key: cord-0742121-mo1bj909
authors: Thomas, Suma; Patel, Divyang; Bittel, Barbara; Wolski, Kathy; Wang, Qiuqing; Kumar, Anirudh; Il’Giovine, Zachary J.; Mehra, Reena; McWilliams, Carla; Nissen, Steve E.; Desai, Milind Y.
title: Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial
date: 2021-02-12
journal: JAMA Netw Open
DOI: 10.1001/jamanetworkopen.2021.0369
sha: f25821083e2534b082d03d0fd083d5b6d5025aea
doc_id: 742121
cord_uid: mo1bj909

IMPORTANCE: There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression. OBJECTIVE: To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020. INTERVENTION: Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care. OUTCOMES: The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. RESULTS: A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04342728

I have carefully read the COVIDAtoZ Research Study protocol. I agree to conduct this study as 28 outlined herein. Furthermore, I understand that the Cleveland Clinic and the IRB must approve 29 any changes to the protocol in writing before implementation. Diarrhea: 0 = No diarrhea, 1=mild diarrhea, 2=moderate diarrhea, 3=severe diarrhea. Each 83 patient will have a composite score ranging from 0-12/day. The tracking will continue for the 28 84 days of study participation for each subject. They will also be asked to complete a questionnaire 85 at the beginning of study period, day 7, day 14, day 21 and day 28. The purpose of the 86 questionnaire is to assess whether patient received additional medications/ supplements, sought 87 treatment at emergency rooms or were hospitalized, or experienced side effects from the study 88 supplements.

The primary clinical endpoint is the number of days required to reach a 50 percent shown that vitamin C could be protective against coronavirus and human trials have found that 129 vitamin C may decrease susceptibility to viral respiratory infections and pneumonia. As a result 130 of these biologic effects, we hypothesize zinc and vitamin C supplementation may have a 131 potential role in improving the response to an infection such as COVID-2019.

The purpose of the current study is to see whether ascorbic acid and zinc gluconate which Patients will then track their symptoms daily from day 0 to day 28 answering 12 basic 165 questions on illness severity. Symptom assessment tools will be completed by patients daily 166 either electronically or on paper. For those completing the tool electronically a tool will be 167 emailed to the patient daily via RedCap. For those completing the tool on paper a 28 day paper 168 assessment tool will be provided to the patient at the time of consent via email/ 169 courier/text/express mail. For those patients completing a paper tool, a research staff member 170 will contact the patient daily via phone call to obtain their daily assessment scores. Study team 171 members will call patients at days 7, 14, 21, and day 28 of the study period to obtain information 172 regarding hospitalizations, ER visits, additional medications prescribed by a healthcare provider or over the counter, and any side effects from the study supplements that the patient could have 174 experienced. Study team members may also call patients if non-compliance with completion of 175 the daily symptom assessment tool.

Patients seen in the Emergency Department (ER) during the course of study participation will 177 continue to take study supplement(s) (if within the initial 10 days) and continue daily symptom 178 assessments as above.

Patients admitted to the hospital during the course of study participation will no longer be 180 required to continue study supplementation nor track their daily symptoms.

The primary objective will be evaluating the duration of symptoms in the four study 183 arms. We will assess this by counting from when peak symptom score is achieved to when there 184 is a 50% reduction in the symptom severity score. This randomized control trial will aim to prospectively enroll 520 patients who have 234 received a positive confirmed diagnosis of coronavirus 2019. All patients will be followed for 28 235 days to review vital status, hospitalizations, emergency room visits, and need for additional 236 treatment. We assumed the standard of care group will have a 50% reduction of symptom 237 severity in approximately 6± 3 days, and that at least one of the other 3 study groups will reach a 238 50% reduction in 5 ± 3 days. When the sample size in each of the 4 groups is 130, a one-way 239 analysis of variance will have 80% power (2-sided alpha of 0.05) to detect a difference in means 240 characterized by a variance of means, V, of 0.188, assuming that the common standard deviation 241 is 3 days. Our study aims to enroll 520 patients to account for study drop out as well.

The primary endpoint will be the number of days required to reach a 50% reduction in the 244 symptom severity score from peak symptom score.

Additional endpoints to be considered include: 

Descriptive statistics will be generated for all baseline patient characteristics, 256 complications, and endpoints. Frequency counts and percentages will be used to summarize 257 binary and categorical data. Continuous data will be summarized using means ± standard 258 deviation, median and interquartile range, and minimum/maximum values. ANOVA tests will be 259 used to describe the difference in number of days to a 50% reduction on the symptom severity 260 score between the four groups. All pairwise comparisons will be generated and adjusted for 261 multiple comparisons using the Tukey method. reported to the IRB as per current IRB reporting policies. 289 We will have a study safety committee to evaluate data for an increased signal for adverse side- Data will be stored on in a REDCAP database. There is an instance of this database 294 maintained as a resource at Cleveland Clinic. REDCAP is maintained by Cleveland Clinic but is 295 accessible on and off campus in secure fashion. We will analyze the data using SAS, version 9.4 296 or other programs as the discretion of the investigators or statisticians. The data will be entered 297 into the database after completion of the procedure. Those members of the study team that have 298 been delegated by the Principal Investigator to do so, are the only individuals that will have 299 permission to enter and access the data in the study RedCap database. There is risk even with 300 using secure database that personal health information that there may be loss of confidentiality.

Furthermore, some disclosures of public health information will take place consistent with public 302 health requirements as a part of the study. submit to the PI a written request along with a signed Sub-Investigator Statement of Assurance.

The PI is responsible for authorizing the release of data to Sub-Investigators and tracking these 317 uses with a brief description of their activity.

The PI confirms no data from this database will be released without a written request 319 from the sub-investigator and that the data provided will not contain identifiers unless consent 320 from subjects has been obtained. 

Clinical features of patients infected with 2019 novel 334 coronavirus in Wuhan

Characteristics of and Important Lessons From the Coronavirus 337 Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From 338 the Chinese Center for Disease Control and Prevention

Vitamin C for preventing and treating the common cold (Review)

Zinc for the Common Cold

Reduction in duration of common cold by zinc gluconate 347 lozenges in a double-blind study

Zinc lozenges and common cold: A meta-analysis comparison of zinc acetate 350 and zinc gluconate and zinc dosage

Vitamin C administration in the critically ill: a summary of recent meta-analyses

Vitamin C and Infections

SARS-CoV-2 Cell Entry Depends on 358 ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

A combination of high-dose vitamin C plus zinc for the 361 common cold

Zinc in Infection and Inflammation

Zn(2+) 365 inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores 366 block the replication of these viruses in cell culture

Vitamin C, respiratory infections and the immune system

The effect of ascorbic acid on infection chick-embryo 372 ciliated tracheal organ cultures by coronavirus

Ascorbic Acid and infectious bronchitis infections in broilers