – vitamin D3, vitamin C, vitamin K2, and zinc. Upon enrolment 
and randomization, participants will be provided either dietary supplements or placebo by the study staff. 
Study interventions are to be started as soon as possible after enrolment and randomization and will 
continue for 21 days. Participants will be responsible for taking their doses and will be required to return 
all unused study product to the CHI or their local pharmacy to be properly destroyed. Phone calls will be 
made to participants at weeks 1, 2, 3, and 4 post-enrolment to check in and inquire about compliance and 
potential side effects.  
 
All pill bottles will bear labels that comply with Health Canada Regulations. These labels will be in both 
official languages and contain the expiry date, storage conditions, lot number and the name and address 
of the manufacturer. An additional statement will be added to each label indicating that it is an 
investigational product to be used only by a qualified investigator, the trial’s sponsor name and address, 
and protocol code. All study products will be packaged in sealed bottles. Participants will be instructed to 
store all products as indicated on the product label in a location that is out of reach of children and not to 
use if the seal is broken. Product accountability records will be maintained to track dispensation, returns 
and destruction of the study product, and will be maintained by the study staff at the Centre for Health 
Innovation (CHI). Product inventory will be stored as indicated on the label with daily temperature 
monitoring.    
Information regarding all investigational products, including dosing, timing, absolute contraindications 
and rationale for use, is summarized below and in section 3.5.  
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. Cholecalciferol is the most used supplemental form of vitamin D and is the proposed form 
for this study. The importance of vitamin D for bone and dental health and for absorption of calcium and 
phosphorus are well recognized. Moderate doses of Vitamin D have been shown to reduce the duration 
and severity of upper respiratory tract infections,22 whereas low doses showed no effect,22 and 
preliminary reports show Vitamin D levels and vitamin D supplementation may reduce COVID-19 disease 
severity and progression.25,35-39 Given only 68% of Canadians have a vitamin D level of >50 nmol/L on 


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average,40 a loading dose is necessary to quickly elevate levels in the average Canadian to sufficiency (≥75 
nmol/L) and a maintenance dose is necessary to maintain these levels for the duration of the trial. 
Vitamin C: 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. Reductions in ascorbate levels in people with infections, the common 
cold, and pneumonia have been observed and may be due to increases in reactive oxidation species during 
the immune response.18 A review of clinical trials and predictive models indicated that doses ≥ 6g per day 
may be effective in reversing this decline and reducing common cold symptom severity and duration 
compared to controls.18,19,41 In 18 ICU patients with COVID-19 meeting ARDS criteria, 94.4% had 
undetectable vitamin C levels and 5.6% had low levels (2.4 mg/L), indicating an acute situational deficiency 
due to SARS-CoV-2 infection.42 A dose schedule of 2g three times daily will be used in an effort to maximize 
absorption as absorption decreases as the dose increases.43 
 
Zinc: 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. Zinc has long been studied in people with 
the common cold for the reduction of symptom severity and duration with proposed mechanisms include 
inhibiting binding of the rhinovirus in the nasal mucosa,44 inhibiting proteolysis during the rhinovirus cell 
cycle,45 and inhibiting rhinovirus replication.46 Reviews of zinc administration for common cold symptoms 
show doses ≥ 75mg per day outperform doses below that threshold,23,47 indicating a clear target dose. Of 
the available forms, zinc acetate has seen the largest reduction in the common cold compared to other 
salts48 and will be the formulation used in this study. Whereas many common cold studies administer zinc 
in a lozenge form due to is local effects in the nasal cavity, rhinorrhea is less common in patients with 
SARS-CoV-2.49 Based on this and the difficulty of creating a placebo lozenge, capsule form is likely not 
disadvantageous and the most feasible formulation for application. 
 
Vitamin K2: 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. Vitamin K2 has also been implicated in the risk of 
cardiovascular disease and type-2 diabetes, which are common among people with severe COVID-19. 
Menaquinone-7 (MK-7) may confer protection for pulmonary elastic fibers against calcification through 
MK-7-dependent matrix Gla protein activity.51 Coagulopathy coupled with reduced vitamin K status has 
been seen in patients with severe COVID-19 and correlates with decreased survival,26,52,53 thus our goal 
will be to achieve and maintain sufficient levels to correct deficiencies that may be associated with poorer 
outcomes. While the recommended daily allowance (RDA) is 90-120 micrograms,54 240 micrograms will 
be administered in order to ensure the majority of participants, with a range of vitamin K statuses, achieve 
sufficiency within the short period of time. Doses of up to 360 micrograms of MK-7 for 12 weeks have 
been found to be well tolerated and safe,55 with predominantly extrahepatic effects.51 Although other 
forms of vitamin K2 can be used, such as menaquinone-4, MK-7 was chosen as it has superior 


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bioavailability and clinical efficacy to this and other forms of vitamin K2.54,56-58 Vitamin K is contraindicated 
with vitamin K antagonist anticoagulants, such as Warfarin. Although anticoagulant therapy is common 
among hospitalized patients with COVID-19, TOH administers low molecular weight heparins or heparin 
as anticoagulants; thus, there is no potential for any interactions. Vitamin K2 additionally has a strong 
safety profile; a review of recent literature found there were no adverse effects related to blood 
coagulation for people taking MK-7 at doses up to 6 mcg/kg/day in adults.55 
 
3.5. Manufacturing & Distribution of Product 
 
Investigational products (including active treatments and placebo) for this study will be manufactured and 
distributed to participants by Vitazan Herbs and Supplements Inc. Specific formulations of each study 
product are outlined below. 
 
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 
Placebo Equivalent: microcrystalline cellulose capsule, 350 mg 
Absolute Contraindications: history of hypervitaminosis D, hypercalcemia or sarcoidosis 
 
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. 
Placebo Equivalent: Medium chain triglyceride oil 
Absolute Contraindications: history of hypervitaminosis D, hypercalcemia or sarcoidosis; warfarin or 
another vitamin K antagonist anticoagulant 
 
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. 
Placebo Equivalent: microcrystalline cellulose capsule, 350 mg 


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Absolute Contraindications: calcium oxalate kidney stones, end stage chronic kidney disease, cephalexin, 
tetracycline antibiotics  
 
3.6. Concomitant Medications & Stopping Rules 
 
All concomitant medications and natural health products from enrolment to end of study (3 months) will 
be recorded. All information will be participant-reported. Absolute contraindications are outlined in the 
exclusion criteria and in section 3.5. Should a participant be placed on one of these medications or be 
diagnosed with one of the conditions, they will stop taking the study product. Participants may also be 
instructed to either temporarily or permanently discontinue the intervention if the participant does not 
tolerate the intervention at the discretion of study doctor or treating doctor. There are no required rescue 
medications for this study.  
 
3.6.1. Standard of Care and Hospitalizations 
 
Currently, no standard of care treatments exist for patients in the community diagnosed with COVID-19. 
The study team will not provide specific medical advice for participants regarding the severity of their 
COVID-19 symptoms aside from what is recommended by Ottawa Public Health. Study staff will follow 
public health guidelines and give the following procedure to participants: 
 
“If you have any questions about COVID-19, please speak with your family doctor or contact Ottawa Public 
Health at 613-580-6744. If you are in distress (significant trouble breathing, chest pain, fainting, or have a 
significant worsening of any chronic disease symptom), please go to the nearest emergency department 
or call 911.” 
 
Participants who are hospitalized during the study will stop all study activities (i.e., treatments, 
questionnaires, and phone calls) and follow all recommendations given by the hospital, including 
treatments given post-discharge. Standard of care treatments at the hospital for COVID-19 will be the 
responsibility of the treating physician. If a participant receives treatments while at home, these standard 
of care treatments will not be withheld in any case and always supersede study interventions if there is a 
concern for potential interaction or side effect with the concomitant treatment. Participants will be 
instructed to resume study activities once they return home as tolerated. The incidence of hospitalization 
will be tracked using The Ottawa Hospital’s electronic medical record (EPIC) through notifications sent to 
the trial coordinator. Information regarding hospitalizations is also collected during phone follow-ups.  
 
3.7. Outcome Measurements & Timeline 
 
Participant-Reported Overall Health: measured using the EuroQol visual analogue scale (EQ-VAS).59 The 
EQ-VAS records the respondent’s overall current health on a vertical scale between 0 and 100, where the 
end points are labelled “the best health you can imagine” (i.e., a score of 100) and “the worst health you 


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can imagine” (i.e., a score of 0). The EQ-VAS will be filled out each day while on the intervention (21 days 
total). 
 
