Dietary Supplements to Reduce Symptom Severity and Duration in People With SARS-CoV-2: A Randomized, Double Blind, Placebo Controlled Clinical Trial
Phase: PHASE3
Conditions: Covid19
Sponsor: The Canadian College of Naturopathic Medicine

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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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