key: cord-0681885-ean4awiy authors: Elamir, Yasmine M.; Amir, Hajira; Lim, Steven; Rana, Yesha Patel; Lopez, Carolina Gonzalez; Feliciano, Natalia Viera; Omar, Ali; Grist, William Paul; Via, Michael A. title: A Randomized Pilot Study Using Calcitriol in Hospitalized Patients date: 2021-09-08 journal: Bone DOI: 10.1016/j.bone.2021.116175 sha: 558d3e90039a28e589c641635d91e46606fd02ad doc_id: 681885 cord_uid: ean4awiy The systemic illness associated with SARS-CoV-2 infection results in hospitalization rate of 380.3 hospitalizations per 100,000 population, overwhelming health care systems. Vitamin D regulates expression of approximately 11,000 genes spanning many physiologic functions that include regulation of both innate and adaptive immune function. We investigate potential benefit of calcitriol therapy given to patients hospitalized with COVID-19. This was an open label, randomized clinical trial of calcitriol or no treatment given to hospitalized adult patients with COVID-19. Subjects were randomly assigned treatment with calcitriol 0.5 mcg daily for 14 days or hospital discharge; or no treatment [1:1] at time of enrollment. We enrolled 50 consecutive patients, 25 per trial arm. The change in peripheral arterial oxygen saturation to the inspired fraction of oxygen (SaO2/FIO2 ratio) on admission and discharge between the groups the control group had an average increase of +13.2 (+/- 127.7) on discharge and the calcitriol group had an increase of +91.04 (+/- 119.08) (p= .0305), suggesting an improvement in oxygenation among subjects who received calcitriol. Additionally, 12 patients in the control group required oxygen supplementation on admission and 21 of them were discharged on room air. 14 subjects needed oxygen supplementation in the calcitriol group on admission while all 25 were discharged on room air. Other clinical markers showed the average length of stay was 9.24 (± 9.4) in the control group compared to 5.5 (± 3.9) days in the calcitriol group (p= .14). The need for ICU transfer was 8 in the control group and 5 in the calcitriol group. There were 3 deaths and 4 readmissions in the control group and 0 deaths and 2 readmissions in the calcitriol group. This pilot study illustrates improvement in oxygenation among hospitalized patients with COVID-19 treated with calcitriol and suggests the need for a larger randomized trial. None of the authors have anything to disclose regarding the below. 1. Service on Board of Directors 2. Consulting (other than Advisory Boards or Board of Directors) 3. Position in a company, employment or executive position in pharmaceutical, medical device, or diagnostic companies; including industry scientists in the bone and mineral field 4. Serving as an expert witness or consultant in litigation for commercial entities 5. Honoraria or royalties for books or publications or for lectures (speaker fees) or participating in a speakers bureau 6. Research grants, direct salary support or other financial support from commercial entities 7. Stock holdings and/or stock options in pharmaceutical, medical device, or diagnostic companies 8. Partnerships, warrants, royalties for inventions (licensing revenues) or other ownership interest 9. No institutional investigation regarding conflict of interest, responsible conduct in research, animal welfare, human subjects, or laboratory safety compliance exists 10. Or any other situation or transaction or formal role where we have interest Data Availability Statement: The data that support the findings of this study will be openly available in a public archive. The systemic illness associated with SARS-CoV-2 infection results in hospitalization rate of 380.3 hospitalizations per 100,000 population, overwhelming health care systems. Vitamin D regulates expression of approximately 11,000 genes spanning many physiologic functions that include regulation of both innate and adaptive immune function. We investigate potential benefit of calcitriol therapy given to patients hospitalized with COVID-19. This was an open label, randomized clinical trial of calcitriol or no treatment given to hospitalized adult patients with COVID-19. Subjects were randomly assigned treatment with calcitriol 0.5 mcg daily for 14 days or hospital discharge; or no treatment (1:1) at time of enrollment. We enrolled 50 consecutive patients, 25 per trial arm. The change in peripheral arterial oxygen saturation to the inspired fraction of oxygen (SaO2/FIO2 ratio) on admission and discharge between the groups the control group had an average increase of +13.2 (+/-127.7) on discharge and the calcitriol group had an increase of +91.04 (+/-119.08) (p= .0305), suggesting an improvement in oxygenation among subjects who received calcitriol. Additionally, 12 patients