Health Status: Measured by combining one level from each of the five dimensions of the EuroQol 5-
dimension 5-level (EQ-5D-5L) questionnaire59 (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) to form a unique health state. Each dimension is divided into five levels of perceived 
problems: 1 – no problem, 2 – slight problems, 3 – moderate problems, 4 – severe problems, and 5 – 
unable to perform/extreme problems. The EQ-5D-5L questionnaire will be filled in at baseline (i.e., before 
starting the intervention) and weeks 1, 2, 3, 4, 8, and 12.  
 
Symptom Severity & Duration: Measured using an internally-developed questionnaire specific for the 
most common COVID-19 symptoms, which include: fever, cough, shortness of breath, fatigue, headache, 
myalgia/arthralgia (body aches), nausea, vomiting, diarrhea, chills, altered taste, altered smell, and nasal 
congestion.11,60 Each symptom will be rated based on severity with a 4 point scale (0-3): 0-none, 1-slight, 
2-moderate, and 3-severe. Participants will fill in this questionnaire each day while receiving treatment 
(i.e., for 21 days). 
 
The questionnaire is largely based on recommendations from the US Food and Drug Administration (FDA) 
guidance document for investigators conducting community clinical trials for COVID-19 prevention or 
treatment.61 The symptoms were selected based on the most commonly reported COVID-19 symptoms in 
both the hospital and community setting.11,60 Some of the same symptoms are also included in the 
questionnaire being used in a study of vitamin C and zinc (COVIDAtoZ) at the Cleveland clinic, potentially 
allowing for comparison of results.29   
Incidence of delayed return to usual health: Measured through follow-up calls with participants after the 
treatment period has ended. Participants will be contacted at weeks 4, 8, and 12 to assess this. The 
incidence of delayed return to usual health will be defined as the presence of any symptoms related to 
COVID-19 at the time of these calls as reported by the participant. Those experiencing prolonged COVID-
19 symptoms lasting 4-12 weeks will be classified as experiencing “ongoing symptomatic COVID-19,” while 
those still afflicted at 12 weeks will be classified as having “post-COVID-19-syndrome.”62 
Hospitalization: the rate and type of hospitalization, as well as the length of stay, will be collected from 
participant medical records where possible and will otherwise be self-reported. Information will be 
collected throughout the 12-week study period. 
All-Cause Mortality: date of death will be collected through medical records and obituary searches when 
medical records are not available.  Information will be collected throughout the 12-week study period. 
3.7.1. Phone Calls 
 
Follow-up calls will take place during weeks 1, 2, 3, 4, 8, and 12 to assess for outcomes, compliance, and 
as a general check-in with participants. Intervals will be based on the date of enrolment. Calls will be 
permitted to occur within 3 days of the interval date for weeks 1, 2, 3, & 4 and within 7 days for weeks 8 
and 12.  


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3.7.2. Measurement of Fever 
 
Temperatures will be taken by the participant using a digital oral thermometer provided by the research 
staff. Participants will be instructed to wait 30 minutes after consumption of any fluids before taking their 
temperature. Consumption of fluids, especially cold,63 can alter oral temperature readings by clinically 
meaningful amounts for up to 30 minutes,63,64 which, if unaddressed, may lead to measurement errors.  


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Table 1: Schedule of Events 
 
Time of Assessment 
Screening 
(pre-enrolment) 
Baseline 
(Prior to 
intervention) 
Days 
1-6 
Day 7 
Days 
8-13 
Day 14 
Days 
15-20 
Day 21 
Week 
4 
Week 
8 
Week 
12 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
Medical History & Current 
Medications 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
Study Intervention 
 
 
 
 
 
 
 
 
 
 
 
EQ-VAS 
 
 
 
 
 
 
 
 
 
 
 
Symptom Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
Phone Call Follow-Up 
• 
Concomitant Medications 
• 
Adverse Events 
• 
Hospitalizations 
• 
Delayed return to usual 
health 
 
 
 
 
 
 
 
 
 
 
 
EQ-VAS: EuroQol Visual Assessment Scale; EQ-5D-5L: EuroQol 5-Dimension 5-Level. EQ-VAS and symptom questionnaires must be filled in on the appropriate days. A 3-day window 
will be allowed for EQ-5D-5L completion and phone call follow-up for the first 4 weeks. The window will increase to 5 days for weeks 8 and 12. Compliance to the intervention will 
be participant-reported and take place on day 21 or week 4.   
 
 


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Table 2: Outcome Assessment Methods 
Objective 
Assessment Method 
Participant-reported health  
EQ-VAS 
Health Status 
EQ-5D-5L 
Symptom severity & duration of COVID-
19 symptoms 
Internally developed 
questionnaire 
Incidence of delayed return to usual 
health 
Call with participants  
Incidence of Hospitalizations, including 
ER, acute care, and ICU admissions. 
 
Length of Stay 
Data will be gathered through 
medical records and through 
calls with the participant 
Incidence of Mortality 
Data will be gathered through 
medical records or through 
obituary searches if medical 
records are not available 
 
4. Study Conduct 
 
4.1. Ethical Considerations & Study Oversight 
 
Ethical approval for this study will be sought from Research Ethics Boards (REBs) of the Ottawa Health 
Sciences Network (OHSN) and Canadian College of Naturopathic Medicine (CCNM). Renewals will be 
submitted and approved annually by each REB. The protocol, informed consent form, recruitment 
materials, and all participant materials will receive approval from both REBs prior to any participant being 
enrolled. This trial will also be submitted to both the Natural and Non-Prescription Health Products 
Directorate (NNHPD) and Therapeutic Products Directorate (TPD) of Health Canada. The trial will be 
registered on clinicaltrials.gov and updated regularly as per ethical requirements. The trial can be found 
by searching the NCT number NCT04780061  
This study will be conducted according to the Canadian and international standards of Good Clinical 
Practice (GCP), the Health Canada Food and Drug Act, Part C, Division 5, Drugs for Clinical Trials Involving 
Human Subjects and Part 4 of Health Canada’s Natural and Non-Prescription Health Product Regulations 
for Clinical Trials. 
4.2. Quality Control and Quality Assurance 
 
4.2.1. Monitoring 
 
The trial will have a quality control monitoring process in place to verify that all data are accurate and 
complete. Site investigators will permit trial-related monitoring, audits and regulatory inspections, and 
direct access to source data/documents. The monitor will generate a site monitoring report for the site 


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investigator to detail significant findings, deviations, deficiencies, plausibility, record completeness and 
any corrective actions to be taken. Full information can be found in the monitoring plan document. 
4.2.2. Standard Operating Procedures (SOPs) 
 
The Ottawa Hospital Research Institute (OHRI) and the Centre for Health Innovation (CHI) will follow their 
individual institutional SOPs. A Procedures Manual, as well as study-specific SOPs, will be developed for 
study-specific procedures. These documents will be used to facilitate study conduct and training.  
4.2.3. Adherence to the Protocol 
 
4.2.3.1. Protocol Amendments 
 
All amendments to this protocol will be reviewed by both REBs and submitted to the NNHPD and the TPD 
as either a notification or Clinical Trial Application Amendment (CTA-A). Both the principal investigator 
and qualified investigator will sign the approved protocol prior to implementation, and each investigator 
and member of the research team will be adequately trained prior to carrying out and study-specific tasks 
after the approval of the amendment. 
4.2.3.2. Protocol Deviations 
 
No deviations from this protocol will be permitted without the prior written approval of the Sponsor, 
except when the modification is needed to eliminate an immediate hazard or hazards to participants. Any 
deviations that may affect a participant’s treatment or informed consent, especially those increasing 
potential risks, will receive prior approval from the REB unless performed to remove an immediate safety 
risk to the participants. In this case they will be reported to the REB immediately thereafter. Any 
departures from the protocol will be documented in the participant’s file. 
 
