Covid19
Conditions
Keywords
Natural Health Products, NHP, Dietary Supplements, Vitamin C, Vitamin D, Vitamin K, Zinc, COVID-19, SARS-CoV-2
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).
Interventions
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.
DIETARY_SUPPLEMENTVitamin C/Zinc
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.
DIETARY_SUPPLEMENTVitamin K2/D
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
Placebo equivalent of Vitamin C/Zinc and Vitamin D3.
Placebo equivalent of Vitamin K2/D
Sponsors
Ottawa Hospital Research Institute
Vitazan Professional
New Roots Herbal
The Canadian College of Naturopathic Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults (≥18) who test positive for SARS-CoV-2 in an outpatient setting 2. Access to internet
Exclusion criteria
1. Symptom onset greater than 4 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 8. Currently taking either of the following antibiotics: cephalexin, tetracyclines 9. Participating in an investigational study or participation in an investigational study within the past 30 days 10. Any reason which, under the discretion of the qualified investigator or delegate, would preclude the patient from participating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participant-reported Overall Health | During the intervention period (Daily for 21 days) | Measured using the EuroQol Visual Assessment Scale (EQ-VAS). Scores each day range from 0 (worst health imaginable) and 100 (best health imaginable). Scores summed over a 21-day period for a total range of 0-2100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of COVID-19 on the Health Status of Participants | Baseline plus weeks 1, 2, 3, 4, 8, and 12 | Measured using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire. Scores are converted into a unique health state. Health states are converted to an index value between 0 and 1, where 1 is considered the best possible health and 0 is the worst possible health. |
| Symptom Severity of Common COVID-19 Symptoms | During the intervention period (Daily for 21 days) | Measured using an internally-developed questionnaire. Includes fever, cough, shortness of breath, fatigue, headache, myalgia/arthralgia, nausea, vomiting, diarrhea, congestion, loss of taste, and loss of smell. Scores range from 0-3 for each symptom, totaling 0-42 for each day. 0 = no symptom, 1 = mild symptom, 2 = moderate symptom, 3 = severe symptom. Scores converted into a number out of 100 and summed over 21 days for a range of 0-2100 where a higher score indicates a higher symptom severity (i.e., a worse outcome). |
| Total Symptom Duration | During the intervention period (21 days) | Measured as the time to a complete reduction of symptoms with no relapses (i.e., a 0 in all categories on the symptom questionnaire). |
| Incidence of Delayed Return to Usual Health | 12 weeks | Measured by the number of people experiencing ongoing symptomatic COVID-19 (symptoms persisting between 4 and 12 weeks) and the number of people experiencing post-COVID-19 syndrome (symptoms persisting at least 12 weeks) |
| Number of Participants With a Hospital Visit or Admission | 12 weeks | Includes ER visits, acute care admissions, and ICU admissions |
Countries
Canada
Participant flow
Recruitment details
Participants were enrolled from outpatient COVID-19 test centres associated with The Ottawa Hospital. The primary site for enrolment and coordination of the study was The Centre for Health Innovation, Ottawa, Canada with support from the Ottawa Hospital Research Institute.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Vitamin C, Vitamin D3, Vitamin K2, Zinc | 42 |
| Control Placebo (Microcrystalline cellulose + medium chain triglyceride oil) | 44 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Withdrawal by Subject | 5 | 8 |
Baseline characteristics
| Characteristic | Treatment | Total | Control |
|---|---|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 12.7 | 38.9 years STANDARD_DEVIATION 13.8 | 39.9 years STANDARD_DEVIATION 14.9 |
| Comorbidities Asthma | 7 Participants | 16 Participants | 9 Participants |
| Comorbidities Cancer | 0 Participants | 1 Participants | 1 Participants |
| Comorbidities Chronic Kidney Disease | 0 Participants | 0 Participants | 0 Participants |
| Comorbidities Chronic Obstructive Pulmonary Disorder | 0 Participants | 2 Participants | 2 Participants |
