COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial)

• ClinicalTrials.gov Identifier: NCT04344041
• Recruitment Status: Recruiting
• First Posted: April 14, 2020
• Last Update Posted: October 5, 2020
• Sponsor: University Hospital, Angers
• Collaborator: Mylan Laboratories
• Information provided by (Responsible Party): University Hospital, Angers

Tracking Information

• First Submitted Date: April 9, 2020
• First Posted Date: April 14, 2020
• Last Update Posted Date: October 5, 2020
• Actual Study Start Date: April 15, 2020
• Estimated Primary Completion Date: May 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 9, 2020): Number of death of any cause, during the 14 days following the inclusion and intervention. [ Time Frame: Day 14 ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 4, 2020)

• Number of death of any cause, during the 28 days following the inclusion and intervention. [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the WHO Ordinal Scale for Clinical Improvement (OSCI) for COVID-19 [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19 [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Rate of patients with at least one severe adverse event at day 28, according to the regulations [ Time Frame: Day 28 ]
• Number of death of any cause during the 14 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD <25nmol/L) at baseline [ Time Frame: Day 14 ]
• Number of death of any cause during the 28 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD <25nmol/L) at baseline [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD <25nmol/L) at baseline [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at baseline [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Number of death of any cause during the 14 days following the inclusion and intervention, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 14 ]
• Number of death of any cause during the 28 days following the inclusion and intervention, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the OSCI for COVID-19, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Number of death of any cause during the 14 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 14 ]
• Number of death of any cause during the 28 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Number of death of any cause during the 14 days following the inclusion and intervention, depending on evolution of serum vitamin D concentration between day 0 and day 7 [ Time Frame: Day 14 ]
• Number of death of any cause during the 28 days following the inclusion and intervention, depending on evolution of serum vitamin D concentration between day 0 and day 7 [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the OSCI for COVID-19, depending on evolution of serum vitamin D concentration between day 0 and day 7 [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19, depending on evolution of serum vitamin D concentration between day 0 and day 7 [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Number of death of any cause during the 14 days following the inclusion and intervention, compared to mortality data in French hospital geriatric units from the current national survey by the French Society of Geriatrics and Gerontology [ Time Frame: Day 14 ]

Original Secondary Outcome Measures (submitted: April 9, 2020)

• Number of death of any cause, during the 28 days following the inclusion and intervention. [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the WHO Ordinal Scale for Clinical Improvement (OSCI) for COVID-19 [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19 [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Rate of patients with at least one severe adverse event at day 28, according to the regulations [ Time Frame: Day 28 ]
• Number of death of any cause during the 14 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD <25nmol/L) at baseline [ Time Frame: Day 14 ]
• Number of death of any cause during the 28 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD <25nmol/L) at baseline [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD <25nmol/L) at baseline [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at baseline [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Number of death of any cause during the 14 days following the inclusion and intervention, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 14 ]
• Number of death of any cause during the 28 days following the inclusion and intervention, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the OSCI for COVID-19, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19, depending on serum vitamin D concentration achieved at day 7 (25-OHD<75nmol/L or 25-OHD≥75nmol/L) [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Number of death of any cause during the 14 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 14 ]
• Number of death of any cause during the 28 days following the inclusion and intervention, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 28 ]
• Clinical evolution between day 0 and day 14 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 14 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome
• Clinical evolution between day 0 and day 28 based on the change of the OSCI for COVID-19, in patients with severe hypovitaminosis D (25-OHD<25nmol/L) at day 0, depending on serum vitamin D concentration achieved at day 7 (<75nmol/L or ≥75nmol/L) [ Time Frame: Day 28 ]
  OSCI ranges from 0 to 8, higher score meaning poorer outcome

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

Descriptive Information

• Brief Title: COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial)
• Official Title: COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial)

Brief Summary

Vitamin D is a secosteroid hormone produced by the skin during Summer exposure to UVB rays. Hypovitaminosis D is common in Winter (October to March) at Northern latitudes above 20 degrees North, and from April to September at Southern latitudes beyond 20 degrees below the equator.

In the past, coronaviruses and influenza viruses have exhibited very high seasonality, with outbreaks occurring preferentially during the Winter. The Covid-19 pandemic is indeed more severe above Winter latitudes of 20 degrees, while it remains until now less severe in the Southern hemisphere, with a much lower number of deaths.

Preclinical research suggests that the SARS-Cov-2 virus enters cells via the angiotensin converting enzyme 2 (ACE2). Coronavirus viral replication downregulates ACE2, thereby dysregulating the renin-angiotensin system (RAS) and leading to a cytokine storm in the host, causing acute respiratory distress syndrome (ARDS).

Research also shows that vitamin D plays a role in balancing RAS and in reducing lung damage. On the contrary, chronic hypovitaminosis D induces pulmonary fibrosis through activation of RAS. Similarly, hypovitaminosis D has been strongly associated in the literature with ARDS, as well as with a pejorative vital prognosis in resuscitation but also in geriatric units, and with various comorbidities associated to deaths during SARS-Cov-2 infections. Conversely, vitamin D supplementation has been reported to increase immunity and to reduce inflammatory responses and the risk of acute respiratory tract infections.