4.3. Screening and Recruitment 
 
4.3.1. Screening by Clinical Staff 
 
Clinical screening will be facilitated by a clinical team at TOH under the direction of Melissa Brett, Manager 
of Patient Safety and Clinical Quality at TOH. Nurses from this team, who are not part of the research 
team, are responsible for contacting any person who tests positive for COVID-19 at a test centre 
associated with TOH who does not have access to MyChart or has access but has not reviewed their result 
in a timely manner. The clinical team will have knowledge if the potential participant is OK to be contacted 
for research through EPIC (The Ottawa Hospital’s electronic medical record system) or will ask this 
question if no information is entered in EPIC. Nursing staff will notify the trial coordinator of all potentially 
eligible and interested patients through EPIC. Study staff at the CHI will then contact each patient by 
phone and further determine their eligibility for the study. If a patient is interested and eligible, they will 


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be taken through the informed consent process and sign an electronic informed consent form using Adobe 
Sign.  
 
4.3.2. Screening by Research Staff 
 
Research screening will be done in partnership with The Ottawa Hospital’s COVID-19 data warehouse 
team under the direction of Deanna Rothwell. The data warehouse will generate a list of all patients who 
test positive for COVID-19 at a test centre associated with TOH. This list will be sent to the research team 
daily and will function as the equivalent to a clinic’s daily appointment list. Research staff will conduct 
individual chart review to determine if the patient has consent to contact enabled in EPIC, whether they 
have MyChart enabled, and whether they have reviewed their result. If the patient is marked as “OK to 
contact,” has MyChart enabled and has viewed their result, the research team will contact them about 
the study. If the patient is interested and eligible, they will be taken through the informed consent process 
and sign an electronic informed consent form using Adobe Sign.  
 
4.3.3. Community Outreach  
 
Recruitment posters will be put up virtually using the Centre for Health Innovation’s website, 
newsletter, Facebook, LinkedIn, and Instagram. This is an effort to reach patients who have received a 
positive diagnosis at test centres not associated with TOH.  
 
4.3.4. Consent to Contact via e-mail 
 
Verbal consent will be obtained prior to sending any study materials, including the consent form, or 
communicating in any way by e-mail. The risks of using e-mail will be discussed with the potential study 
participant using the template provided by the OHRI. Participants may decline consent to contact via e-
mail and receive the consent form and study materials by mail; however, they must comply with the study 
inclusion criteria to return a signed consent form within 4 days of the onset of their first symptoms.  
 
4.4. Informed Consent 
 
All participants for this study will be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. Each 
participant will have sufficient opportunity to discuss the study, have all their questions addressed and 
consider the information in the consent process prior to agreeing to participate. Participants may 
withdraw consent at any time during the study. This consent form will be signed and dated by the 
participant, and the investigator and/or designated research professional obtaining the consent. The 
original signed informed consent form will be retained in the participant’s study files and a copy will be 
provided to the participant.  
 
 


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4.5. Randomization, Blinding, and Control 
 
Participants will be randomized in a 1:1 ratio using a web-based tool provided and maintained by an 
independent statistician at the Ottawa Methods Centre. Randomization will be based on mixed block sizes 
of 4 and 6 to ensure adequate balance at all stages of recruitment.  
 
All products will have an equivalent placebo such that each product and pill bottle are both 
indistinguishable from the treatment, except for the lot number, which will allow Vitazan to distinguish 
between treatment and placebo. Study participants and research staff will remain blinded for the duration 
of the study until recruitment is finished and all analyses are completed. The Data Safety and Monitoring 
Board (DSMB) may request that participants be unblinded if they are concerned about participant safety 
(e.g., due to the distribution of adverse events). In this case, the PI and QI will be notified of the unblinding 
and this will be documented and stored in the study binder.  
 
Compliance to the study protocol will be participant-reported during the weekly calls by the research staff. 
Participants will be instructed to return all partially used and unused investigational products to the CHI 
or their local pharmacy for destruction. All efforts will be made to ensure participants start the study 
product as soon as possible after enrolment and randomization. Days from symptom onset to starting the 
study product will be monitored and compared between arms to ensure consistency. 
 
4.6. Setting 
 
This study will take place in Ottawa and will involve personnel from the Centre for Health Innovation and 
The Ottawa Hospital & Ottawa Hospital Research Institute. Day-to-day study activities, including screening 
& recruitment, outcome collection & follow-up, and product dispensing & tracking, will be managed by 
study staff at the CHI under the supervision of the principal investigator. The principal investigator will 
communicate regularly with the qualified investigator and other members of the research team to ensure 
proper trial conduct. Study interventions will be taken at home by study participants.  
 
5. Sample Size Determination and Power Calculation 
 
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). 
  
 
 
 


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6. Data Collection, Analysis, and Management 
 
6.1. Data Collection 
 
All data – including participant-reported and coordinator-facilitated data – will be collected on paper case 
report forms (CRFs) or electronic CRFs (eCRFs) that will be developed and maintained specifically for this 
project. Collected data will be entered into a secure database located at the CHI. Study staff at the CHI 
will be responsible for data collection and entry. All personnel involved in data collection and/or entry or 
data management will be appropriately trained by the trial coordinator.  
 
6.2. Data Analysis 
 
6.2.1. Analysis Plan 
 
6.2.1.1. Participant-Reported Overall Health & Health Status 
 
The primary outcome analysis of participant-reported overall health will be conducted using an area under 
the curve approach comparing the mean difference between arms in the EQ-VAS over the 21-day 
intervention period. Scores will range from 0-2100 (i.e., 0-100 for 21 days) for each participant.  
 
Health status will be measured using the crosswalk value approach. Each level from each domain of the 
EQ-5D-5L is aggregated to form a number defining a unique health state, with 11111 (i.e., a “1” in all 
domains) representing the best possible health status and 55555 (i.e., a “5” in all domains) representing 
the worst possible health status. Raw values will be converted to an index value out of 1. Differences in 
mean index values will be compared between arms at various time points over the 12-week study period. 
Index values will be calculated using the United States crosswalk value set provided by the EuroQol 
group.65,66  
 
6.2.1.2. Symptom Severity & Duration 
 
Symptom severity will be conducted using an area under the curve approach comparing the difference in 
total symptom scores over the 21-day intervention period between both arms. This gives a score range of 
0-882 for each participant (i.e., 0-42 each day for 21 days). As a secondary analysis, we will compare the 
severity of each symptom individually using the same area under the curve approach. Scores for each 
symptom will range from 0-63 (i.e., 0-3 each day for 21 days). The incidence of severe symptoms (i.e., 
reporting a “3” for any symptom) will also be compared between arms throughout the intervention 
period.  
 
The symptom duration analysis will compare the median time to symptom resolution from the start of 
the intervention period (or the first onset of symptoms if no symptoms were present at the start of the 
intervention period) up to the end of the intervention period (day 21) between both arms. Symptom 
resolution will be defined as a zero in all categories with no relapses.  


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6.2.1.3. Incidence of Delayed Return to Usual Health 
 
The incidence of participants experiencing ongoing symptomatic COVID-19 and post-COVID-19 syndrome 
will be compared between both arms.  
 
6.2.1.4. Rate of Hospitalizations 
 
The incidence of ER visits, acute care admissions, and ICU admissions over the 12-week study period will 
be compared between arms. Length of hospitalization (i.e., length of stay) will also be compared between 
arms; hospitalization will be defined as the time of change to inpatient status until the time of discharge 
(i.e., time spent in emergency will not be included in the length of stay analysis).  
  
6.2.1.5. All-Cause Mortality 
 
The incidence of deaths in both arms will be gathered using medical records and obituary searches. 
 
6.2.2. Statistical Methods 
 
All analyses will follow an intention to treat approach. Continuous and quasi-continuous variables 
(participant-reported health & health status, primary & secondary severity analyses, and length of stay) 
will be compared between arms using unadjusted t-tests. Dichotomous outcomes (incidence of severe 
symptoms, delayed return to usual health, hospitalizations and deaths) will be compared between arms 
using Chi-square tests or Fisher’s exact tests where appropriate. Time to symptom resolution will be 
displayed graphically with Kaplan-Meier curves and differences between arms will be compared with a 
log-rank test. 
 
6.3. Data Management and Monitoring 
 
Data Management: All study data, including paper CRFs, eCRFs, and the electronic database, will be 
managed by the trial coordinator under the supervision of the principal investigator. Participants will have 
the option to fill in written CRFs or eCRFs through the Research Electronic Data Capture (REDCap) 
platform. Study data in REDCap will be stored on a secure server managed by the Canadian College of 
Naturopathic Medicine and accessible only to delegated personnel. Paper CRFs will be kept at the CHI in 
locked cabinets. The REDCap database will be validated by two separate study staff. Full details are 
available in the Data Management Plan. 
 
