Coronavirus 2019 (COVID-19)- Using Ascorbic Acid and Zinc Supplementation (COVIDAtoZ)

• ClinicalTrials.gov Identifier: NCT04342728
• Recruitment Status: Completed
• First Posted: April 13, 2020
• Last Update Posted: February 16, 2021
• Sponsor: The Cleveland Clinic
• Information provided by (Responsible Party): Milind Desai, The Cleveland Clinic

Tracking Information

• First Submitted Date: April 8, 2020
• First Posted Date: April 13, 2020
• Last Update Posted Date: February 16, 2021
• Actual Study Start Date: April 8, 2020
• Actual Primary Completion Date: December 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 12, 2020)

Symptom Reduction [ Time Frame: 28 days ]

Number of days to reach a 50 percent reduction in the cumulative 0-36 symptom score with each symptom evaluated on a 0-3 scale. Assessed symptoms are Fever, Cough, Shortness of Breath, Fatigue, Muscle or body aches, Headache, New loss of taste, New loss of smell, Congestion or runny nose, Nausea, Vomiting, Diarrhea. Each patient will have a composite score ranging from 0-36/day

Original Primary Outcome Measures (submitted: April 8, 2020)

Symptom Reduction [ Time Frame: 28 days ]

Outpatients who test positive for the Coronavirus 2019; number of days required in which they reach a 50 percent reduction in the cumulative 0-12 score symptom category of fever based on a 0-3 scale: 0 = ≤98.6, 1 = >98.6- 100.6, 2 = > 100.6 - 102.6, 3 = >102; Cough on a 0-3 scale: 0 = no cough, 1 = mild, 2 = moderate, 3 = severe; Shortness of Breath on a 0-3: 0 = no shortness of breath, 1 = with moderate intensity exercise 2 = with walking on flat surface 3 = short of breath with getting dressed or daily activities; and Fatigue on a 0-3 scale: 0 = No fatigue/energetic, 1=mild fatigue, 2=moderate fatigue, 3=severe fatigue. Each patient will have a composite score ranging from 0-12/day

Current Secondary Outcome Measures (submitted: August 12, 2020)

• Symptom Resolution: Fever [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of fever based on a 0-3 scale: 0 = ≤98.6, 1 = >98.6- 100.6, 2 = > 100.6 - 102.6, 3 = >102.6
• Symptom Resolution: Cough [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of cough based on a 0-3 scale: 0 = no cough, 1 = mild, 2 = moderate, 3 = severe
• Symptom Resolution: Shortness of Breath [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of shortness of breath based on a 0-3 scale: 0 = no shortness of breath, 1 = with moderate intensity exercise 2 = with walking on flat surface 3 = short of breath with getting dressed or daily activities
• Symptom Resolution: Fatigue [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of fatigue based on a 0-3 scale: 1=mild fatigue, 2=moderate fatigue, 3=severe fatigue.
• Symptom Resolution: Muscle/body aches [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of muscle/body aches based on a 0-3 scale: 1=mild muscle/body aches, 2=moderate muscle/body aches , 3=severe muscle/body aches.
• Symptom Resolution: Headache [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of headache based on a 0-3 scale: 1=mild headache, 2=moderate headache, 3=severe headache.
• Symptom Resolution: New loss of taste [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of new loss of taste based on a 0-3 scale: 1=mild loss of taste, 2=moderate loss of taste, 3=severe loss of taste.
• Symptom Resolution: New loss of smell [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of new loss of smell based on a 0-3 scale: 1=mild loss of smell, 2=moderate loss of smell, 3=severe loss of smell.
• Symptom Resolution: Congestion/ runny nose [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of congestion/runny nose on a 0-3 scale: 1=mild congestion/runny nose , 2=moderate congestion/runny nose , 3=severe congestion/runny nose .
• Symptom Resolution: Nausea [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of nausea on a 0-3 scale: 1=mild nausea, 2=moderate nausea, 3=severe nausea.
• Symptom Resolution: Vomiting [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of vomiting on a 0-3 scale: 1=mild vomiting, 2=moderate vomiting, 3=severe vomiting.
• Symptom Resolution: Diarrhea [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of diarrhea on a 0-3 scale: 1=mild diarrhea, 2=moderate diarrhea, 3=severe diarrhea.
• Day 5 Symptoms [ Time Frame: 5 days ]
  Total symptom composite score at day 5 of study supplementation: Symptom categories of fever based on a 0-3 scale: 0 = ≤98.6, 1 = >98.6- 100.6, 2 = > 100.6 - 102.6, 3 = >102; Cough on a 0-3 scale: 0 = no cough, 1 = mild, 2 = moderate, 3 = severe; Shortness of Breath on a 0-3: 0 = no shortness of breath, 1 = with moderate intensity exercise 2 = with walking on flat surface 3 = short of breath with getting dressed or daily activities; and Fatigue on a 0-3 scale: 0 = No fatigue/energetic, 1=mild fatigue, 2=moderate fatigue, 3=severe fatigue.
• Hospitalizations [ Time Frame: 28 days ]
  Differences in hospitalization events between the study arms
• Severity of Symptoms [ Time Frame: 28 days ]
  Differences in severity of symptoms between study arms
• Adjunctive Medications [ Time Frame: 28 days ]
  Differences in number of patients who were prescribed adjunctive medications for their diagnosis between study arms
• Supplementation Side Effects [ Time Frame: 28 days ]
  Differences in number of patients in study arms who experienced side effects from the supplements.

