COVID-19 is a global pandemic. So far encouraging results have been shown in different parts of the world with the utilisation of hydroxycloroquine, zinc, and azithromycin, and early studies into some of these, plus some with Vitamin C, have also proven beneficial. Vitamin D levels have also been shown to be an important indicator to the severity of symptoms in COVID-19 patients.
Study Design
Type of study A multi-centre, open-label, randomized controlled trial evaluating the efficacy
and safety of therapy with azithromycin, hydroxychloroquine, zinc, vitamin D3/B12 and IV
vitamin C compared with azithromycin, hydroxychloroquine, zinc, vitamin D3/B12 in
participants with COVID-19.
Expected number of participants The sample size for the study is a minimum of 100
participants in each arm. However, this sample size may change as this trial has an adaptive
design.
Allocation procedure Randomization: Eligible patients that have provided informed written
consent will be randomized by independent researcher. Randomization will be in randomly
permuted blocks (undisclosed sizes to maintain concealment of allocation). The allocation
will be communicated to site personnel and participants will be made aware of their
assignment. It is not practical to use placebo in this trial.
Stratification: randomization will be stratified by site and age (65 years or younger, over
65 years of age).
Duration of the study period for each subject Participants will be followed for 45 days from
the time of randomization. Data of events occurring during hospital will be obtained from
hospital records supplemented by a telephone call or follow up at 7-10 days and at 45 days
after randomization.
Adaptive design features
Adaptive intervention arms: The Steering Committee will keep abreast of other ongoing trials
and if other promising interventions emerge, may recommend adding (or replacing) one arm with
the new promising intervention.
Adaptive sample size: Sample size calculations are based on disease progression rates that
are not well known. The investigators remain flexible, and the Data Safety Committee (DSMC)
will be monitoring the possibility that the assumptions for sample size calculations may be
modified with emerging information from this trial or other ongoing trials. If recruitment is
going well, the steering committee may decide to extend recruitment as long as the
independent DSMC does not terminate the trial for clear evidence of efficacy, futility (low
probability) to detect a clinically meaningful difference (e.g. a 20% RRR in events) or
concerns about safety.
Study Procedures Direct electronic data entry will be utilized in this trial. The
investigators will use Redcap platform and software (www.project-redcap.org).
Consenting process Due to the stringent measures in infection control in hospitals,
digitalised consent will be obtained instead of written consent on paper. Be this preferably
from the patient or his legal representative. All patients will be in strict contact and
droplet precautions and there may be an imperative to minimise use of personal protective
equipment (PPE) by staff due to resource limitations.
The consenting process will be as follows:
- The clinical team will inform a potential participant in the trial that an investigator
will contact them
- To minimise PPE use, the investigator will make telephone contact with the patient. If
an interpreter is required for the consent discussion, this will be by the telephone
interpreter service. An informed consent discussion will be held with each participant
by a site investigator or their delegate.
- The Patient Information Sheet and Consent form (PICF) will be emailed to the patient or
the clinical team will take it into the room for viewing by the patient. These documents
will be left in the patient's room
- The participant will be given time to ask questions and consider whether to participate
in the research.
- Verbal consent will be recorded in both the participant's medical record and study
consent form. This will state that the terms and conditions were all read and agreed to
and all questions asked were answered. The full PICF, including the signed consent page
(by the investigator), will be uploaded into the electronic database.
- If the patient is too unwell or is unable to use a digital device, to personally give
consent, written consent can be obtained from their next of kin, or other adult family
members, or partner or legal representative.
- The following day, the investigator or clinical team will verbally confirm with the
participant that they have consented to participate. A copy of the signed consent form
will then either be emailed to the participant or sent via post. The participant, their
next of kin or legal representative will send a return email confirming their consent.
Interventions
Blinding: Participants and healthcare providers will not be blinded to treatment. To account
for this, the investigators have objective outcome definitions to minimize the opportunity
for bias to influence event assessment.