in the control group required oxygen supplementation on admission and 21 of them were discharged on room air. 14 subjects needed oxygen supplementation in the calcitriol group on admission while all 25 were discharged on room air. Other clinical markers showed the average length of stay was 9.24 (± 9.4) in the control group compared to 5.5 (± 3.9) days in the calcitriol group (p= .14). The need for ICU transfer was 8 in the control group and 5 in the calcitriol group. There were 3 deaths and 4 readmissions in the control group and 0 deaths and 2 readmissions in the calcitriol group. The systemic illness that manifests SARS-CoV-2 infection has resulted in a cumulative hospitalization rate of 380.3 hospitalizations per 100,000 population according to the Centers for Disease Control (CDC). A triggered cytokine storm commonly results in acute respiratory distress syndrome (ARDS), multiorgan system failure, and is potentially fatal in approximately 2-3% of cases, including over 50% of patients who require mechanical ventilation. (1) Emerging therapies including remdesivir and corticosteroids demonstrate modest benefits. (2) Vitamin D regulates expression of approximately 11,000 genes spanning many physiologic functions that include regulation of both innate and adaptive immune function, pulmonary cytokine release, and induction of autophagy as an immune defense. Hospitalized and severely ill patients exhibit high rates of vitamin D deficiency, potentially impacting these immune pathways. (5-7) Lower serum concentration 25-hydroxyvitamin D is associated with adverse outcomes including increased susceptibility to SARS-CoV-2 infection, and increased severity of symptoms in the course of COVID-19. (8, 9) Activation of vitamin D-dependent pathways may provide clinical benefit to patients with SARS-CoV-2 infection. As the biochemically active metabolite, 1,25(OH)2D or calcitriol, is useful over other forms of vitamin D as therapy in patients with hypocalcemia or with secondary hyperparathyroidism due to renal insufficiency. (3) We investigate potential activation of vitamin D-dependent pathways in a trial of calcitriol therapy given to patients who are hospitalized with COVID-19. The study protocol was approved by the Mount Sinai Program for the protection of Human subjects/Institutional Review Board (IRB) for enrollment at all sites involved. Verbal consent was obtained from all patients about the outcomes that would be measured, and potential benefits and side effects with subsequent acceptance recorded in the electronic medical record. This was an open label, randomized clinical trial investigating the use of calcitriol in hospitalized patients with COVID-19. We planned to enroll 50 consecutive hospitalized adult patients with COVID-19 admitted to Mount Sinai Beth Israel, Mount Sinai Morningside, and Mount Sinai West Hospitals. Patients were excluded if they are admitted directly to the intensive care unit (ICU), if they had any of the following: hypercalcemia and/or hyperphosphatemia on admission blood tests, untreated disorders of calcium metabolism including hyperparathyroidism, hypoparathyroidism, chronic renal insufficiency with glomerular filtration rate < 30 ml/min, or if they are prescribed calcitriol for any reason outside of the study. Patients were also excluded if they declined to participate prior to enrollment. Any subject who withdrew from the trial or who left the hospital against medical advice would be included in intention to treat analysis. Eligible patients were allocated at a 1:1 calcitriol, no calcitriol ratio through electronic randomization on the day of admission. Enrolled subjects were assigned treatment with calcitriol 0.5 mcg daily for 14 days or hospital discharge, whichever came first; or no treatment. The remainder of the patient's care was determined by the primary team and may include treatment with remdesivir (200 mg for one day followed by 100mg for 4 days), dexamethasone (6 mg daily for 10 days), or convalescent plasma, as well as supplemental O2. Medication was supplied by the inpatient pharmacy. Outcomes of the effectiveness of calcitriol in the treatment of COVID-19 included oxygen requirements, length of hospital stay, need for ICU admission, mortality, and readmission. Clinical samples for SARS-CoV-2 diagnostic testing were obtained for all hospital admissions at each medical center by nasopharyngeal exudate sampling. Procedures for RNA extraction and real-time RT-PCR were undertaken at on-site testing using Roche Cobas 6800 System or Agena Mass ARRAY System. Erlangen, Germany), ferritin, and, ESR (Excite 40 Random access ESR Analyzer 8060), Creactive protein (Abbott Architect Analyzer, Siemens Healthineers, Erlangen, Germany, IL-6 (Siemens