Original Secondary Outcome Measures (submitted: April 8, 2020)

• Symptom Resolution: Fever [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of fever based on a 0-3 scale: 0 = ≤98.6, 1 = >98.6- 100.6, 2 = > 100.6 - 102.6, 3 = >102.6
• Symptom Resolution: Cough [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of cough based on a 0-3 scale: 0 = no cough, 1 = mild, 2 = moderate, 3 = severe
• Symptom Resolution: Shortness of Breath [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of shortness of breath based on a 0-3 scale: 0 = no shortness of breath, 1 = with moderate intensity exercise 2 = with walking on flat surface 3 = short of breath with getting dressed or daily activities
• Symptom Resolution: Fatigue [ Time Frame: 28 days ]
  The number of days required to reach a score of 0 from the symptom category of fatigue based on a 0-3 scale: 1=mild fatigue, 2=moderate fatigue, 3=severe fatigue.
• Day 5 Symptoms [ Time Frame: 5 days ]
  Total symptom composite score at day 5 of study supplementation: Symptom categories of fever based on a 0-3 scale: 0 = ≤98.6, 1 = >98.6- 100.6, 2 = > 100.6 - 102.6, 3 = >102; Cough on a 0-3 scale: 0 = no cough, 1 = mild, 2 = moderate, 3 = severe; Shortness of Breath on a 0-3: 0 = no shortness of breath, 1 = with moderate intensity exercise 2 = with walking on flat surface 3 = short of breath with getting dressed or daily activities; and Fatigue on a 0-3 scale: 0 = No fatigue/energetic, 1=mild fatigue, 2=moderate fatigue, 3=severe fatigue.
• Hospitalizations [ Time Frame: 28 days ]
  Differences in hospitalization events between the study arms
• Severity of Symptoms [ Time Frame: 28 days ]
  Differences in severity of symptoms between study arms
• Adjunctive Medications [ Time Frame: 28 days ]
  Differences in number of patients who were prescribed adjunctive medications for their diagnosis between study arms
• Supplementation Side Effects [ Time Frame: 28 days ]
  Differences in number of patients in study arms who experienced side effects from the supplements.

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

Descriptive Information

• Brief Title: Coronavirus 2019 (COVID-19)- Using Ascorbic Acid and Zinc Supplementation
• Official Title: Coronavirus Disease 2019- Using Ascorbic Acid and Zinc Supplementation (COVIDAtoZ) Research Study A Randomized, Open Label Single Center Study
• Brief Summary: The purpose of this study is to examine the impact of ascorbic acid (vitamin c) and zinc gluconate in reducing duration of symptoms in patients diagnosed with coronavirus disease 2019 (COVID-19). Patients above the age of 18 who present to the Cleveland Clinic outpatient testing and receive a positive test for COVID-19 will be invited to participate.

Detailed Description

We aim to see whether ascorbic acid and zinc gluconate which has limited side effect profile and is readily available over the counter can decrease the duration of symptoms seen in patients with new diagnosis of COVID-2019. A secondary purpose is to see whether Zinc and/or Ascorbic acid supplementation can prevent progression of the severe manifestations of the disease including development of dyspnea and acute respiratory distress syndrome which may require hospitalization, mechanical ventilation, and or lead to death.

This is a single-center, prospective, randomized study which plans to enroll 520 patients with a principal diagnosis of COVID-2019, managed in an outpatient setting, who presented after being sent by a healthcare provider to get tested and receive a PCR (Polymerase Chain Reaction) -assay based confirmed diagnosis of the disease. All patients who agree to participate in the study will answer a baseline questionnaire about their symptoms at the time of inclusion. Patients will then be randomized to one of 4 study arms. Patients in Arm A (n=130) will receive vitamin C (to be taken divided over 2-3 times a day with meals), patients in Arm B (n=130) will receive zinc gluconate to be taken at bedtime, patients in Arm C (n=130) will receive both vitamin C (to be taken divided over 2-3 times a day with meals) and zinc gluconate (taken at bedtime). Patients in arms A, B and C will take study supplements daily for 10 days. Patients in Arm D (n=130) will not receive any of the study medications and continue on standard of care. Patients will then track their symptoms daily from day 0 to day 28 answering 12 basic questions on illness severity.They will stop filling out their daily questions once they reach reach the end of the 28 day study period or at time of hospitalization; whichever comes first . Study team members will call patients at days 7, 14, 21, and 28 of the study period to assess need for hospitalization, ER visit, or additional medications prescribed by a healthcare provider, and any side effects from the supplements that the patient could have experienced.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:

A single-center, prospective, open label four arm study (1. Zinc only 2. Zinc and ascorbic acid 3. Ascorbic acid only 4. Standard of care.