Data Safety and Monitoring Board (DSMB): External oversight for this trial will be provided by an 
independent DSMB. The primary responsibility of the DSMB is to protect the safety and welfare of 
participants who take part in this clinical trial and to ensure the integrity of the clinical trial.  The DSMB 
will meet either in-person or remotely to discuss matters related to the safety of study participants 
(SAE/SUADR), validity and integrity of the data, enrollment rate relative to expectations, characteristics 


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of participants, retention of participants, adherence to the protocol (potential or real protocol deviations) 
and data completeness.   
The DSMB will review the interim data of stage II once 100 participants are enrolled or after 2 months, 
whichever comes first. The DSMB may review data at other times as determined by emerging results. 
Based on review of the safety data, the DSMB can recommend continuation of the study without 
modification(s), study interruption, study termination, or modification of the trial, where 
applicable. Further information regarding the DSMB review process is provided in the Study DSMB 
Charter.  
7. Adverse Events and Safety 
 
7.1. Definitions 
 
7.1.1. Adverse Event 
 
According to the principles of ICH GCP, an Adverse Event (AE) is any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product, a natural health product, 
or for whom a treatment intervention is provided, and which does not necessarily have to have a causal 
relationship with this treatment. 
 
7.1.2. Serious Adverse Event 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: results in death, is 
life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.  The term ‘life-
threatening’ in the definition of ‘serious’ refers to an event in which the patient was at risk of death at the 
time of the event. As such, it does not refer to an event which hypothetically might have caused death if 
it were more severe. 
 
7.1.3. Adverse Drug Reaction 
 
An adverse drug reaction is defined as a noxious and unintended response to a medicinal product related 
to any dose. This means that a causal relationship between a medicinal product and an adverse event is 
at least a reasonable possibility.  
 
7.2. Collection and Reporting 
 
AEs will be collected for each participant using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. AE collection will begin following the start of the study intervention and will cease 1 
week after the intervention is stopped. The exception will be AEs subject to expedited reporting to Health 
Canada or local REBs (defined below), in which case the AE(s) in question will be followed until completion. 


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Participants in both arms will be asked about adverse events each week while they are on study (day 7, 
14, 21, and 28).  
 
Adverse events will be reported to local REBs according to local requirements. Normally this would include 
timely reporting for events that are deemed to be unexpected, serious, and related to the study 
intervention. All other adverse events will be reported to the REB only in the annual renewal report. The 
frequency and nature of serious adverse events will be documented and reported to the DSMB.  
 
All serious adverse drug reactions will be reported to the TPD and NNHPD. These adverse events are 
subject to expedited reporting. The sponsor will notify both directorates as soon as possible but no later 
than 7 calendar days after the sponsor becomes aware of the event for fatal or life-threatening events, 
and no later than 15 days after becoming aware of non-fatal/non-life threatening events. Within 8 days 
after having informed the NNHPD and TPD of a serious unexpected adverse drug reaction, the sponsor 
must submit a report as complete as possible that includes an assessment of the importance and 
implication of any findings. The final report should include relevant previous experience with the same or 
similar health products.  
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also usually 
be considered serious.  Examples of such events are intensive treatment in an emergency room or at 
home that does not require inpatient hospitalization or other severe adverse events that do not meet the 
criteria for being serious. 
7.2.1. Exceptions 
 
AEs will not be recorded if the participant experiences classic or other symptoms of COVID-19 that are not 
deemed serious as defined above. These include fever, new or worsening cough, shortness of 
breath/difficulty breathing, fatigue, myalgia/arthralgia, sore throat, sputum production, dysphagia 
(difficulty swallowing), new olfactory or taste disorders, pneumonia, rhinorrhea (runny nose), 
chills/shakes, or nasal congestion. Such events are expected in a population who are COVID-19 positive 
and are not deemed deviations from the normal course of the disease. GI disturbances (e.g., nausea, 
vomiting, diarrhea, upset stomach) are also considered symptoms of COVID-19 but will be reported as 
AEs as they are expected side effects of the interventions being studied.   
 
7.3. Expected Adverse Events 
 
According to the Health Canada approved product monographs, reports in the literature and clinical 
experience, the expected adverse events associated with each component of the intervention are listed 
below. Any other symptoms experienced by a participant (provided they are not COVID-19 related) would 
be considered unexpected.  


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Vitamin D: nausea/vomiting, constipation, upset stomach 
 
Vitamin C: GI upset (nausea, vomiting, appetite loss, stomach discomfort, diarrhea, gastric ulcer), 
headache, hyperoxaluria, apparent decrease in uric acid levels 
 
Vitamin K: GI upset (nausea, vomiting, appetite loss, stomach discomfort, diarrhea, gastric ulcer) 
 
Zinc: nausea/vomiting, abdominal pain, diarrhea 
 
There are no expected serious adverse events for this population.  
 
8. Privacy and Confidentiality 
 
Participant personal health information (PHI) will be kept confidential unless release is required by law. 
Representatives of the OHSN-REB, OHRI, CCNM REB, NNHPD, or TPD may review original medical records 
under the supervision of Dr. Seely’s staff for audit purposes. 
Participants will not be identified in any publications or presentations resulting from this study, unless 
permission is given by the participant. All paper case report forms will be kept in locked cabinets in a 
locked office and all databases will be password protected on a secure server. These documents and 
relevant source documents will be kept for a period of 25 years as required by Health Canada. Case report 
forms will be shredded, and databases will be erased at the end of this retention period.  
9. Dissemination and Knowledge Transfer 
 
The work done in this study will be disseminated in the form of scientific presentations to complementary, 
integrative and traditional medical conferences within Canada and internationally. Presentations will be 
accompanied by published abstracts. The principal mechanism for knowledge transfer will be publication 
and will include the use of social media as well as press.  We will target the most reputable clinical journal 
for publication due to the potential impact of this investigation.  
 
10. Relevance and Impact 
 
Several vaccines have shown promise for their short-term effectiveness in preventing COVID-19,67-69 and 
to date two have been approved by Health Canada; however, long-term efficacy data is not yet available 
and  distribution to the entire Canadian population will not be immediate. Therefore, many researchers 
are working hard in the interim to identify potential agents that can be used as treatments for COVID-19. 
Developing treatments to reduce the severity of COVID-19 infections in community-dwelling adults has 
the potential to not only reduce the morbidity and mortality of the infection, but also reduce the burden 
on the healthcare system. A wide base of evidence exists to support the types of interventions being used 
in this study with regards to other upper respiratory tract infections; however, there are currently no 
randomized, double-blind, placebo-controlled studies published on these interventions for COVID-19.  


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As other organizations are also looking into dietary supplements and other natural therapies for the 
treatment of COVID-19 symptoms,27-32 consistency in the findings is essential. Regardless of outcome, the 
results of this and other similar studies will inform patients and the scientific community of the 
effectiveness of dietary supplements for the treatment of COVID-19 symptoms. If a collective positive 
result is seen, this study could corroborate a safe, affordable treatment option for those suffering from 
the virus. If a negative outcome is seen, it will help prevent patients from using unproven protection from 
a natural therapy and paying out of pocket for an ineffective therapy. Although a vaccine-based immunity 
may be on the horizon for COVID-19, the virus is still very much a threat to the general population. 
Vaccines will never be 100% effective, and the long-term effectiveness of the most promising vaccines has 
yet to be determined. Research into potential community treatments of COVID-19 continues to be 
important and has the potential to contribute to public health management of this pandemic and its 
associated societal burden. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11. References 
 
