Therapies to Prevent Progression of COVID-19, Including Hydroxychloroquine, Azithromycin, Zinc, and Vitamin D3 With or Without Intravenous Vitamin C: An International, Multicenter, Randomized Trial

BRETHREN, I WANT YOU TO NOTICE HOW MANY TIMES DR. ZELENKO’S PROTOCOL IS MENTIONED IN THIS ARTICLE FROM AUSTRALIA.

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Review began 11/03/2021
Review ended 11/22/2021
Published 11/25/2021
© Copyright 2021
Ried et al. This is an open access article
distributed under the terms of the Creative
Commons Attribution License CC-BY 4.0.,
which permits unrestricted use, distribution,
and reproduction in any medium, provided
the original author and source are credited.

NIIM Research, National Institute of Integrative Medicine, Melbourne, AUS 2. Health and Nutrition, Torrens University, Melbourne, AUS 3. Discipline of General Practice, The University of Adelaide, Adelaide, AUS 4. Gold Coast Clinic, National Institute of Integrative Medicine, Gold Coast, AUS 5. NIIM Clinic, National Institute of Integrative Medicine, Melbourne, AUS
Corresponding author: Karin Ried, karinried@niim.com.au

Abstract

Background
COVID-19 is a global pandemic. Treatment with hydroxychloroquine (HCQ), zinc, and azithromycin (AZM), also known as the Zelenko protocol, and treatment with intravenous (IV) vitamin C (IVC) have shown encouraging results in a large number of trials worldwide. In addition, vitamin D levels are an important
indicator of the severity of symptoms in patients with COVID-19.

Objectives

Our multicenter, randomized, open-label study aimed to assess the effectiveness of HCQ, AZM, and zinc
with or without IVC in hospitalized patients with COVID-19 in reducing symptom severity and duration and
preventing death.

Methods

Hospitalized patients with COVID-19 in seven participating hospitals in Turkey were screened for eligibility and randomly allocated to receive either HCQ, AZM, and zinc (group 1) or HCQ, AZM, zinc plus IV vitamin C treatment (group 2) for 14 days. The patients also received nontherapeutic levels of vitamin D3.
The trial is registered on the Australian and New Zealand Clinical Trial Registry ACTRN12620000557932 and has been approved by the Australian Therapeutic Goods Administration (TGA).

Results

A total of 237 hospitalized patients with COVID-19 aged 22-99 years (mean: 63.3 ± 15.7 years) were enrolled in the study. Almost all patients were vitamin D deficient (97%), 55% were severely vitamin D deficient (<25 nmol/L) and 42% were vitamin D deficient (<50 nmol/L); 3% had insufficient vitamin D levels (<75 nmol/L),
and none had optimal vitamin D levels.
Of the patients, 73% had comorbidities, including diabetes (35%), heart disease (36%), and lung disease (34%).

All but one patient (99.6%; n = 236/237) treated with HCQ, AZM, and zinc with or without high-dose IV vitamin C (IVC) fully recovered. Additional IVC therapy contributed significantly to a quicker recovery (15 days versus 45 days until discharge; p = 0.0069).
Side effects such as diarrhea, nausea, and vomiting, reported by 15%-27% of the patients, were mild to moderate and transient. No cardiac side effects were observed. Low vitamin D levels were significantly correlated with a higher probability of admission to the intensive
care unit (ICU) and longer hospital stay.

Sadly, one 70-year-old female patient with heart and lung disease died after 17 days in ICU and 22 days in the hospital. Her vitamin D level was 6 nmol/L on admission (i.e., severely deficient).

Conclusions

Our study suggests that the treatment protocol of HCQ, AZM, and zinc with or without vitamin C is safe and

effective in the treatment of COVID-19, with high dose IV vitamin C leading to a significantly quicker recovery. importantly, our study confirms vitamin D deficiency to be a high-risk factor of severe COVID-19 disease and hospitalization, with 97% of our study’s patient cohort being vitamin D deficient, 55% of these being severely vitamin D deficient, and none had optimal levels.
Future trials are warranted to evaluate the treatment with a combination of high-dose vitamin D3 in addition to HCQ, AZM, and zinc and high-dose intravenous vitamin C.

