Oral 25-hydroxyvitamin D3 and COVID-19

• ClinicalTrials.gov Identifier: NCT04386850
• Recruitment Status: Recruiting
• First Posted: May 13, 2020
• Last Update Posted: June 12, 2020
• Sponsor: Tehran University of Medical Sciences
• Collaborator: Boston University
• Information provided by (Responsible Party): Tehran University of Medical Sciences

Tracking Information

• First Submitted Date: May 11, 2020
• First Posted Date: May 13, 2020
• Last Update Posted Date: June 12, 2020
• Actual Study Start Date: April 14, 2020
• Estimated Primary Completion Date: November 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 10, 2020)

• COVID-19 (SARA-Cov-2) infection [ Time Frame: 60 days ]
  Percentage of patients with acute respiratory tract infection symptoms (e.g. fever, cough, dyspnea) with no other etiology that fully explains the clinical presentation accompanied by chest computed tomography (CT) scan findings compatible with Covid-19 or patients with a COVID-19 positive test by the polymerase chain reaction (PCR)
• Severity of COVID-19 (SARA-Cov-2) infection [ Time Frame: 60 days ]
  Percentage of mild, moderate and sever forms of COVID-19 based on WHO criteria
• Hospitalization [ Time Frame: 60 days ]
  Percentage of patients who need to be hospitalized
• Disease duration [ Time Frame: 60 days ]
  Days from the first symptom/positive test to discharge from hospital/negative test
• Death [ Time Frame: 60 days ]
  Rate of death due to COVID-19 during the study
• Oxygen support [ Time Frame: 60 days ]
  Percentage of COVID patients who need oxygen support

Original Primary Outcome Measures (submitted: May 11, 2020)

• COVID-19 (SARA-Cov-2) infection [ Time Frame: 60 days ]
  patients over 18 years of age with acute respiratory tract infection symptoms (e.g. fever, cough, dyspnea) with no other etiology that fully explains the clinical presentation accompanied by chest computed tomography (CT) scan findings compatible with Covid-19 or definite diagnosis of Covid-19 with real-time polymerase chain reaction (PCR)
• Severity of COVID-19 (SARA-Cov-2) infection [ Time Frame: 60 days ]
  Mild, moderate and sever based on WHO criteria
• Hospitalization [ Time Frame: 60 days ]
  Need to admission in Hospital
• Disease duration [ Time Frame: 60 days ]
  from first symptom/positive test to discharge from hospital/negative test
• Death [ Time Frame: 60 days ]
  The mortality of COVID-19 during the study
• Oxygen support [ Time Frame: 60 days ]
  Need to oxygen support

Current Secondary Outcome Measures (submitted: June 10, 2020)

• Type of oxygen support [ Time Frame: 60 days ]
  Percentage of COVID patients who require each: Nasal cannula, Non-invasive ventilation or high-flow nasal cannula, Invasive mechanical ventilation, Invasive mechanical ventilation and ECMO
• Symptoms of COVID-19 [ Time Frame: 60 days ]
  Percentage of COVID patients who display each: fever, dry cough, coughing sputum or blood, sore throat, headache, diarrhea and shortness of breath
• Serum Levels of 25-hydroxyvitamin D3 [ Time Frame: 60 days ]
  Serum Levels of 25-hydroxyvitamin D3 (ng/ml) by HPLC
• Serum levels of calcium [ Time Frame: 60 days ]
  Serum calcium concentration (mg/dl)
• Serum levels of phosphorus [ Time Frame: 60 days ]
  Serum phosphorus concentration (mg/dl)
• Serum levels of creatinine [ Time Frame: 60 days ]
  Serum creatinine concentration (mg/dl)
• Serum levels of albumin [ Time Frame: 60 days ]
  Serum albumin concentration (g/dl)
• Serum levels of the blood urea nitrogen (BUN) [ Time Frame: 60 days ]
  Serum concentration of the blood urea nitrogen (mg/dl)
• Serum levels of the parathyroid hormone (PTH) [ Time Frame: 60 days ]
  Serum concentration of the parathyroid hormone (pg/ml)

Original Secondary Outcome Measures (submitted: May 11, 2020)

