Vitamin D Supplementation and Clinical Improvement in COVID-19

Vitamin D Supplementation and Changes of Hematology Parameter, Coagulation Profile, and Clinical Improvement Among COVID-19 Patients

Background and objective Vitamin D is important as the interaction between vitamin D and its receptors at the immune cells stimulates innate and adaptive immunity. Deficiency in vitamin D is associated with increased susceptibility to infection and it is commonly found in Indonesia. Several studies indicate the potential of vitamin D supplementation against Coronavirus Disease 2019 (COVID-19), particularly in combating the proinflammatory situation as well as coagulopathy. This study aims to evaluate the supplementation of vitamin D in COVID 19 patients, particularly the changes in hematology parameters and other clinical parameters.

Method A double-blind randomized clinical trial is conducted among moderate COVID 19 patients. High-dose of vitamin D is given orally in the intervention group, compared with a low dose of vitamin D. Hematology parameters, D Dimer, conversion time on Polymerase Chain Reaction (PCR) test, and clinical symptoms are assessed

Hypothesis High Dose vitamin D shows a better hematology parameter, short PCR conversion time, and faster clinical recovery

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Dietary supplement: Vitamin D3 10000 IU; Dietary supplement: Vitamin D3 1000 IU

Detailed Description

Population:

The COVID 19 patients admitted to hospital with moderate severity, defined as Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level.

Methodology:

A double-blind randomized clinical trial allocated with simple random sampling

Intervention:

5000 International unit/ IU of vitamin D3 (Cholecalciferol) given orally twice daily (total 10000 IU per day)

Comparison group:

1000 International unit/ IU of vitamin D3 (Cholecalciferol) given once daily

Variables to be collected :

• The level of 25-hydroxyvitamin D in the blood
• D-Dimer
• Platelet-to-Lymphocyte Ratio (PLR)
• Total Lymphocyte Count (TLC)
• Neutrophil to Lymphocyte Ratio (NLR)
• Age
• Sex
• Comorbidities including chronic diseases
• Body Mass Index
• Handgrips Strength
• Anticoagulant administration
• Clinical Symptoms and days to recover
• Length of Stay
• Time to PCR conversion where the PCR is conducted every two days

Sample size and recruitment

Following the study in Saudi Arabia, the sample size was derived from the days to achieve recovery, where the group who received the 5000 D had an average recovery day of 6.2 ± 0.8. The intervention is expected to shorten the average recovery days up to 10%. Using the difference between the two means, the effect size derived from this result is 0.775. With 5% type 1 error and 90% power and equal allocation (1:1), the number needed for each group is 30 participants

Participants are allocated consecutively according to the permutation of the simple random sampling.

Proposed statistical analysis

1. Descriptive statistics
2. Repeated measures ANOVA
3. a Linear mixed model or generalized estimated equation will be applied to adjust the variables in the baseline

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Indonesia
  • South Sulawesi
    • Makassar, South Sulawesi, Indonesia, 76124
      • Wahidin Sudirohusodo General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

1. Inclusion Criteria:

   1. Belongs to moderate case
   2. Diagnosed using PCR test
   3. Showing a vitamin D deficiency (<30 ng/dL).

2. Exclusion Criteria

   1. Pregnant or doing breastfeeding
   2. Patient under specific medication (Tuberculosis, or HIV, or malignancy) or undergo hemodialysis
   3. Receive vitamin D supplementation prior to allocation.
   4. Tested negative less than 5 days after receiving vitamin D
   5. Creatinine >2,0 mg/dL
   6. Blood Calcium >10,5 mg/dL.
   7. Ventilated
   8. Hypersensitive to vitamin D
   9. Consistent desaturation <85% with oxygen supplementation and require High-Flow Nasal Cannula (HFNC)/Extracorporeal membrane Oxygenation (ECMO) via a ventilator.
   10. Refuse to attend blood examination for follow up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Dose Vitamin D3; A chewing tablet of 5000 IU of vitamin D3 is given twice daily, orally in the morning and evening for two weeks	Dietary supplement: Vitamin D3 10000 IU; Tablet of 5000 IU of vitamin D3 given twice daily; Other Names: Hi-D Cholecalciferol 5000
Active Comparator: Low Dose Vitamin D3; A chewing tablet of 1000 IU of vitamin D3 is given once daily, orally in the morning for two weeks	Dietary supplement: Vitamin D3 1000 IU; Tablet of 1000 IU of vitamin D3 given once daily; Other Names: Hi-D Cholecalciferol 1000