Categories: Infectious Disease, Therapeutics, Integrative/Complementary Medicine
Keywords: vitamin d, intravenous vitamin c, zinc, hydroxychloroquine, covid-19 treatment, covid-19

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or COVID-19, has affected millions of people worldwide. COVID-19 was first reported by the World Health Organization in December 2019 and was declared a worldwide pandemic in March 2020. Exploring therapies potentially of benefit for COVID-19 has been a public health emergency.
SARS-CoV-2 enters cells by binding to the ACE2 receptor. Higher blood levels of ACE2 reflect shedding from the myocardium and pulmonary epithelium and identify patients who are vulnerable to the development of life-threatening complications.
Early in the pandemic, the combination of hydroxychloroquine (HCQ), azithromycin (AZM), and zinc, alsoknown as the Zelenko protocol, had shown great promise in the treatment of COVID-19 [1,2].
In vitro, chloroquine increases the endosomal pH required for the virus to fuse with cells and interferes with the glycosylation of SARS-CoV-2 cell receptors, thereby blocking viral infection [3,4]. Investigatorsperformed a time-of-addition assay, which showed that chloroquine is effective at both the entry and post-entry stages of the SARS-CoV-2 infection in cells. Hydroxychloroquine has greater in vitro potency thanchloroquine against SARS-CoV-2 and, because of its enhanced safety profile, can be given at higher doses
than chloroquine [5].
As of October 2021, a meta-analysis of more than 290 worldwide trials involving more than 412,000 patientsfound that HCQ significantly reduced morbidity and mortality in patients with COVID-19. Specifically, when HCQ is used in early treatment, a meta-analysis of 32 studies involving more than 54,600 patients suggested HCQ to improve symptoms and prevent death by 64%-75% (all early treatment studies (n = 32): RR, 0.36
(0.29-0.46), p < 0.0001; early treatment studies reporting mortality (n = 13): RR, 0.25 (0.16-0.40), p < 0.0001)
[6].
Azithromycin is a macrolide antibiotic that has been found to inhibit the viral tropism and replication of Zika and Ebola viruses [7,8]. An in vitro study has shown the activity of azithromycin (AZM) in combination with hydroxychloroquine (HCQ) against SARS-CoV-2 [9].
In addition, the effectiveness of this combination therapy of HCQ and AZM, when used early, as was demonstrated in a clinical study involving 83 patients in Turkey, reduced recovery time and shortened hospital length of stay [10].

In therapeutic doses, HCQ has a high safety profile and works as a zinc ionophore, enabling zinc to enter a virus-infected cell, increasing intracellular zinc concentrations [11].
Zinc itself has antiviral properties, boosting both innate and humoral immunity [12]. High intracellular concentrations of zinc are essential to inhibit viral replication and proliferation, including coronavirus RNA-dependent RNA polymerase activity [13].

The Zelenko COVID-19 treatment protocol consists of the following triple therapy for five consecutive days in addition to standard supportive care: zinc sulfate (220 mg capsule once daily, containing 50 mg elemental zinc), HCQ (200 mg twice daily), and AZM (500 mg once daily) [2].

In addition, intravenous vitamin C (IVC) has known immune-stimulating and antiviral properties [14] and had shown promise as a treatment for acute respiratory syndrome and pneumonia [15]. Recent studies reported on the benefits of IVC therapy for COVID-19 [16,17].

Furthermore, a large number of studies (n > 200) have demonstrated low vitamin D levels to be a risk factor for the severity of COVID-19 symptoms and hospitalization [18-20].