• Type of oxygen support [ Time Frame: 60 days ]
  Nasal cannula, Non-invasive ventilation or high-flow nasal cannula, Invasive mechanical ventilation, Invasive mechanical ventilation and ECMO
• Symptoms of COVID-19 [ Time Frame: 60 days ]
  fever, dry cough, coughing sputum or blood, sore throat, headache, diarrhea and shortness of breath
• Serum Levels of 25-hydroxyvitamin D3 [ Time Frame: 60 days ]
  Serum Levels of 25-hydroxyvitamin D3 by HPLC
• Biochemical measurements [ Time Frame: 60 days ]
  serum levels of calcium, phosphorus, creatinine, albumin, BUN, LFTs, and PTH

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Oral 25-hydroxyvitamin D3 and COVID-19
• Official Title: Preventive and Therapeutic Effects of Oral 25-hydroxyvitamin D3 on Coronavirus (COVID-19) in Adults
• Brief Summary: The goal of this clinical trial is to investigate the therapeutic efficacy of rapidly correcting vitamin D deficiency in adults with the use of 25-hydroxyvitamin D3 [25(OH)D3] for reducing the risk of acquiring the SARS-CoV-2 (COVID-19) viral infection and mitigating morbidity and mortality associated with this infection. This evidence-based hypothesis is related to several observations. Macrophages, activated T and B lymphocytes have a vitamin D receptor and 1,25-dihydroxyvitamin D3 induces defensin protein synthesis, influences immunoglobulin production and modulates T-cell cytokine production and functions. 1,25-dihydroxyvitamin D3 also reduces the angiotensin-converting enzyme 2 (ACE2) that is believed to serve as the binding site and gateway for COVID-19 to become infectious. This is a multicenter randomized3 doubleblinded placebo-controlled study aimed at determining the benefits of 25(OH)D3 treatment for the prevention of COVID-19 infection and improving clinical outcomes in infected patients. The investigators plan to recruit 1500 subjects in 3 study groups that include hospital health providers, patients with a positive test for COVID-19 and their relatives with a negative test. Eligible subjects in each study group with a documented serum level of 25(OH)D < 20 ng/mL will be randomized. Recruited subjects will be given 25 mcg of 25(OH)D3 daily or an identically appearing placebo at the time of randomization for two months. Three hospitals will participate and the sample size is foreseen to be equally distributed between the three. Since the clinical trial is designed as minimal risk a formal committee for data monitoring is not foreseen. However, potential toxicity will be monitored every 4 weeks with a serum calcium, albumin and creatinine by the PI and the study coordinators. If the corrected serum calcium increases above 10.6 mg/dl and a repeat confirms that the calcium is above 10.6 mg/dL the subject will be dropped from the study and referred to his or her PCP. Early signs and symptoms of vitamin D toxicity associated with hypercalcemia are increased thirst, increase in frequency of urination, especially at night. The subjects will be followed up weekly by phone to ask about their sign and symptoms.
• Detailed Description: Improvement in the vitamin D status i.e. total serum 25-hydroxyvitamin D in children and adults has been associated with reduced risk of upper respiratory tract infections including influenza A infection. The rationale for giving 25(OH)D3 rather than vitamin D3 is to rapidly improve the vitamin D status of the subjects who are at high risk of acquiring COVID 19 or who are infected by this very aggressive viral infection. It takes approximately 6-8 weeks to achieve a steady state blood level of 25(OH)D when ingesting a daily dose of vitamin D3 whereas ingesting 25(OH)D3 results in a rapid rise in its blood level reaching steady state within 48 hours. Based on the available literature it is reasonable to consider the possibility that vitamin D deficiency could increase risk of acquiring COVID 19 infection and exacerbating its infectivity and the body's cytokine response to it. It therefore seems plausible that the rapid improvement in vitamin D status by providing 25(OH)D3 may contribute to reducing the severity of illness caused by COVID-19, particularly in settings where hypovitaminosis D is frequent especially in people of color. Arguably, there is little evidence to date that improving the vitamin D status will reduce the infectivity risk or mitigate the devastating health consequences of COVID-19 infection. The proposed study to rapidly improve vitamin D status in adults who are at high risk of acquiring COVID- 19 or who are at risk for its morbidity and mortality will test the veracity of this evidence based hypothesis. Results from this study, especially if positive, would have far reaching global health consequences. Vitamin D3, vitamin D2 and 25-hydroxyvitamin D3 are readily available worldwide and could be quickly instituted as a rapid cost-effective method to help combat this pandemic.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is a multicenter randomized double-blinded placebo-controlled clinical trial with parallel groups and allocation 1:1.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

All subjects in a stratified random sampling method based on age, sex, BMI and serum level of 25(OH)D (<10 ng/dL vs 10 to <20 ng/dL) with serum calcium <=10.6 mg/dL will be recruited in the 25(OH)D3 or placebo group. The clinical coordinator will determine this with a computer-generated randomization program. Subjects in the case group will receive 25 mcg of 25(OH)D3 once daily at bedtime for 2 months and the control group will receive placebo daily for 2 months.