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Recovery Time	Defined as the time where the clinical symptoms resolve completely (including cough and other symptoms of pneumonia)	from baseline to the time when the symptoms disappear, assessed for up to 3 months
Length of Stay	Defined as the duration of receiving hospital care	from the admission time to the time of hospital discharge, assessed for up to 3 months
PCR Conversion time	Defined as the duration of the time to obtain negative result on PCR	from the time of diagnosis until proven negative in PCR test, assessed for up to 3 months
Platelet to Lymphocyte Ratio / PLR in blood	Defined as the ratio of platelet divided by lymphocyte value. A value of >180 indicates worse prognosis	Changes of PLR value from baseline to one week
Total Lymphocyte Count (TLC) in blood	Defined as the ratio of platelet divided by lymphocyte value. A value of less 2000 cell/ mm3 defined as depletion and indicates worse prognosis	Changes of TLC value from baseline to one week
Neutrophil-Lymphocyte Ratio (NLR) in blood	Defined as the ratio of Neutrophil divided by lymphocyte value. A value of less than 3.13 indicates worse prognosis	Changes of TLC value from baseline to one week
D-Dimer	The D-dimer indicates the degree of fibrin degradation that is associated with blood clot breakage. A value of >500 ug/L indicates worse outcome	Changes of D-dimer value from baseline to one week

Collaborators and Investigators

• Sponsor: Bumi Herman
• Investigators: Principal Investigator: Sisca Agustia, MD, Hasanuddin University; Principal Investigator: Amirah Faisal, MD, Hasanuddin University; Principal Investigator: Zahratul Fajri, Hasanuddin University; Principal Investigator: Nurpudji Taslim, Prof, Hasanuddin University; Principal Investigator: Suryani Armyn, Prof, Hasanuddin University; Principal Investigator: Haerani Rasyid, Prof, Hasanuddin University; Principal Investigator: Agussalim Bukhari, Prof, Hasanuddin University; Principal Investigator: Irawaty Djaharuddin, Prof, Hasanuddin University

Publications and helpful links

General Publications

• Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. J Infect Public Health. 2020 Oct;13(10):1373-1380. doi: 10.1016/j.jiph.2020.06.021. Epub 2020 Jun 20.
• Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open. 2020 Sep 1;3(9):e2019722. doi: 10.1001/jamanetworkopen.2020.19722.
• Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol. 2020 Jul;84:106504. doi: 10.1016/j.intimp.2020.106504. Epub 2020 Apr 13.
• Yao Y, Cao J, Wang Q, Shi Q, Liu K, Luo Z, Chen X, Chen S, Yu K, Huang Z, Hu B. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care. 2020 Jul 10;8:49. doi: 10.1186/s40560-020-00466-z. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2021
• Primary Completion (Actual): September 30, 2021
• Study Completion (Actual): November 1, 2021

Study Registration Dates

• First Submitted: November 12, 2021
• First Submitted That Met QC Criteria: November 17, 2021
• First Posted (Actual): November 19, 2021

Study Record Updates

• Last Update Posted (Actual): November 19, 2021
• Last Update Submitted That Met QC Criteria: November 17, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Vitamin D; COVID-19; D-Dimer; Hematology parameter; PCR Conversion; Clinical Recovery
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: 0411212204

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No data sharing will be done

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No