Open Access Original
Article DOI: 10.7759/cureus.19902

Adequate vitamin D levels are of great importance in the prevention of respiratory infections, as vitamin D
protects against pathogens including viruses via the innate and adaptive immune systems, involving white
blood cells and T-cells [21].
In our study, we aimed to assess the optimal treatment protocol for hospitals to consider in their treatment
for patients with COVID-19, in order to reduce the severity and duration of symptoms and save lives.
Patients presenting at hospitals with COVID-19 symptoms were randomly allocated to the Zelenko protocol
(HCQ + AZM + zinc) or the Zelenko protocol plus IV vitamin C.
All enrolled patients also received supplementation of 5000 IU/day of vitamin D3, an adequate dose if levels
of vitamin D are insufficient (51-75 nmol/L); however, this dose is considered inadequate for vitamin D
deficiency (<50 nmol/L). Materials And Methods Trial design and participants Our study is an international, multicenter, open-label, randomized controlled trial evaluating the efficacy and safety of therapies with hydroxychloroquine (HCQ), azithromycin (AZM), zinc, and vitamin D3 alone (group 1) or HCQ + AZM + zinc in combination with IV vitamin C (group 2) in hospitalized patients with COVID-19. For stage 1 of the trial, we aimed to recruit 200 patients. The trial was conducted in Australia and Turkey between January and June 2021. Stage 1 of the trial took place primarily in Turkey and involved seven participating hospitals in Eskisehir, Elazig, Istanbul, Erzincan, and Izmir. The trial was approved by the National Health and Medical Research Council (NHMRC)-endorsed National Institute of Integrative Medicine (NIIM) Human Research Ethics Committee in Australia, the Turkish Ethics Committees at the Ministry of Health in Turkey, and participating hospitals. The trial is registered on the Australian and New Zealand Clinical Trial Registry ACTRN12620000557932 and has been approved by the Australian Therapeutic Goods Administration (TGA). All eligible participants provided electronic written informed consent. Inclusion criteria The inclusion criteria were as follows: (1) age ≥ 18 years, (2) informed written consent, and (3) diagnosis of active symptomatic COVID-19 confirmed by polymerase chain reaction (PCR) testing via nasal and/or oral swab at the time of enrolment for quantitative PCR assessment. Exclusion criteria The exclusion criteria were as follows: (1) known G-6-PDH deficiency; (2) contraindication to hydroxychloroquine, azithromycin, or vitamin C, allergy to study interventions, epilepsy, serious hearing or visual problems, advanced liver disease, history of severe depression, calcium oxalate stones, and pregnant or lactating women; (3) already receiving hydroxychloroquine, azithromycin, vitamin C >3 g daily, or an experimental antiviral; (4) history of fever
(e.g., night sweats and chills) and/or acute respiratory infection (e.g., cough, shortness of breath, and sore
throat) of more than seven days’ duration; (5) calculated creatinine clearance of <30 mL/minute; (6) baseline
electrocardiogram (ECG) showing QTc ≥ 470 for males and QTc ≥ 480 for females; and (7) receipt of a drug
known to increase QTc, such as quetiapine, amiodarone, and sotalol.
Intervention
Group 1 received HCQ + zinc + AZM + vitamin D3, whereas group 2 received vitamin C + group 1
interventions. Hydroxychloroquine (HCQ) was given as 400 mg peroral (PO) once a day for one day, followed
by 200 mg once a day for six days. Azithromycin (AZM) was given as 500 mg PO on day 1, followed by 250 mg
PO once daily for four days. Zinc citrate was given as 30 mg elemental zinc PO daily for 14 days. Vitamin D3
was given as 5,000 IU PO daily for 14 days. IV vitamin C (sodium ascorbate) was given as 50 mg/kg every six
hours on day 1, followed by 100 mg/kg every six hours (four times daily, 400 mg/kg/day) for seven days
(average: 28 g/day; maximum dose: 50 g/24 hours for those weighing more than 125 kg).
Data collection
Project management and data collection were carried out by appointed teams at the participating sites.
The participants’ gender, age, disease severity, comorbidities (smoking, diabetes, heart disease, lung
disease, and immunosuppression), other medications, and trial outcomes were entered into an electronic
2021 Ried et al. Cureus 13(11): e19902. DOI 10.7759/cureus.19902 3 of 11