1. 
Pascarella G, Strumia A, Piliego C, et al. COVID-19 diagnosis and management: a comprehensive 
review. Journal of internal medicine. 2020;288(2):192-206. 
2. 
World Health Organization. Coronavirus Disease 2019 (COVID-19) Situation Report 194. 2020. 
3. 
Health Canada. Health Canada authorizes Moderna COVID-19 vaccine. 
https://www.canada.ca/en/health-canada/news/2020/12/health-canada-authorizes-moderna-
covid-19-vaccine.html. Published 2020. Accessed December 23, 2020. 
4. 
Health Canada. Health Canada authorizes first COVID-19 vaccine. 
https://www.canada.ca/en/health-canada/news/2020/12/health-canada-authorizes-first-covid-
19-vaccine0.html. Published 2020. Accessed December 23, 2020. 
5. 
Health Canada. Canada’s COVID-19 Immunization Plan: Saving Lives and Livelihoods. In:2020. 
6. 
Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 
Vaccine. N Engl J Med. 2020. 
7. 
Frederiksen LSF, Zhang Y, Foged C, Thakur A. The Long Road Toward COVID-19 Herd Immunity: 
Vaccine Platform Technologies and Mass Immunization Strategies. Front Immunol. 
2020;11:1817. 
8. 
Health Canada. Remdesivir authorized with conditions for the treatment of patients in Canada 
with severe COVID-19 symptoms. https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-
sc/2020/73621a-eng.php. Published July 28, 2020. Accessed August 18, 2020. 
9. 
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-
blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578. 
10. 
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary 
Report. N Engl J Med. 2020. 
11. 
Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, 
Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. Jama. 2020. 
12. 
Michienzi SM, Badowski ME. Can vitamins and/or supplements provide hope against 
coronavirus? Drugs in context. 2020;9. 
13. 
Beigmohammadi MT, Bitarafan S, Hoseindokht A, et al. Impact of vitamins A, B, C, D, and E 
supplementation on improvement and mortality rate in ICU patients with coronavirus-19: a 
structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21(1):614. 
14. 
Hu XY, Wu RH, Logue M, et al. Andrographis paniculata (Chuān Xīn Lián) for symptomatic relief 
of acute respiratory tract infections in adults and children: A systematic review and meta-
analysis. PLoS One. 2017;12(8):e0181780. 
15. 
Ding Y, Chen L, Wu W, Yang J, Yang Z, Liu S. Andrographolide inhibits influenza A virus-induced 
inflammation in a murine model through NF-κB and JAK-STAT signaling pathway. Microbes 
Infect. 2017;19(12):605-615. 
16. 
Heinz SA, Henson DA, Austin MD, Jin F, Nieman DC. Quercetin supplementation and upper 
respiratory tract infection: A randomized community clinical trial. Pharmacol Res. 
2010;62(3):237-242. 
17. 
Pitt HA, Costrini AM. Vitamin C prophylaxis in marine recruits. JAMA. 1979;241(9):908-911. 
18. 
Hemilä H. Vitamin C and Infections. Nutrients. 2017;9(4). 
19. 
Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane 
Database Syst Rev. 2013(1):Cd000980. 
20. 
Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute 
respiratory tract infections: systematic review and meta-analysis of individual participant data. 
Bmj. 2017;356:i6583. 


Dietary supplements for COVID-19 
Version Date: September 3rd, 2021 
 
Page 27 of 29 
 
21. 
Shimizu Y, Ito Y, Yui K, Egawa K, Orimo H. Intake of 25-Hydroxyvitamin D3 Reduces Duration and 
Severity of Upper Respiratory Tract Infection: A Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Comparison Study. J Nutr Health Aging. 2018;22(4):491-500. 
22. 
Jung HC, Seo MW, Lee S, Kim SW, Song JK. Vitamin D₃ Supplementation Reduces the Symptoms 
of Upper Respiratory Tract Infection during Winter Training in Vitamin D-Insufficient Taekwondo 
Athletes: A Randomized Controlled Trial. Int J Environ Res Public Health. 2018;15(9). 
23. 
Science M, Johnstone J, Roth DE, Guyatt G, Loeb M. Zinc for the treatment of the common cold: 
a systematic review and meta-analysis of randomized controlled trials. Cmaj. 
2012;184(10):E551-561. 
24. 
Lau FH, Majumder R, Torabi R, et al. Vitamin D Insufficiency is Prevalent in Severe COVID-19. 
medRxiv. 2020:2020.2004.2024.20075838. 
25. 
Ohaegbulam KC, Swalih M, Patel P, Smith MA, Perrin R. Vitamin D Supplementation in COVID-19 
Patients: A Clinical Case Series. Am J Ther. 2020. 
26. 
dofferhoff ASP, I.; Schurgers, L.J.; Walk, J.; van den Ouweland, J.M.; Hackeng, T.M.; de Jong, P.A.; 
Gosens, R.; Lux, P.; van Daal, H.; Maassen, C.; Maassen, E.G.; Kistemaker, L.E.; Vermeer, C.; 
Wouters, E.F.; Janssen, R. . Reduced Vitamin K Status as a Potentially Modifiable Prognostic Risk 
Factor for COVID-19. Pre-Prints. 2020(2020040457 (doi: 10.20944/preprints202004.0457.v2)). 
27. 
Angers Hospital. COVID-19 and Vitamin D Supplementation: A Multicentre Randomized Trial of 
High Dose Versus Standard Vitamin D3 in High-Risk COVID-19 Patients (CoVit Trail). 
NCT04344041. 
28. 
MGC Pharmaceuticals. A phase II Controlled Clinical Study Designed to Evaluate the Effect of 
ArtemiC in Patients Diagnosed with COVID-19. NCT04382040. 
29. 
desai M. Coronavirus 2019 (COVID-19) - Using Ascorbic Acid and Zinc Supplementation 
(COVIDAtoZ). NCT04342728. 
30. 
Montano-Loza A. Vitamin D and COVID-19 Management. NCT04385940. 
31. 
Castillo M. Vitamin D on Prevention and Treatment of COVID-19 (COVITD-19). NCT04334005. 
32. 
Seguy D. Impact of Zinc and Vitamin D3 supplementation on the Survival of Aged Patients 
Infected with COVID-19 (ZnD3-CoVici). NCT04351490. 
33. 
Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom Duration and Risk Factors for Delayed Return 
to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network 
- United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-998. 
34. 
NICE. COVID-19 rapid guideline: managing the long-term effects of COVID-19. 2020. 
35. 
Panagiotou G, Tee SA, Ihsan Y, et al. Low serum 25-hydroxyvitamin D (25[OH]D) levels in 
patients hospitalised with COVID-19 are associated with greater disease severity. Clin Endocrinol 
(Oxf). 2020. 
36. 
Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. J Infect 
Public Health. 2020. 
37. 
Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Deficiency 
and Treatment with COVID-19 Incidence. medRxiv. 2020. 
38. 
Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? Lancet Diabetes 
Endocrinol. 2020;8(7):570. 
39. 
Castillo ME, Entrenas Costa LM, Vaquero Barrios JM, et al. "Effect of Calcifediol Treatment and 
best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and 
Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study". J 
Steroid Biochem Mol Biol. 2020:105751. 
40. 
Janz T, Pearson C. Vitamin D blood levels of Canadians. Statistics Canada Ottawa (Canada); 2013. 
41. 
Hume R, Weyers E. Changes in leucocyte ascorbic acid during the common cold. Scott Med J. 
1973;18(1):3-7. 