High-dose oral vitamin D3 supplementation has been shown to decrease short-term mortality in resuscitation patients with severe hypovitaminosis D (17% absolute risk reduction). It is considered safe to take oral vitamin D supplementation at doses up to 10,000 IU/day for short periods, particularly in older adults, i.e. a population that is mostly affected by hypovitaminosis D and who should receive at least 1,500 IU of vitamin D daily to ensure satisfactory vitamin D status.

Vitamin D supplementation is mentioned as a potentially interesting treatment for SARS-Cov-2 infection but on a scientific basis with a low level of evidence until now.

We hypothesize that high-dose vitamin D supplementation improves the prognosis of older patients diagnosed with COVID-19 compared to a standard dose of vitamin D.

Detailed Description

• Inclusion visit A clinical examination is carried out. Social-demographic measures, health history, clinical examination measures (including OSCI score) and biological measures are collected.

Randomization is conducted on the day of the inclusion visit. The ZYMAD® 400,000 IU (2 vials of 200,000 IU) or 50,000 IU (1 vial of 50,000 IU) treatment is given to the patient.

• Visit at day 7 A blood test is carried out by a nurse to determine the serum 25-OHD, creatrinine, albumine and calcium concentrations.
• Visit at day 14 A visit or telephone call allows recording the onset of clinical events of interest. The drugs received as part of the usual treatment during the last 14 days are collected.
• Visit at day 28 A visit or telephone call allows recording the onset of clinical events of interest. The drugs received as part of the usual treatment during the last 14 days are collected.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Coronavirus

Intervention

• Drug: cholecalciferol 200,000 IU
  Patients receive a vitamin D supplementation of 400,000 IU in a single oral dose.
• Drug: cholecalciferol 50,000 IU
  Patients receive a vitamin D supplementation of 50,000 IU in a single oral dose

Study Arms

• Experimental: Intervention group
  High dose of vitamin D3
  Intervention: Drug: cholecalciferol 200,000 IU
• Active Comparator: Comparator group
  Standard dose of vitamin D3
  Intervention: Drug: cholecalciferol 50,000 IU

• Publications *: Annweiler C, Beaudenon M, Gautier J, Simon R, Dubée V, Gonsard J, Parot-Schinkel E; COVIT-TRIAL study group. COvid-19 and high-dose VITamin D supplementation TRIAL in high-risk older patients (COVIT-TRIAL): study protocol for a randomized controlled trial. Trials. 2020 Dec 28;21(1):1031. doi: 10.1186/s13063-020-04928-5.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 9, 2020): 260
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2021
• Estimated Primary Completion Date: May 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age ≥ 65 years old
• Infection with COVID-19 diagnosed with RT-PCR SARS-CoV-2 or withCT-scan of the chest suggesting viral pneumonia of peripheral predominance in a clinically relevant context
• Patient seen in hospitalization or consultation or in nursing home
• Diagnosed within the preceding 3 days

• Having at least one of the following two risk factors for complications:

  • age ≥75 years
  • Peripheral capillary oxygen saturation (SpO2) ≤ 94% ambient air, or a partial oxygen pressure (PaO2) to fraction of inspired oxygen (FiO2) ratio ≤ 300 mmHg
• Patients affiliated with or benefitting from a social security scheme
• Written and signed consent of the patient or a relative or, if not possible, emergency inclusion procedure

Exclusion Criteria:

• Organ failure requiring admission to a resuscitation or high dependency unit
• Comorbidity that is life-threatening in the short-term (life expectancy <3 months)
• Any reason that makes follow-up at day 28 impossible
• Vitamin D supplementation in the previous month, with the exception of treatment providing less than 800 IU of vitamin D per day
• Contraindication for vitamin D supplementation: active granulomatosis (sarcoidosis, tuberculosis, lymphoma), history of calcic lithiasis, known hypervitaminosis D or hypercalcemia, known intolerance to vitamin D
• Participation in another simultaneous trial
• Persons deprived of their liberty by administrative or judicial decision, persons under psychiatric care under duress, adults subject to a legal protection measure
• Peripheral capillary oxygen saturation (SpO2) ≤92% in spite of an oxygen therapy > 5L/min

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 65 Years and older (Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cédric ANNWEILER; 241354725 ext +33; cedric.annweiler@chu-angers.fr

Contact: DCRI Angers; 02 41 35 36 37 ext +33; DRCI-promotion-interne@chu-angers.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT04344041
• Other Study ID Numbers: 2020-001602-34
• Has Data Monitoring Committee: Yes

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: Not Provided
• Responsible Party: University Hospital, Angers
• Study Sponsor: University Hospital, Angers
• Collaborators: Mylan Laboratories
• Investigators: Not Provided
• PRS Account: University Hospital, Angers
• Verification Date: October 2020