Healthineers, Erlangen, Germany) Respiratory function was assessed by peripheral oxygen saturation. To assess respiratory status and oxygen requirement, the ratio of peripheral arterial oxygen saturation to the inspired fraction of oxygen (SpO2/FIO2) was calculated. The peripheral arterial oxygenation was completed with SpO2 pulse oximeter. The validity of this measure as a surrogate for the pressure arterial oxygen to the fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio has been demonstrated in numerous studies (10) Statistical Analysis Descriptive statistics were used for demographic, laboratory, and clinical prognostic factors related to COVID-19 for each treatment arm. This included age, race, sex, body mass index, comorbidities, COVID-19 treatments utilized, and baseline IL-6 and procalcitonin levels. The comparison between groups of quantitative variables were performed by using t-test for qualitative variables, χ2 tests and Fisher exact tests (with frequencies <5) were used as well as a Mann-Whitney test for length of stay. The comparison for the improvement in SpO2/FIO2 ratio was performed using t-test. We enrolled 50 consecutive patients, 25 per trial arm between September 2020-December 2020. Baseline characteristics of each group is given in table 1. No subject withdrew from the study. Primary outcome and other clinical outcomes are given in figure 1 and table 2 . The average length of stay was 9.24 (± 9.4) in the control group compared to 5.5 (± 3.9) days in the calcitriol group (p= .14). The need for transfer to ICU was 8 in the control group and 5 in the calcitriol group (p=.33). There were 3 deaths and 4 readmissions in the control group and 0 deaths and 2 readmissions in the calcitriol group. 12 patients in the control group required oxygen supplementation on admission and 21 of them were discharged on room air. 14 subjects needed oxygen supplementation in the calcitriol group on admission while all 25 were discharged on room air. When comparing change in oxygen saturation using SaO2/FIO2 ratio on admission and discharge between the groups the control group had an average increase of +13.2 (+/-127.7) on discharge and the calcitriol group had an increase of +91.04 (+/-119.08) (p= .0305) (figure 1). No adverse effects were observed (table 3), including no hypercalcemia or hyperphosphatemia. Our study shows a significant reduction in oxygen requirements in patients hospitalized with COVID-19 who received calcitriol. Since ICU patients were not included, routine arterial blood gas assessment was not available. The PaO2/FIO2 ratio is a highly regarded parameter of respiratory function and serves as a predictor of ICU mortality in patients with sepsis and ARDS. (11) that were also given losartan suggests that vitamin D functions, in part, by up-regulating the pulmonary renin/angiotensin system to mitigate lung damage. (19) This same system is disrupted by COVID-19 infection. (20) Human trials with cholecalciferol therapy for ARDS have mixed results. In a randomized trial, patients that underwent esophagectomy demonstrated a transient reduction in markers of ARDS with 300,000 IU treatment of cholecalciferol compared to placebo. (21) The authors argue that declining levels of VDBP that were observed in this trial may explain the short-lived benefit of cholecalciferol that was observed. In another randomized trial of 475 mechanically ventilated ICU patients given 540,000 units cholecalciferol vs placebo, a 44% reduction in hospital mortality was observed in the cholecalciferol treated patients among the subgroup of patients with 25-hydroxyvitamin D levels less than 12 ng/ml. (22) In addition, the cholecalciferol treated patients demonstrated a further reduction in mortality that persisted for 6 months of follow up. (22) A larger, multicenter trial is currently underway. (23) Limitations of our trial include lack of a placebo and lack of blinding. It is unlikely this would affect the SaO2/FIO2 endpoint. Additionally, 25-hydroxyvitamin D levels were not measured in our study. Enrollment of patients without regard to vitamin D status strengthens the generalizability of the results. Sample size was another limitation. The patients in the control group had a higher percentage of patients above 65 years of age and certain co morbidities such as hypertension and diabetes mellitus were higher in that group. The statistical non significance in these baseline characteristics could be due to the small sample size. The low cost and high availability make calcitriol an attractive candidate for therapy in hospitalized patients with moderate to severe COVID-19. Further study of this approach is warranted. Clinical Characteristics of Covid-19 in China. 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