Dietary supplements for COVID-19 
Version Date: September 3rd, 2021 
 
Page 28 of 29 
 
42. 
Chiscano-Camón L, Ruiz-Rodriguez JC, Ruiz-Sanmartin A, Roca O, Ferrer R. Vitamin C levels in 
patients with SARS-CoV-2-associated acute respiratory distress syndrome. Crit Care. 
2020;24(1):522. 
43. 
Padayatty SJ, Levine M. New insights into the physiology and pharmacology of vitamin C. Cmaj. 
2001;164(3):353-355. 
44. 
Novick SG, Godfrey JC, Godfrey NJ, Wilder HR. How does zinc modify the common cold? Clinical 
observations and implications regarding mechanisms of action. Med Hypotheses. 
1996;46(3):295-302. 
45. 
Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc 
with capsid polypeptides. J Virol. 1976;18(1):298-306. 
46. 
Geist FC, Bateman JA, Hayden FG. In vitro activity of zinc salts against human rhinoviruses. 
Antimicrob Agents Chemother. 1987;31(4):622-624. 
47. 
Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2013(6):Cd001364. 
48. 
Hemilä H. Zinc lozenges may shorten the duration of colds: a systematic review. Open Respir 
Med J. 2011;5:51-58. 
49. 
Fu L, Wang B, Yuan T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in 
China: A systematic review and meta-analysis. J Infect. 2020;80(6):656-665. 
50. 
Akbulut AC, Pavlic A, Petsophonsakul P, et al. Vitamin K2 Needs an RDI Separate from Vitamin 
K1. Nutrients. 2020;12(6). 
51. 
Berenjian A, Sarabadani Z. How menaquinone-7 deficiency influences mortality and morbidity 
among COVID-19 patients. Biocatal Agric Biotechnol. 2020;29:101792. 
52. 
Dalmeijer GW, van der Schouw YT, Magdeleyns E, Ahmed N, Vermeer C, Beulens JW. The effect 
of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 
2012;225(2):397-402. 
53. 
Dofferhoff ASM, Piscaer I, Schurgers LJ, et al. Reduced vitamin K status as a potentially 
modifiable risk factor of severe COVID-19. Clin Infect Dis. 2020. 
54. 
Schwalfenberg GK. Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human 
Health. J Nutr Metab. 2017;2017:6254836. 
55. 
Marles RJ, Roe AL, Oketch-Rabah HA. US Pharmacopeial Convention safety evaluation of 
menaquinone-7, a form of vitamin K. Nutr Rev. 2017;75(7):553-578. 
56. 
Sato T, Inaba N, Yamashita T. MK-7 and Its Effects on Bone Quality and Strength. Nutrients. 
2020;12(4). 
57. 
Sato T, Schurgers LJ, Uenishi K. Comparison of menaquinone-4 and menaquinone-7 
bioavailability in healthy women. Nutr J. 2012;11:93. 
58. 
Halder M, Petsophonsakul P, Akbulut AC, et al. Vitamin K: Double Bonds beyond Coagulation 
Insights into Differences between Vitamin K1 and K2 in Health and Disease. Int J Mol Sci. 
2019;20(4). 
59. 
EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 
1990;16(3):199-208. 
60. 
Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom Duration and Risk Factors for Delayed Return 
to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network 
- United States, March-June 2020. MMWR Morbidity and mortality weekly report. 
2020;69(30):993-998. 
61. 
US Food and Drug Admiinistration. Assessing COVID-19-RelatedSymptoms in Outpatient Adult 
and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 
Prevention or Treatment: Guidance for Industry. 
https://www.fda.gov/media/142143/download. Published 2020. Accessed. 


Dietary supplements for COVID-19 
Version Date: September 3rd, 2021 
 
Page 29 of 29 
 
62. 
National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-
term effects of COVID-19. https://www.nice.org.uk/guidance/ng188. Published 2020. Accessed 
January 3, 2021. 
63. 
Newman BH, Martin CA. The effect of hot beverages, cold beverages, and chewing gum on oral 
temperature. Transfusion. 2001;41(10):1241-1243. 
64. 
Quatrara B, Coffman J, Jenkins T, et al. The effect of respiratory rate and ingestion of hot and 
cold beverages on the accuracy of oral temperatures measured by electronic thermometers. 
Medsurg Nurs. 2007;16(2):105-108, 100. 
65. 
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 
2001;33(5):337-343. 
66. 
Craig BM, Rand K. Choice Defines QALYs: A US Valuation of the EQ-5D-5L. Med Care. 
2018;56(6):529-536. 
67. 
BioNTech SE. Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of RNA 
Vaccine Candidates Against COVID-19 in Healthy Individuals. In:2020. 
68. 
ModernaTX Inc. A Study to Evaluate the Safety, Reactogenicity, and Effectiveness of mRNA-1273 
Vaccine in Adults Aged 18 Years and Older to Prevent COVID-19. In:2020. 
69. 
AstraZeneca. Phase III Double-blind, Placebo-controlled Study of AZD1222 for the Prevention of 
COVID-19 in Adults. In:2020. 
 

ICF_001.pdf: 
Dietary Supplements for COVID-19: Informed Consent Form 
Version Date: January 17th, 2022 
 
Page 1 of 11 
 
 
PARTICIPANT INFORMED CONSENT FORM 
 
 
Study Title: Dietary Supplements to Reduce Symptom Severity and Duration for People with SARS-CoV-
2: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial 
 
OHSN REB: 20210072-01H 
CCNM REB: CCNMREB036.Seely.Wilson 
 
Study Doctors: Dr. Dugald Seely ND, MSc 613-792-1222 ext. 2 at The Centre for Health Innovation 
 
 
Dr. Kumanan Wilson, MD, MSc, 613-737-8899 ext. 17921 at The Ottawa Hospital 
 
Sponsor: Ottawa Hospital Research Institute 
 
Funding Agency:  Ottawa Integrative Cancer Centre Foundation and private support from Mavis and 
Martin Sacher 
 
Emergency Contact Number: Please dial 911 or proceed to the nearest emergency department 
 
Non-emergency contact numbers are noted at the end of this document under the section heading 
“contacts.” 
 
Introduction 
 
You are being asked to participate in the above clinical trial (a type of study that involves research). You 
are invited to participate in the study because you have been diagnosed with SARS-CoV-2, also known as 
Coronavirus 2019 or COVID-19, in the Ottawa community. This consent form will help you make an 
informed choice about your participation. Please read this form carefully before you decide if you would 
like to participate. Ask the study doctor and study team as many questions as you like. We encourage you 
to discuss your options with family, friends or your healthcare team. The study staff will tell you about the 
study timelines for making your decision. 
 
Participation in this study is completely voluntary. You have the option to not participate at all or you 
may choose to leave the study at any time. Whatever you choose, it will not affect the usual medical care 
that you might receive outside the study. 
 
 
 


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Do the investigators have any conflicts of interest? 
 
Dr. Dugald Seely, the Principal Investigator on this trial, is the Co-Founder & CEO of the Centre for Health 
Innovation (CHI), and the Executive Director of Research & Clinical Epidemiology for the Canadian 
College of Naturopathic Medicine (CCNM). Although CCNM will be paying the CHI and the Ottawa 
Hospital Research Institute (OHRI) to conduct the study, the Principal Investigators and these institutions 
do not otherwise benefit financially from the study. There are no other conflicts of interest to declare related 
to this study. 
 
Vitazan Herbs and Supplements Inc. is the supplier of product for this study and will be providing it to the 
research staff free of charge. This study is also receiving funding from an outside source. The suppliers or 
funders did not have any role in the design of the study, nor will they play a role in the collection, analysis, 
or interpretation of the data, the writing of the final manuscript, or the decision to submit the manuscript 
for publication.   
 
What is the background information for this study?  
  
The purpose of this study is to determine the effects of specific dietary supplements for people who have 
SARS-CoV-2 (COVID-19) who are not in the hospital (staying at home during recovery). The dietary 
supplements being studied are vitamin D, vitamin C, vitamin K2 and zinc. 
 
More specifically, this trial will study the effects of these supplements on your overall health, the 
seriousness of your COVID-19 symptoms, and length or your symptoms. We will also study to see if these 
supplements change the need for hospital admissions and medical care.  
 
Currently, there are no approved treatments for COVID-19 in the community. Health Canada, the 
regulatory body that oversees the use of drugs and natural health products in Canada, has not approved the 
sale or use of vitamin D, vitamin K2, vitamin C, or zinc for the treatment of COVID-19; however, Health 
Canada has allowed all of these products to be used in this study.  
 
Why is this study being done? 
 
The purpose of this study is to determine whether or not taking these dietary supplements will improve the 
overall health and decrease symptom severity and duration of people diagnosed with COVID-19. To do 
this, half of the participants will receive these supplements and the other half will receive a placebo. A 
placebo is a harmless pill that looks and tastes like the supplements but does not contain any active 
ingredients (in this case vitamin C, vitamin D, vitamin K2 and zinc will be absent). The placebo is not 
intended to have any effect on your symptoms and is used to make the study more reliable.  
 
What other choices are there? 
 
You do not have to take part in this study. There may be other clinical trials for COVID-19 that you are 
eligible for. If you choose not to participate, you will not be denied any treatments that may be given to you 


Dietary Supplements for COVID-19: Informed Consent Form 
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Page 3 of 11 
 
by your healthcare providers. We recommend you continue to follow the advice given to you by Ottawa 
Public Health and The Ottawa Hospital 
 
How many people will take part in this study? 
 
We hope to enroll 200 people from the Ottawa community in this study over the next 4 months. The trial 
should take 7 months to complete and the complete results should be known in 9-12 months. 
 
What will happen during this study? 
 
Assignment to a group 
 
If you decide to participate in this study, you will be “randomized” to a group that receives either the dietary 
supplements or a placebo. Randomization means that you are put into a group by chance (like flipping a 
coin). You will have an equal (50%) chance of being placed in either group. Neither you, the study staff, 
nor the study doctors can choose which group you will be put in. This is a double-blind study, meaning 
you, the study staff, study doctors, and your usual healthcare providers will not know which group you are 
in. Your group assignment can be identified if medically necessary.  
 
