International ALLIANCE Study of Therapies to Prevent Progression of COVID-19

NCT ID: NCT04395768

Last Updated: 2020-09-11

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-09
• Study Completion Date: 2021-12-31

Brief Summary

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.

Detailed Description

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.

Conditions

COVID19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Vitamin C

Participants will receive vitamin C in addition to active comparator treatment:

Inpatients: IV Vitamin C (Sodium Ascorbate) 50mg/kg every 6hrs on day 1 followed by 100mg/kg every 6hrs (4x per day; 400mg/kg/day) for 7 days (average 28g/day; maximum dose of 50g/24hrs for those weighing more than 125kg). Can be converted to 1 gram three times per day PO on hospital discharge) Outpatients: Vitamin C Outpatient trial: 200mg/kg x1 IV, then 1 gram PO three times per day for 7 days;

Plus Active Comparator treatment:

Hydroxychloroquine Hydroxychloroquine 400mg (2x200mg) PO for 1 day, followed by 200mg PO per day for 6 days Azithromycin 500 mg PO on day 1 followed by 250 mg PO once daily for 4 days Zinc Citrate 30mg elemental zinc PO daily Vitamin D3 5,000iu PO daily for 14 days Vitamin B12 (Methylcobalamin) 500mcg PO daily for 14 days

Group Type: EXPERIMENTAL

Vitamin C

Intervention Type: DIETARY_SUPPLEMENT

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)

Hydroxychloroquine

Intervention Type: DRUG

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Azithromycin

Intervention Type: DRUG

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Zinc Citrate

Intervention Type: DIETARY_SUPPLEMENT

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Vitamin D3

Intervention Type: DIETARY_SUPPLEMENT

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Vitamin B12

Intervention Type: DIETARY_SUPPLEMENT

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Control

Hydroxychloroquine Hydroxychloroquine 400mg (2x200mg) PO for 1 day, followed by 200mg PO per day for 6 days Azithromycin 500 mg PO on day 1 followed by 250 mg PO once daily for 4 days Zinc Citrate 30mg elemental zinc PO daily Vitamin D3 5,000iu PO daily for 14 days Vitamin B12 (Methylcobalamin) 500mcg PO daily for 14 days

Group Type: ACTIVE_COMPARATOR

Hydroxychloroquine

Intervention Type: DRUG

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Azithromycin

Intervention Type: DRUG

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Zinc Citrate

Intervention Type: DIETARY_SUPPLEMENT

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Vitamin D3

Intervention Type: DIETARY_SUPPLEMENT

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Vitamin B12

Intervention Type: DIETARY_SUPPLEMENT

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Interventions

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)

Intervention Type: DIETARY_SUPPLEMENT

Hydroxychloroquine

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Intervention Type: DRUG

Azithromycin

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Intervention Type: DRUG

Zinc Citrate

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Intervention Type: DIETARY_SUPPLEMENT

Vitamin D3

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Intervention Type: DIETARY_SUPPLEMENT

Vitamin B12

Active comparator group will receive: a combination of 2 drugs and 3 dietary supplements

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

Sodium ascorbate; Plaquenil; Z-Pak; Zithromax; Cholecalciferol; Methylcobalmin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Integrative Medicine, Australia

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Karin Ried, PhD

Role: PRINCIPAL_INVESTIGATOR

National Institute of Integrative Medicine, Australia

Locations

National Institute of Integrative Medicine

Melbourne, Victoria, Australia

Site Status: RECRUITING

Countries

Australia

Central Contacts

Karin Ried, PhD

Role: CONTACT

karinried@niim.com.au

0061399129545

Taufiq Binjemain, MD

Role: CONTACT

tbinjemain@gmail.com

0061498049362

Facility Contacts

Karin Ried, PhD

Role: primary

karinried@niim.com.au

Other Identifiers

Alliance-COVID19

Identifier Type: -

Identifier Source: org_study_id