online database using Microsoft Forms questionnaires.
Outcomes
Primary Outcome
The primary outcome was mortality or need for invasive mechanical ventilation at any time in the first 15
days from enrolment.
Secondary Efficacy Outcomes
The secondary efficacy outcomes (measured at both 15 and 45 days from enrolment) are mortality, invasive
mechanical ventilation, need for humidified high-flow oxygen, admission to the intensive care unit (ICU),
days in the hospital, days in the ICU, renal replacement therapy, and extracorporeal support.
The secondary efficacy outcomes also include the World Health Organization (WHO) Master Protocol ordinal
score at day 15 as follows: (1) not hospitalized, no limitations on activities; (2) not hospitalized, limitation
on activities; (3) hospitalized, not requiring supplemental oxygen; (4) hospitalized, requiring
supplemental oxygen; (5) hospitalized, on noninvasive ventilation or high-flow oxygen devices; (6)
hospitalized, on invasive mechanical ventilation or ECMO; and (7) death.
Secondary Safety Outcomes
The secondary safety outcomes are QTc prolongation (>500 ms) 24 hours following the initial dose of study
drugs, serious ventricular arrhythmia (including ventricular fibrillation) or sudden unexpected death in the
hospital, and any of the following adverse events in the first 10 days from enrolment: diarrhea, grade 2
or greater; nausea, grade 2 or greater; and vomiting, grade 2 or greater (Appendices).
Adaptive design features
The study was overseen by the Steering Committee consisting of chief investigators (TB, KR, and AS) and
investigators at recruited sites. Independent Data Safety Monitoring Committees (DSMC) at participating
hospitals monitored the progress and safety of the trial treatment and were to make recommendations on
whether to continue, modify, or stop the trial for safety or ethical reasons.
Sample size calculation
In stage 1, the sample size required is n = 100 in each intervention arm in order to have a statistical power of
80% to detect a relative risk reduction (RRR) of 30% in the proportion progressing to mechanical ventilation
or death, compared with standard care, and assuming a standard-of-care risk of progression of 30%. Since
the participants were hospitalized, we assumed minimal (<1%) loss to follow-up. The total sample size was n
= 200.
Analyses were performed using IBM SPSS version 26. Statistical significance was set at p < 0.05. The primary
analysis of efficacy was conducted under the intention-to-treat principle; all randomized participants were
included in the analyses. Descriptive analysis was conducted on all variables. Any variable differences
between groups were included in analyses as covariates. Differences between the groups and comparison of
continuous outcome variables were analyzed using Student’s t-test or analysis of covariance (ANCOVA) and
chi-square analysis for dichotomous variables or Mann-Whitney U-tests for ranking variables. Correlations
between variables were assessed using Pearson’s correlation coefficient.
Results
Seven hospital sites in Turkey participated in the multicenter trial (Figure 1).

Adequate vitamin D levels are of great importance in the prevention of respiratory infections, as vitamin D
protects against pathogens including viruses via the innate and adaptive immune systems, involving white
blood cells and T-cells [21].
In our study, we aimed to assess the optimal treatment protocol for hospitals to consider in their treatment
for patients with COVID-19, in order to reduce the severity and duration of symptoms and save lives.
Patients presenting at hospitals with COVID-19 symptoms were randomly allocated to the Zelenko protocol
(HCQ + AZM + zinc) or the Zelenko protocol plus IV vitamin C.
All enrolled patients also received supplementation of 5000 IU/day of vitamin D3, an adequate dose if levels
of vitamin D are insufficient (51-75 nmol/L); however, this dose is considered inadequate for vitamin D
deficiency (<50 nmol/L). Materials And Methods Trial design and participants Our study is an international, multicenter, open-label, randomized controlled trial evaluating the efficacy and safety of therapies with hydroxychloroquine (HCQ), azithromycin (AZM), zinc, and vitamin D3 alone (group 1) or HCQ + AZM + zinc in combination with IV vitamin C (group 2) in hospitalized patients with COVID-19. For stage 1 of the trial, we aimed to recruit 200 patients. The trial was conducted in Australia and Turkey between January and June 2021. Stage 1 of the trial took place primarily in Turkey and involved seven participating hospitals in Eskisehir, Elazig, Istanbul, Erzincan, and Izmir. The trial was approved by the National Health and Medical Research Council (NHMRC)-endorsed National Institute of Integrative Medicine (NIIM) Human Research Ethics Committee in Australia, the Turkish Ethics Committees at the Ministry of Health in Turkey, and participating hospitals. The trial is registered on the Australian and New Zealand Clinical Trial Registry ACTRN12620000557932 and has been approved by the Australian Therapeutic Goods Administration (TGA). All eligible participants provided electronic written informed consent. Inclusion criteria The inclusion criteria were as follows: (1) age ≥ 18 years, (2) informed written consent, and (3) diagnosis of active symptomatic COVID-19 confirmed by polymerase chain reaction (PCR) testing via nasal and/or oral swab at the time of enrolment for quantitative PCR assessment. Exclusion criteria The exclusion criteria were as follows: (1) known G-6-PDH deficiency; (2) contraindication to hydroxychloroquine, azithromycin, or vitamin C, allergy to study interventions, epilepsy, serious hearing or visual problems, advanced liver disease, history of severe depression, calcium oxalate stones, and pregnant or lactating women; (3) already receiving hydroxychloroquine, azithromycin, vitamin C >3 g daily, or an experimental antiviral; (4) history of fever
(e.g., night sweats and chills) and/or acute respiratory infection (e.g., cough, shortness of breath, and sore
throat) of more than seven days’ duration; (5) calculated creatinine clearance of <30 mL/minute; (6) baseline
electrocardiogram (ECG) showing QTc ≥ 470 for males and QTc ≥ 480 for females; and (7) receipt of a drug
known to increase QTc, such as quetiapine, amiodarone, and sotalol.
Intervention
Group 1 received HCQ + zinc + AZM + vitamin D3, whereas group 2 received vitamin C + group 1
interventions. Hydroxychloroquine (HCQ) was given as 400 mg peroral (PO) once a day for one day, followed
by 200 mg once a day for six days. Azithromycin (AZM) was given as 500 mg PO on day 1, followed by 250 mg
PO once daily for four days. Zinc citrate was given as 30 mg elemental zinc PO daily for 14 days. Vitamin D3
was given as 5,000 IU PO daily for 14 days. IV vitamin C (sodium ascorbate) was given as 50 mg/kg every six
hours on day 1, followed by 100 mg/kg every six hours (four times daily, 400 mg/kg/day) for seven days
(average: 28 g/day; maximum dose: 50 g/24 hours for those weighing more than 125 kg).
Data collection
Project management and data collection were carried out by appointed teams at the participating sites.
The participants’ gender, age, disease severity, comorbidities (smoking, diabetes, heart disease, lung
disease, and immunosuppression), other medications, and trial outcomes were entered into an electronic
2021 Ried et al. Cureus 13(11): e19902. DOI 10.7759/cureus.19902 3 of 11