Study Intervention 
 
Group 1 (treatment group)  
 
If you are randomized to the treatment group, the interventions will include three products: one bottle with 
capsules containing vitamin C and zinc, one bottle with one capsule containing an initial dose of vitamin 
D, and one bottle with liquid drops containing a mix of vitamin D and vitamin K2.  
 
Group 2 (control group) 
 
If you are randomized to the placebo group, you will receive similar-looking products to the treatment 
group, but the capsules and liquid drops will not contain the supplements.  
 
The instructions for taking the study products are the same regardless of what group you are placed in and 
are described in the section “Treatments” below. 
 
What are the study procedures? 
 
Throughout the study, you will be asked to take the required pills and liquid drops, complete questionnaires, 
and be available for six phone or online check-ins. If you choose to participate, you will receive an 
information sheet with all the information below.  
 
 
 
 


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Treatments 
 
Participation in this study will involve you taking dietary supplements or a placebo each day for 21 days at 
your own home. Instructions for when to take each supplement are as follows: 
 
Vitamin D (or placebo): One capsule (50,000 units) once on day 1 (this is called a “loading dose,” a larger 
dose that you take only once) 
 
Vitamin D + Vitamin K (or placebo): 4 drops twice daily at breakfast and dinner for 21 days. Each day you 
will take 240 mcg vitamin K and 1000 units Vitamin D (or placebo).  
 
Vitamin C + Zinc (or placebo): 3 capsules 3 times daily at breakfast, lunch, and dinner for 21 days. Each 
day you will take 6 g vitamin C and 75 mg zinc (or placebo).  
 
The Vitamin D and Vitamin C + Zinc capsule placebos are made of a compound called “microcrystalline 
cellulose,” and the Vitamin D + Vitamin K liquid placebo is made of “medium chain triglyceride (MCT) 
oil.” Microcrystalline cellulose, or “cellulose,” is a common non-medicinal ingredient added to most 
supplements and prescription drugs. MCT oil is the non-medicinal ingredient in the Vitamin D + Vitamin 
K treatment.  
 
You will be asked to not throw out any study product at the end of the 21-day period. The product must be 
disposed of properly. You may do this by returning the study product to the CHI after the 21 day period or 
by taking them to your local pharmacy and asking the pharmacist to destroy them. More detailed 
instructions will be given to you by the research staff when it is time to dispose of the products. 
 
Questionnaires 
 
If you choose to participate in the study, you will be asked to fill in short questionnaires at different time 
points during the 12 weeks that you are enrolled in the study. Before starting the study products, you will 
fill in a demographics questionnaire that asks about your height, weight, age, sex, race, vaccination status, 
and health conditions.  The next questionnaire set asks about the symptoms you are experiencing and your 
overall health. This will be filled out each day you are taking the study products (i.e., once daily for 21 
days). The final questionnaire asks about five dimensions of your health: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. This questionnaire will be filled in before you start any 
study products, as well as once during weeks 1, 2, 3, 4, 8, and 12 of the study. Each of these questionnaire 
sets should take no longer than five minutes to complete. 
 
Questionnaires can be completed on paper or through the internet using software called Research Electronic 
Data Capture (REDCap). REDCap is the software we will be using to collect data for the study. If you 
choose to answer questionnaires through REDCap, you will receive an email with a link to each 
questionnaire. This process will be explained in detail by the research staff if you choose this option.  
 
 
 


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Phone Check Ins 
 
As part of the study, a member of the research team will contact you once during weeks 1, 2, 3, 4, 8, and 
12 to ask you about any side effects or concerns and ask you a few questions. Each check-in will take 
between 5-15 minutes. The check-ins will be done by phone. They will be scheduled ahead of time.   
 
Taking Your Temperature 
 
You will be asked to take and write down your oral temperature on the daily questionnaire each day for 21 
days. You will be provided with an oral (by mouth) thermometer and detailed instructions on how to use it.  
 
Following Public Health Procedures 
 
Participation in this study does not change any public health directives and we ask that you follow all 
instructions given to you by Ottawa Public Health (or another public health agency) and The Ottawa 
Hospital. Any questions regarding public health measures should be directed to Ottawa Public Health or 
your primary healthcare provider.  
 
Hospitalization 
 
If you are hospitalized at any point during the study, you will stop all study activities. This means you will 
not take the study product, answer questionnaires, or participate in phone check-ins while you are in the 
hospital. Once you are back home, you may resume all study procedures.  
 
What are the responsibilities as a study participant?  
  
It is important to remember the following things during this study:   
• 
Talk to the study staff if you have any questions or concerns.  
• 
Tell the study staff if anything about your health has changed.  
• 
Tell the study staff about all prescription and non-prescription medications, including natural health 
products, you are taking while taking part in the study 
• 
Follow the product intervention instructions provided to you. 
• 
Do your best to participate in all phone call check-ins from research staff. 
• 
Complete all of the questionnaires to the best of your ability. 
• 
Call the study doctor or one of the study staff if you experience any side effects, even if you are 
unsure whether they have anything to do with this study.  
 
How long will participants be in the study? 
 
Your participation in the study will last 12 weeks in total. You will only take the study product for the first 
21 days.  
 
 
 


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Can participants choose to leave the study? 
 
You can choose to end your participation in this research (called withdrawal) at any time without providing 
a reason. This decision will not affect your future care at the hospital or the CHI. If you decide to withdraw 
from the study, please note the following: 
• 
If you decide to stop your study intervention you should contact the study doctor or the study team 
first. They will discuss the related issues or possible safety concerns for you.    
• 
If you choose not to participate, a final visit(s) may need to be completed to ensure your safety and 
well-being.   
• 
If you withdraw your consent, the study team will no longer collect your personal health 
information for research purposes, unless it is needed for review of safety. Information that was 
recorded before you withdrew will be used for the purposes of the study, but no information will 
be collected or sent to the sponsors after you withdraw your permission. 
 
If you wish to withdraw your consent, the research team will ask if it is OK to continue to collect 
information from your medical chart and to contact you for follow-up if necessary. You can choose to 
accept or decline both of these requests. If you accept, you will still be considered a study participant but 
will not have to fill in any more questionnaires or participate in any check-ins.  
 
Can participation in this study end early? 
 
The study doctor will stop your participation in this study early, without your consent, for reasons such as: 
• 
The study doctor feels it is in your best interest 
• 
The sponsor cancels the study 
• 
Regulatory authorities (such as Health Canada) or research ethics boards withdraw permission for 
this study to continue 
• 
You do not follow the study staff’s instructions 
 
What are the risks or harms of participating in this study?  
 
If you are randomized to the dietary supplement group you will be required to take vitamin C, vitamin D, 
vitamin K2 and zinc each day. The risks we know about the short-term consumption of each supplement 
are listed below; however, there could be additional risks we do not know about when taking these study 
products. Please note that there are more risks associated with longer-term consumption of some of these 
products. If you wish to continue supplementation after the end of the study, please discuss this with your 
family doctor, naturopathic doctor, or pharmacist. 
 
Vitamin D 
• 
Rare: nausea, constipation, upset stomach, high blood calcium levels 
 
Vitamin C 
• 
Rare: stomach upset, nausea, headache, apparent decrease in blood uric acid levels 
• 
Common but not serious: mild diarrhea 
 


Dietary Supplements for COVID-19: Informed Consent Form 
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Vitamin K2 
• 
Rare: stomach upset 
 
Zinc 
• 
Rare: low blood copper levels, vomiting 
• 
Common but not serious: stomach upset, indigestion, nausea* 
 
* These side-effects become rare when zinc is taken with food 
 
Certain medications and conditions are contraindicated with the study products, meaning they cannot be 
taken at the same. Please inform the study team if there are any changes to the medications or natural health 
products you are taking. Please stop taking the study product and immediately inform the study staff if the 
following happens: 
• 
You are placed on a vitamin K-antagonist anticoagulant (i.e., a blood thinner. E.g., Warfarin) 
• 
You are placed on cephalexin or tetracycline antibiotics (e.g., tetracycline, doxycycline) 
• 
You are diagnosed with kidney stones, hypercalcemia (high blood calcium), or hypervitaminosis 
D (high blood vitamin D) 
 
What are the benefits of participating in this study? 
 
If you agree to take part in this study, the study products may or may not be of direct benefit to you. Your 
participation may help the researchers to determine if there are beneficial effects of a combination dietary 
supplement involving these ingredients for people with COVID-19. This may benefit people who are 
diagnosed in the future.  
 