Masking: None (Open Label)
Primary Purpose: Supportive Care

Condition

• COVID
• Corona Virus Infection

Intervention

• Dietary Supplement: Ascorbic Acid
  Readily available marketed open label ascorbic acid
  Other Name: Vitamin C
• Dietary Supplement: Zinc Gluconate
  Readily available marketed open label zinc gluconate
  Other Name: Zinc
• Dietary Supplement: Ascorbic Acid and Zinc Gluconate
  Readily available marketed open label ascorbic acid and zinc gluconate
  Other Name: Vitamin C and Zinc
• Other: Standard of Care
  Readily available prescribed medications/ supplements- None study supplements
  Other Name: Standard prescribed medications/ supplements

Study Arms

• Active Comparator: Ascorbic Acid
  8000 mg of ascorbic acid divided into 2-3 doses/day with food.
  Intervention: Dietary Supplement: Ascorbic Acid
• Active Comparator: Zinc Gluconate
  50 mg of zinc gluconate to be taken daily at bedtime
  Intervention: Dietary Supplement: Zinc Gluconate
• Active Comparator: Ascorbic Acid and Zinc Gluconate
  8000 mg of ascorbic acid divided into 2-3 doses/day with food and 50 mg of zinc gluconate to be taken daily at bedtime.
  Intervention: Dietary Supplement: Ascorbic Acid and Zinc Gluconate
• Standard of Care
  Standard of care medications only as prescribed by patient's physician.
  Intervention: Other: Standard of Care

Publications *

• O'Byrne L, Webster KE, MacKeith S, Philpott C, Hopkins C, Burton MJ. Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction. Cochrane Database Syst Rev. 2022 Sep 5;9(9):CD013876. doi: 10.1002/14651858.CD013876.pub3.
• O'Byrne L, Webster KE, MacKeith S, Philpott C, Hopkins C, Burton MJ. Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction. Cochrane Database Syst Rev. 2021 Jul 22;7(7):CD013876. doi: 10.1002/14651858.CD013876.pub2.
• Thomas S, Patel D, Bittel B, Wolski K, Wang Q, Kumar A, Il'Giovine ZJ, Mehra R, McWilliams C, Nissen SE, Desai MY. 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. JAMA Netw Open. 2021 Feb 1;4(2):e210369. doi: 10.1001/jamanetworkopen.2021.0369.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2021): 214
• Original Estimated Enrollment (submitted: April 8, 2020): 520
• Actual Study Completion Date: February 11, 2021
• Actual Primary Completion Date: December 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Outpatients ≥ 18 years presenting to Cleveland Clinic Health System in Ohio and Florida who test positive for COVID-19 having any of the following symptoms

  1. Fever or chills
  2. Shortness of breath or difficulty breathing
  3. Cough
  4. Fatigue
  5. Muscle or body Aches
  6. Headache
  7. New loss of taste
  8. New loss of smell
  9. Congestion or runny nose
  10. Nausea
  11. Vomiting
  12. Diarrhea

Women of child bearing potential:

1. have had a menstrual period within the past 30 days, or
2. have had previous sterilization, or
3. are perimenopausal (less than 1 year) who have a negative pregnancy test, or
4. women of childbearing potential who do not meet the above and have a negative pregnancy test.

Exclusion Criteria:

• Patients who are found to be positive during hospitalization
• Patients who reside outside Ohio or Florida.

• Pregnant women:

  1. Current known pregnancy
  2. Positive pregnancy test (women of child bearing potential who have not had previous sterilization as defined as hysterectomy or tubal ligation)
• Women of childbearing potential who do not meet the above criteria, last menstrual period greater than 30 days and have a positive pregnancy test.
• Lactating Women
• End stage kidney disease
• Advanced liver disease awaiting transplant
• History of Calcium Oxalate kidney stones.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04342728
• Other Study ID Numbers: IRB 20-361
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Milind Desai, The Cleveland Clinic
• Original Responsible Party: Same as current
• Current Study Sponsor: The Cleveland Clinic
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Milind Desai, M. D.; The Cleveland Clinic
• Principal Investigator: Suma Thomas; The Cleveland Clinic

• PRS Account: The Cleveland Clinic
• Verification Date: February 2021