online database using Microsoft Forms questionnaires.
Outcomes
Primary Outcome
The primary outcome was mortality or need for invasive mechanical ventilation at any time in the first 15
days from enrolment.
Secondary Efficacy Outcomes
The secondary efficacy outcomes (measured at both 15 and 45 days from enrolment) are mortality, invasive
mechanical ventilation, need for humidified high-flow oxygen, admission to the intensive care unit (ICU),
days in the hospital, days in the ICU, renal replacement therapy, and extracorporeal support.
The secondary efficacy outcomes also include the World Health Organization (WHO) Master Protocol ordinal
score at day 15 as follows: (1) not hospitalized, no limitations on activities; (2) not hospitalized, limitation
on activities; (3) hospitalized, not requiring supplemental oxygen; (4) hospitalized, requiring
supplemental oxygen; (5) hospitalized, on noninvasive ventilation or high-flow oxygen devices; (6)
hospitalized, on invasive mechanical ventilation or ECMO; and (7) death.
Secondary Safety Outcomes
The secondary safety outcomes are QTc prolongation (>500 ms) 24 hours following the initial dose of study
drugs, serious ventricular arrhythmia (including ventricular fibrillation) or sudden unexpected death in the
hospital, and any of the following adverse events in the first 10 days from enrolment: diarrhea, grade 2
or greater; nausea, grade 2 or greater; and vomiting, grade 2 or greater (Appendices).
Adaptive design features
The study was overseen by the Steering Committee consisting of chief investigators (TB, KR, and AS) and
investigators at recruited sites. Independent Data Safety Monitoring Committees (DSMC) at participating
hospitals monitored the progress and safety of the trial treatment and were to make recommendations on
whether to continue, modify, or stop the trial for safety or ethical reasons.
Sample size calculation
In stage 1, the sample size required is n = 100 in each intervention arm in order to have a statistical power of
80% to detect a relative risk reduction (RRR) of 30% in the proportion progressing to mechanical ventilation
or death, compared with standard care, and assuming a standard-of-care risk of progression of 30%. Since
the participants were hospitalized, we assumed minimal (<1%) loss to follow-up. The total sample size was n
= 200.
Analyses were performed using IBM SPSS version 26. Statistical significance was set at p < 0.05. The primary
analysis of efficacy was conducted under the intention-to-treat principle; all randomized participants were
included in the analyses. Descriptive analysis was conducted on all variables. Any variable differences
between groups were included in analyses as covariates. Differences between the groups and comparison of
continuous outcome variables were analyzed using Student’s t-test or analysis of covariance (ANCOVA) and
chi-square analysis for dichotomous variables or Mann-Whitney U-tests for ranking variables. Correlations
between variables were assessed using Pearson’s correlation coefficient.
Results
Seven hospital sites in Turkey participated in the multicenter trial (Figure 1).

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