How will participant information be kept confidential?  
 
If you decide to participate in this study, the investigator(s) and study staff will look at your personal health 
information held at The Ottawa Hospital and collect only the information they need for this study.  
 
“Personal health information” is health information about you that could identify you because it includes 
information such as your name, address, telephone number, date of birth, new and existing medical records, 
or the types, dates and results of various tests and procedures. Records identifying you will be kept 
confidential and, to the extent permitted by the applicable laws, will not be disclosed or made publicly 
available, except as described in this consent document.  
 
Authorized representatives of the following organizations may look at your original (identifiable) 
medical/clinical and study records at The Ottawa Hospital or the Centre for Health Innovation where these 
records are held to check that the information collected for the study is correct and follows proper laws and 
guidelines: 
• 
The Ottawa Hospital Research Institute, the sponsor of the study 
• 
Researchers at the CHI or TOH who are involved with the study, 
• 
The Ottawa Health Science Network Research Ethics Board and Canadian College of 
Naturopathic Medicine Research Ethics Board, who oversee the ethical conduct of this study, 


Dietary Supplements for COVID-19: Informed Consent Form 
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• 
Health Canada, as they oversee the use of therapeutic drugs and natural health products in 
Canada. 
 
Study staff from the Centre for Health Innovation (CHI) will receive and retain your name, telephone 
number, and email address in order to conduct the phone check-ins and communicate with you at other time 
points if necessary. A Master List provides the link between your identifying information and the study 
number. This list will only be available to Dr. Dugald Seely and his staff at the CHI and will not 
leave these sites. The Master List and coded study records will be password protected and stored on a 
secure server with limited access. All information collected during your participation in this study will 
be identified with a unique study number (for example participant # 001) and will not contain information 
that identifies you.  Documents leaving the CHI will only contain the coded study number. 
 
Your contact information, including name and address, will also be sent to Vitazan Professional in order to 
facilitate the shipment of study product and study materials. 
 
Communication via e-mail is not absolutely secure. We do not recommend that you communicate sensitive 
personal information via e-mail. 
 
You will not be identified in any publications or presentations resulting from this study. Research records 
will be kept for 25 years, as required by Health Canada. At the end of the storage time, all paper records 
will be shredded, and all electronic records will be securely deleted. Your de-identified data from this study 
may be used for other research purposes. If your study data is shared with other researchers, information 
that links your study data directly to you will not be shared. 
 
Even though the likelihood that someone may identify you from the study data is very small, it can never 
be completely eliminated. 
 
Will family doctors or healthcare providers know who is participating in this study?  
 
The study staff will not inform your family doctor or other healthcare providers about your participation in 
the study nor the interventions you are receiving unless you specifically request that they do so. You are 
free to inform your family doctor or other healthcare providers yourself with regards to your progression 
through the study. 
 
Will information about this study be available online? 
 
A description of this clinical trial will be available on http://clinicaltrials.gov. This website will not include 
information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. This research study can be found on the above listed website by using the 
clinical trial registration number NCT04780061. 
 What is the cost to participants?   
 
There is no cost to participating. All study materials and interventions will be provided to you free of charge.  
 
 


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Are study participants paid to be in this study? 
 
You will not be paid for participation in this study. The products listed in the study protocol will be 
provided to you free of charge if you are participating in the study. Any shipping or postage costs you might 
incur will be reimbursed to you by the study team. 
 
In the event of a study-related injury or illness, you will be provided with appropriate medical treatment 
and care. Financial compensation for lost wages, disability or discomfort due to an injury or illness is not 
available through this research.  
 
What are the rights of participants in a research study? 
 
You will be told, in a timely manner, about new information that may be relevant to your willingness to 
stay in this study. You have a right to be informed of the results of this study once the entire study is 
complete. Your rights to privacy are legally protected by federal and provincial laws that require safeguards 
to ensure that your privacy is respected.  
 
By signing this form, you do not give up any of your legal rights against the study doctor, sponsor, or 
involved institutions for compensation, nor does this form relieve the study doctor, sponsor, or their agents 
of their legal and professional responsibilities. You will be given a copy of this informed consent form prior 
to participating in this study. 
 
Whom do participants contact for questions?  
 
If you have any questions about this study, or if you feel that you have experienced a study-related injury 
or illness, you can talk to one of the study doctors. Those people are: 
Centre for Health Innovation  
Dugald Seely, ND, MSc  
429 MacLaren Street, Ottawa ON K2P 0M7  
613-792-1222 ext. 2  
dseely@thechi.ca   
 
Ottawa Hospital Research Institute  
Kumanan Wilson, MD, MSc, FRCPC  
1053 Carling Avenue, Ottawa, ON K1Y 4E9  
613-737-8899 ext. 17921  
kwilson@toh.ca   
 
 
 
You may also contact the study staff at 613-792-1222 ext. 1.  
  
If you have any questions about your rights as a study participant or about ethical issues related to this 
study, you may contact the Ottawa Health Sciences Network Research Ethics Board Chairperson at 613-
798-5555, extension 16719 or the Canadian College of Naturopathic Medicine Research Ethics Board 
Chairperson at REBChair@ccnm.edu.  


Dietary Supplements for COVID-19: Informed Consent Form 
Version Date: January 17th, 2022 
 
Page 10 of 11 
 
Study Title: Dietary Supplements to Reduce Symptom Severity and Duration for people diagnosed with 
SARS-CoV-2: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial 
 
Signatures 
 
• 
I understand I am being asked to participate in a research study about the effects of dietary 
supplements on people diagnosed with COVID-19. 
• 
I have read, or someone has read to me, all pages of this consent form and all my questions were 
answered to my satisfaction. 
• 
I understand that I can withdraw my consent from this study at any time for any reason. 
• 
I voluntarily agree to participate in this study. 
• 
I will be given a copy of this consent form for my records. 
 
 
_____________________________ 
  _____________________________ 
  _________________  
Participant Signature  
 
 
  Printed Name  
  
 
   Date 
 
 
Investigator or Delegate Statement  
 
I have carefully explained the study to the study participant.  To the best of my knowledge, the participant 
understands the nature, demands, risks and benefits involved in taking part in this study.   
 
_____________________________ 
  _____________________________ 
  _________________ 
Signature of Person conducting   
  Printed Name  
 
 
  Date 
consent and Role 
 
 
 
 
 
 
 
 
 
 
 
 


Di et ary S u p pl e m e nts f or C O VI D -1 9 : I nf or m e d C o ns e nt F or m 
V ersi o n D at e: J a n u ary 1 7t h, 2 0 2 2 
 
P a g e 1 1  of 1 1  
 
St u d y Title : Dietar y S u p ple me nts t o Re d uce S y m pt o m Se verit y a n d D urati o n f or pe o ple dia g n ose d wit h 
S A R S -C o V - 2: A Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d Cli nical Trial 
 
 
P artici p a nt Assist a nce  
 
C o m plete t he f oll o wi n g decl ar ati o n o nly if t he p artici p a nt is u n a ble t o re a d: 
 
  T he  c o nse nt f or m was rea d t o t he partici pa nt a n d t he pers o n si g ni n g bel o w attests t hat t he st u d y was 
acc uratel y e x plai ne d t o, a n d a p pare ntl y u n derst o o d b y, a n d c o nse nt was freel y gi ve n b y t he partici pa nt.  
 
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Si g nat ure of I m partial Wit ness      
  Pri nte d Na me     
  
  
  Date  
 
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Relati o ns hi p t o Partici pa nt  
 
C o m plete t he f oll o wi n g decl ar ati o n o nly if t he p artici p a nt   h as li mite d pr oficie ncy i n t he l a n g u a ge i n w hic h 
t he c o nse nt f or m is writte n a n d i nter pret ati o n w as pr ovi de d: 
 
  T he pers o n si g ni n g bel o w acte d as a n i nter preter, a n d attests t hat t his st u d y as set o ut i n t he c o nse nt f or m 
is  acc uratel y  si g ht  tra nslate d  a n d/ or  i nter prete d,  a n d  t hat  i nter pretati o n  was  pr o vi de d  o n  q uesti o ns,  
res p o nses a n d i n a d diti o nal disc ussi o n arisi n g fr o m t his pr ocess. 
 
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Si g nat ure of I nter preter    
   
  Pri nte d Na m e    
  
  
  Date