| Comorbidities Coronary Artery Disease | 0 Participants | 0 Participants | 0 Participants |
| Comorbidities Diabetes | 0 Participants | 2 Participants | 2 Participants |
| Comorbidities Hypertension | 3 Participants | 4 Participants | 1 Participants |
| Comorbidities Immunodeficiency | 0 Participants | 0 Participants | 0 Participants |
| Comorbidities Liver Disease | 0 Participants | 0 Participants | 0 Participants |
| Other Variables Smoking History | 7 Participants | 15 Participants | 8 Participants |
| Other Variables Symptoms at Testing | 38 Participants | 74 Participants | 36 Participants |
| Race/Ethnicity, Customized Asian (East) | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian (South) | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian (Southeast) | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Latin American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Middle Eastern | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 37 Participants | 71 Participants | 34 Participants |
| Sex: Female, Male Female | 17 Participants | 43 Participants | 26 Participants |
| Sex: Female, Male Male | 25 Participants | 43 Participants | 18 Participants |
| Vaccination Status Received First Dose | 41 Participants | 83 Participants | 42 Participants |
| Vaccination Status Received Second Dose | 41 Participants | 83 Participants | 42 Participants |
| Vaccination Status Received Third Dose | 37 Participants | 67 Participants | 30 Participants |
| Vaccination Status Unvaccinated | 1 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 46 |
| other Total, other adverse events | 16 / 44 | 6 / 46 |
| serious Total, serious adverse events | 0 / 44 | 1 / 46 |
Outcome results
Primary
Participant-reported Overall Health
Measured using the EuroQol Visual Assessment Scale (EQ-VAS). Scores each day range from 0 (worst health imaginable) and 100 (best health imaginable). Scores summed over a 21-day period for a total range of 0-2100.
Time frame: During the intervention period (Daily for 21 days)
Population: Participants were included in the analysis of overall health, symptom severity, and symptom duration if they completed the 21-day intervention period, completed at least 11 (52%) daily assessments, and did not miss more than 3 assessments sequentially
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Participant-reported Overall Health | 1790 score on a scale | Standard Deviation 226.6 |
| Control | Participant-reported Overall Health | 1752.6 score on a scale | Standard Deviation 220.7 |
Comparison: An area under the curve approach was used to analyze the primary outcome, whereby participants' scores for each assessment were summed over the 21-day period. For missing values, we imputed the mean of the most recent and first subsequent measurement or carried the last observation forward if there was no subsequent measurement.p-value: 0.53t-test, 2 sided
Secondary
Effect of COVID-19 on the Health Status of Participants
Measured using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire. Scores are converted into a unique health state. Health states are converted to an index value between 0 and 1, where 1 is considered the best possible health and 0 is the worst possible health.
Time frame: Baseline plus weeks 1, 2, 3, 4, 8, and 12
Population: Participants were included in this analysis if they completed a baseline questionnaire.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Effect of COVID-19 on the Health Status of Participants | Week 1 | 0.95 score on a scale | Standard Deviation 0.08 |
| Treatment | Effect of COVID-19 on the Health Status of Participants | Week 4 | 0.96 score on a scale | Standard Deviation 0.08 |
| Treatment | Effect of COVID-19 on the Health Status of Participants | Baseline | 0.88 score on a scale | Standard Deviation 0.1 |
| Treatment | Effect of COVID-19 on the Health Status of Participants | Week 8 | 0.95 score on a scale | Standard Deviation 0.08 |
| Treatment | Effect of COVID-19 on the Health Status of Participants | Week 3 | 0.94 score on a scale | Standard Deviation 0.08 |
| Treatment | Effect of COVID-19 on the Health Status of Participants | Week 12 | 0.96 score on a scale | Standard Deviation 0.07 |
| Treatment | Effect of COVID-19 on the Health Status of Participants | Week 2 | 0.95 score on a scale | Standard Deviation 0.07 |