Consenting participants will be randomized to receive therapy with azithromycin,
hydroxychloroquine, zinc, Vitamin D3/B12 and IV vitamin C or azithromycin, zinc and
hydroxychloroquine, Vitamin D3/B12.
For further details see: Arms & Interventions
The investigators will place no constraints for treating physicians on the therapies with
respect to usual care. The investigators will document information on all key
co-interventions, including information on drugs at the time of randomization and post
randomization /during hospitalization.
Data collection The investigators will collect participant sex, age, disease severity,
comorbidities (smoking, diabetes, heart disease, lung disease, immunosuppression, etc.),
other medications, and trial outcomes.
Participants in this trial will be swabbed (nasal and/or oral) on approximately days 0, 3 and
7 for quantitative polymerase chain reaction (PCR) assessment of viral titre.
Study Outcomes For details see primary & secondary outcome section.
In addition, the investigators will collect data on:
WHO Master Protocol ordinal score at day 15:
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 non-invasive ventilation or high flow oxygen devices;
6. Hospitalized, on invasive mechanical ventilation or ECMO;
7. Death.
Secondary safety outcomes
- QTc prolongation (>500ms) 24 hours following initial dose of study drugs
- Serious ventricular arrhythmia (including ventricular fibrillation) or sudden unexpected
death in hospital
- Any of the following adverse events in first 10 days from enrolment.
- Diarrhoea - grade 2 or greater
- Nausea - grade 2 or greater
- Vomiting - grade 2 or greater
Statistical Considerations
Sample size calculation The minimum sample size required is N=100 in each intervention arm in
order to have 80% statistical power to detect a 30% relative risk reduction (RRR) in the
proportion progressing to mechanical ventilation or death, assuming a standard-of-care risk
of progression of 30%. Since participants will be hospitalized, a minimal (<1%) loss to
follow-up is assumed.
Statistical analysis methods The primary analysis of efficacy will be conducted under the
intention-to-treat principle; all randomized participants will be included in the analyses.
All results will be analyzed with 2-sided level of significance of 0.05.
Dietary Supplement: Vitamin C
In addition to the active comparator, which is a combination of 2 drugs and 3 dietary supplements, the experimental treatment arm will also receive Vitamin C (intravenous or oral)
Other Name: Sodium ascorbate
Drug: Hydroxychloroquine
Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements
Other Name: Plaquenil
Drug: Azithromycin
Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements
Other Name: Array
Dietary Supplement: Zinc Citrate
Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements
Dietary Supplement: Vitamin D3
Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements
Other Name: Cholecalciferol
Dietary Supplement: Vitamin B12
Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements
Other Name: Methylcobalmin
Inclusion Criteria:
1. Age ≥ 18 years
2. Provision of informed consent in writing, can be electronic
3. Diagnosis of active COVID-19
Exclusion Criteria:
1. Known G6PD deficiency
2. Contra-indication to hydroxychloroquine, azithromycin or Vitamin C: allergy to study
interventions, epilepsy, serious hearing or visual problems, history of severe
depression, calcium oxalate stones, advanced liver disease, pregnancy or lactating
3. Already receiving chloroquine, azithromycin, >3 grams Vitamin C daily or an
experimental antiviral
4. History of fever (e.g. night sweats, chills) and/or acute respiratory infection (e.g.
cough, shortness of breath, sore throat) of more than 7 days' duration. Note, if study
numbers not quickly reached, the investigators may decide to include those with
symptoms of longer than 7 days
5. Calculated creatinine clearance of < 30 mL/minute
6. Baseline ECG showing: QTc ≥470 for males, QTc ≥480 for females
7. Receipt of a drug known to increase QTc: quetiapine, amiodarone, sotalol
National Institute of Integrative Medicine
Melbourne, Victoria, Australia
Investigator: Karin Ried, PhD
karinried@niim.com.au
Karin Ried, PhD
0061399129545
karinried@niim.com.au
Taufiq Binjemain, MD
0061498049362
tbinjemain@gmail.com
Karin Ried, PhD, Principal Investigator
National Institute of Integrative Medicine, Australia