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Vitamin D and zinc supplementation to improve treatment outcomes among COVID-19 patients in India: results from a double-blind randomized placebo-controlled trial

Partap et al., Current Developments in Nutrition, doi:10.1016/j.cdnut.2023.101971, NCT04641195
Jul 2023  
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Ventilation -3% Improvement Relative Risk Discharge 14% Recovery, dyspnea, coug.. 11% Recovery, dyspnea 72% Recovery, fever 3% Recovery, cough 17% Recovery, D+Z, dyspnea, c.. 16% Recovery, D+Z, dyspnea 77% Recovery, D+Z, fever 17% Recovery, D+Z, cough 18% Vitamin D  Partap et al.  EARLY TREATMENT  DB RCT Is early treatment with vitamin D beneficial for COVID-19? Double-blind RCT 83 patients in India (April 2021 - August 2022) Higher discharge with vitamin D (not stat. sig., p=0.53) c19early.org Partap et al., Current Developments in.., Jul 2023 Favorsvitamin D Favorscontrol 0 0.5 1 1.5 2+
Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 112 treatments. c19early.org
Early terminated factorial RCT with 46 vitamin D, 48 zinc, 44 vitamin D + zinc, and 43 placebo patients in India.
The most serious outcome (ventilation) numbers do not seem realistic. Authors do not specify outcomes per group, but with one event for non-zinc, we know that either the vitamin D only or the placebo group had zero events, which does not match the reported RRs. All 7 RRs are close to 1.0: for D vs. non-D, Z vs. non-Z, D+Z vs. placebo, D vs. placebo, Z vs. placebo, D<20ng/mL vs. non-D, and D>20ng/mL vs. non-D. This suggests unreliable data or analysis (e.g., inappropriate use of Poisson regression). We will update when authors respond.
The trial is also unusual in that the primary analyses are unadjusted and compare one treatment with a combination of another treatment and placebo.
There are very large baseline differences, e.g., 35 vs. 15% 60+ for zinc vs. non-zinc. There was only 181 patients recruited from 700 planned.
There is limited room for improvement with the population studied that recovered very quickly within a median of 3 days. Oral cholecalciferol takes 3-7 days for complete conversion into the biologically active 1,25-dihydroxyvitamin D. Authors could have provided treatment with much faster onset of action, e.g., using calcitriol.
There was very little improvement in D/zinc levels with the administration used and the baseline deficiency levels. Only 4% of people went from zinc deficient to sufficient, and only 8% went from vitamin D <30ng/mL to >30ng/mL, and most or all of these improvements may have been after patients already recovered.
Notwithstanding the limitations above, we note that, while small, the effect for most outcomes is positive for vitamin D and zinc, and in most cases, the effect in the combined vitamin D + zinc group is larger.
Data for this study is not available.
Cholecalciferol was used in this study. Cholecalciferol requires two hydroxylation steps to become activated - first in the liver to calcifediol, then in the kidney to calcitriol. Calcitriol, paricalcitol, and alfacalcidol are active vitamin D analogs that do not require conversion. This allows them to have more rapid onset of action compared to cholecalciferol. The time delay for cholecalciferol to increase serum calcifediol levels can be 2-3 days, and the delay for converting calcifediol to active calcitriol can be up to 7 days. Results may be better with calcitriol / calcifediol (or paricalcitol, alfacalcidol, etc.).
Study covers zinc and vitamin D.
risk of mechanical ventilation, 3.0% higher, RR 1.03, p = 0.91, treatment 41, control 42, vitamin D vs. placebo.
risk of no hospital discharge, 14.0% lower, HR 0.86, p = 0.53, treatment 41, control 42, vitamin D vs. placebo.
risk of no recovery, 11.0% lower, HR 0.89, p = 0.65, treatment 41, control 42, vitamin D vs. placebo, dyspnea, cough, or fever, Table S8.
risk of no recovery, 72.0% lower, HR 0.28, p = 0.17, treatment 41, control 42, vitamin D vs. placebo, dyspnea, Table S8.
risk of no recovery, 3.0% lower, HR 0.97, p = 0.92, treatment 41, control 42, vitamin D vs. placebo, fever, Table S8.
risk of no recovery, 17.0% lower, HR 0.83, p = 0.51, treatment 41, control 42, vitamin D vs. placebo, cough, Table S8.
risk of no recovery, 16.0% lower, HR 0.84, p = 0.51, treatment 39, control 42, zinc + vitamin D vs. placebo, dyspnea, cough, or fever, Table S8.
risk of no recovery, 77.0% lower, HR 0.23, p = 0.06, treatment 39, control 42, zinc + vitamin D vs. placebo, dyspnea, Table S8.
risk of no recovery, 17.0% lower, HR 0.83, p = 0.57, treatment 39, control 42, zinc + vitamin D vs. placebo, fever, Table S8.
risk of no recovery, 18.0% lower, HR 0.82, p = 0.50, treatment 39, control 42, zinc + vitamin D vs. placebo, cough, Table S8.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Partap et al., 11 Jul 2023, Double Blind Randomized Controlled Trial, placebo-controlled, India, peer-reviewed, 13 authors, study period 22 April, 2021 - 1 August, 2022, trial NCT04641195 (history). Contact: upartap@hsph.harvard.edu, mina@hsph.harvard.edu.
This PaperVitamin DAll
Vitamin D and Zinc Supplementation to Improve Treatment Outcomes among COVID-19 Patients in India: Results from a Double-Blind Randomized Placebo-Controlled Trial
Dr Uttara Partap, Kamal Kant Sharma, Yogesh Marathe, Molin Wang, Sanaa Shaikh, Pradeep D’costa, Gaurav Gupta, Sabri Bromage, Elena C Hemler, Nerges Mistry, Kevin C Kain, Yatin Dholakia, Wafaie W Fawzi
Current Developments in Nutrition, doi:10.1016/j.cdnut.2023.101971
Vitamin D and zinc supplementation to improve treatment outcomes among COVID-19 patients in India: results from a double-blind randomized placebo-controlled trial, Current Developments in Nutrition,
Competing interests All authors declare no conflicts of interest. Summary In a randomized factorial trial in a small population in India, neither vitamin D nor zinc supplementation appeared to improve COVID-19 treatment outcomes. Large-scale data are needed to corroborate findings. J o u r n a l P r e -p r o o f DATA SHARING Data from this study are currently not available to be shared due to regulatory restrictions. J o u r n a l P r e -p r o o f
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