Primary Purpose: Prevention

• Condition: COVID 19

Intervention

Drug: Oral 25-Hydroxyvitamin D3

Subjects in the case group will receive 25 mcg of 25(OH)D3 once daily at bedtime for 2 months and the control group will receive placebo daily for 2 months.

Study Arms

• Experimental: Treatment
  Infected patients with acute respiratory tract infection symptoms (e.g. fever, cough, dyspnea) with no other etiology that fully explains the clinical presentation accompanied by chest computed tomography (CT) scan findings compatible with Covid-19 or with a COVID-19 positive test by the polymerase chain reaction (PCR)
  Intervention: Drug: Oral 25-Hydroxyvitamin D3
• Experimental: Prevention
  This arm of study includes the health care providers and hospital workers with a negative test for COVID-19 and a close patient relative with a negative test for COVID-19 who lives with the infected patients.
  Intervention: Drug: Oral 25-Hydroxyvitamin D3

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 11, 2020): 1500
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 15, 2021
• Estimated Primary Completion Date: November 15, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Older than 18 years old and younger than 75 years old for all study groups.
2. Meet the diagnostic criteria of COVID-19 for different types (including ordinary type, heavy type and critical type) in infected patients.
3. No medications or disorders that would affect vitamin D metabolism
4. Women must be on birth control and not pregnant
5. Ability and willingness to give informed consent and comply with protocol requirements

Exclusion Criteria:

1. Ongoing treatment with pharmacologic doses of vitamin D, vitamin D metabolites or analogues
2. Pregnant or lactating women;
3. Severe underlying diseases, such as advanced malignant tumors, endstage lung disease, etc.
4. History of elevated serum calcium >10.6 mg/dl; that is corrected for albumin concentration or subjects with a history of hypercalciuria and kidney stones.
5. Chronic hepatic dysfunction, chronic kidney disease or intestinal malabsorption syndromes including inflammatory bowel disease.
6. Supplementation with over the counter formulations of vitamin D2 or vitamin D3
7. Use of tanning bed or artificial UV exposure within the last two weeks.
8. Consuming medication affecting vitamin D metabolism or absorption (anticonvulsants, anti-tuberculosis medication glucocorticoids, HIV medications and cholestyramine).
9. Subjects with a history of an adverse reaction to orally administered vitamin D, vitamin D metabolites or analogues.
10. Subjects with a history of conditions that can lead to high serum calcium levels such as sarcoidosis, tuberculosis and some lymphomas associated with activated macrophages which increase the production of 1,25(OH)2D.
11. Inability to give informed consent

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Zhila Maghbooli, PhD; +98 21 6670 6142; zhilayas@gmail.com

Contact: Arash Shirvani, MD, PhD; hn@bu.edu

• Listed Location Countries: Iran, Islamic Republic of

Administrative Information

• NCT Number: NCT04386850
• Other Study ID Numbers: IRCT2020-0401046909N2; IRCT20200401046909N1 ( Registry Identifier: IRCT ); IRCT2020-0401046909N2 ( Registry Identifier: IRCT )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The datasets used and analyzed during the current study will be available from the Study Principal Investigators (zhilayas@gmeil.com) on reasonable request .
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: Beginning 9 month and ending 36 months following article publication.
• Access Criteria: Investigators whose proposed use of the data has been approved by the current study principal investigators.

• Responsible Party: Tehran University of Medical Sciences
• Study Sponsor: Tehran University of Medical Sciences
• Collaborators: Boston University

Investigators

• Study Chair: Mohamadali Sahraian, MD; Tehran University of Medical Sciences
• Principal Investigator: zhila Maghbooli, PhD; Tehran University of Medical Sciences
• Principal Investigator: Michael F Holick, PhD,MD; Boston University
• Principal Investigator: Arash Shirvani, MD, PhD; Boston University

• PRS Account: Tehran University of Medical Sciences
• Verification Date: May 2020