| Control | Effect of COVID-19 on the Health Status of Participants | Week 12 | 0.96 score on a scale | Standard Deviation 0.07 |
| Control | Effect of COVID-19 on the Health Status of Participants | Week 2 | 0.94 score on a scale | Standard Deviation 0.09 |
| Control | Effect of COVID-19 on the Health Status of Participants | Baseline | 0.88 score on a scale | Standard Deviation 0.12 |
| Control | Effect of COVID-19 on the Health Status of Participants | Week 1 | 0.93 score on a scale | Standard Deviation 0.1 |
| Control | Effect of COVID-19 on the Health Status of Participants | Week 3 | 0.91 score on a scale | Standard Deviation 0.1 |
| Control | Effect of COVID-19 on the Health Status of Participants | Week 4 | 0.97 score on a scale | Standard Deviation 0.05 |
| Control | Effect of COVID-19 on the Health Status of Participants | Week 8 | 0.95 score on a scale | Standard Deviation 0.09 |
Secondary
Incidence of Delayed Return to Usual Health
Measured by the number of people experiencing ongoing symptomatic COVID-19 (symptoms persisting between 4 and 12 weeks) and the number of people experiencing post-COVID-19 syndrome (symptoms persisting at least 12 weeks)
Time frame: 12 weeks
Population: Participants were included in this analysis if they completed 12 weeks of follow-up.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment | Incidence of Delayed Return to Usual Health | Ongoing Symptomatic COVID-19 | 6 Participants |
| Treatment | Incidence of Delayed Return to Usual Health | Post COVID-19 Syndrome | 3 Participants |
| Control | Incidence of Delayed Return to Usual Health | Ongoing Symptomatic COVID-19 | 5 Participants |
| Control | Incidence of Delayed Return to Usual Health | Post COVID-19 Syndrome | 3 Participants |
Secondary
Number of Participants With a Hospital Visit or Admission
Includes ER visits, acute care admissions, and ICU admissions
Time frame: 12 weeks
Population: All participants who started the study drug were included in this analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment | Number of Participants With a Hospital Visit or Admission | Acute Care Admissions | 0 Participants |
| Treatment | Number of Participants With a Hospital Visit or Admission | Intensive Care Unit Admissions | 0 Participants |
| Treatment | Number of Participants With a Hospital Visit or Admission | Emergency Room Visits | 2 Participants |
| Control | Number of Participants With a Hospital Visit or Admission | Emergency Room Visits | 4 Participants |
| Control | Number of Participants With a Hospital Visit or Admission | Acute Care Admissions | 0 Participants |
| Control | Number of Participants With a Hospital Visit or Admission | Intensive Care Unit Admissions | 0 Participants |
Secondary
Symptom Severity of Common COVID-19 Symptoms
Measured using an internally-developed questionnaire. Includes fever, cough, shortness of breath, fatigue, headache, myalgia/arthralgia, nausea, vomiting, diarrhea, congestion, loss of taste, and loss of smell. Scores range from 0-3 for each symptom, totaling 0-42 for each day. 0 = no symptom, 1 = mild symptom, 2 = moderate symptom, 3 = severe symptom. Scores converted into a number out of 100 and summed over 21 days for a range of 0-2100 where a higher score indicates a higher symptom severity (i.e., a worse outcome).
Time frame: During the intervention period (Daily for 21 days)
Population: Participants were included in this analysis if they completed the 21-day intervention period, completed at least 11 (52%) daily assessments, and did not miss more than 3 assessments sequentially.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Symptom Severity of Common COVID-19 Symptoms | 166.3 score on a scale | Standard Deviation 92.3 |
| Control | Symptom Severity of Common COVID-19 Symptoms | 192.9 score on a scale | Standard Deviation 153.6 |
p-value: 0.09t-test, 2 sided
Secondary
Total Symptom Duration
Measured as the time to a complete reduction of symptoms with no relapses (i.e., a 0 in all categories on the symptom questionnaire).
Time frame: During the intervention period (21 days)
Population: Participants were included in this analysis if they completed the 21-day intervention period, completed at least 11 (52%) daily assessments, and did not miss more than 3 assessments sequentially.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment | Total Symptom Duration | 13.0 Days |
| Control | Total Symptom Duration | 12.5 Days |
p-value: 0.81Log Rank