Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000557932
Ethics application status
Approved
Date submitted
8/05/2020
Date registered
11/05/2020
Date last updated
23/03/2023
Date data sharing statement initially provided
11/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
International ALLIANCE Study of Therapies to prevent progression of COVID-19, a randomized trial
Scientific title
Therapies to prevent progression of COVID-19, including Hydroxychloroquine, Azithromycin, Zinc, Vitamin D with or without Vitamin C, a multi-centre, international, randomized trial: The International ALLIANCE Study - Stage 1
Secondary ID [1] 301241 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 317409 0
Condition category
Condition code
Infection 315509 315509 0 0
Other infectious diseases
Respiratory 315519 315519 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 1 - Inpatients (Turkey) and outpatients (Australia):
2 trial arms:
Stage 1- 1) Hydroxychloroquine plus zinc plus Vit D3 plus azithromycin
Stage 1 - 2) Hydroxychloroquine plus zinc plus Vit D3 plus azithromycin plus IV Vitamin C

Inpatients: Hydroxychloroquine 400mg PO once a day for 1 day, followed by 200mg PO once a day for 6 days*; *HCQ will be discontinued on the day of discharge
Outpatients: Hydroxychloroquine 400mg PO once

Azithromycin: 500 mg oral tablet on day 1 followed by 250 mg oral tablet once daily for 4 days
Zinc Citrate: 30mg elemental zinc oral tablet daily for 14 days
Vitamin D3: 5,000iu oral capsule daily for 14 days

Trial Arm 1 Plus
Inpatients: IV Vitamin C (Sodium Ascorbate)
50mg/kg every 6hrs on day 1 followed by 100mg/kg every 6hrs (4x day, 400mg/kg/day) for 7 days (average 28g.day; maximum dose of 50g/24hrs for those weighing more than 125kg).
Outpatients: Vitamin C (Sodium Ascorbate): 200mg/kg x1 IV, then 1 gram oral tablet three times per day for 7 days

All treatments will be administered by medical staff briefed on the trial protocol. Adherence and fidelity will be assessed and recorded on the trial specific electronic data collection sheet by medical staff providing the trial treatment.
Intervention code [1] 317540 0
Treatment: Drugs
Comparator / control treatment
No Vit C in comparator group.
Stage 1: Both groups receive Hydroxychloroquine plus zinc plus Vit D3 plus azithromycin.
In both groups, outcomes will be compared to population data on outcomes of standard care without Hydroxychloroquine, zinc, Vit D3, and/or azithromycin.
Control group
Active

Outcomes
Primary outcome [1] 323751 0
Composite: Change in severity and duration of symptoms,
assessed by data linkage to patient medical records
Timepoint [1] 323751 0
once daily for 15 days since enrolment / baseline = admission to hospital
Primary outcome [2] 323752 0
length of hospital stay = days discharge since hospital admission
assessed by data linkage to patient medical records
Timepoint [2] 323752 0
days in hospital since admission at hospital discharge
Primary outcome [3] 323753 0
composite of need for invasive mechanical ventilation* or mortality within 15 days from enrolment assessed by data linkage to patient medical records
*Participants intubated or requiring imminent intubation at the time of enrolment will only be followed for the primary outcome of death.
Timepoint [3] 323753 0
any time within 15 days from enrolment
Secondary outcome [1] 382783 0
Mortality
Timepoint [1] 382783 0
15 and 45 days since enrolment
Secondary outcome [2] 382784 0
Need for and number of days of invasive mechanical ventilation
in case of no need for mechanical ventilation, days = 0
assessed by data linkage to patient medical records
Timepoint [2] 382784 0
at 15 and 45 days since enrolment
Secondary outcome [3] 382785 0
Need for and number of days for humidified high-flow oxygen
assessed by linkage to patient medical records
Timepoint [3] 382785 0
at 15 and 45 days since enrolment
Secondary outcome [4] 382786 0
Admission to ICU
assessed by data linkage to patient medical records
Timepoint [4] 382786 0
15 and 45 days since enrolment
Secondary outcome [5] 382787 0
Days in hospital
assessed by data linkage to patient medical records
Timepoint [5] 382787 0
15 and 45 days since enrolment
Secondary outcome [6] 382788 0
Days in ICU
assessed by data linkage to patient medical records
Timepoint [6] 382788 0
15 and 45 days since enrolment
Secondary outcome [7] 382789 0
Need for and days of renal replacement therapy
assessed by data linkage to patient medical records
Timepoint [7] 382789 0
15 and 45 days since enrolment
Secondary outcome [8] 382790 0
Need for and days of extracorporeal support
assessed by data linkage to patient medical records
Timepoint [8] 382790 0
15 and 45 days since enrolment

Eligibility
Key inclusion criteria
Diagnosis of active COVID-19
Provision of informed consent in writing, can be electronic
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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, more than 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 less than 30 mL/minute
6) Baseline ECG showing: QTc greater than or equal to (>=) 470 for males, QTc greater than or equal to (>=) 480 for females
7) Receipt of a drug known to increase QTc: quetiapine, amiodarone, sotalol

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be centralized by researcher offsite and treatment ID will be provided to participating hospital
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomization using a computerized random number generator by researcher not involved with patient recruitment and treatment
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
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, we assumed minimal (<1%) loss to follow-up.

Outpatient recruitment is ongoing, therefore the target sample size has been increased to n=500 (including n=300 outpatients and n=200 inpatients).

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. Given the rapid assessment of the primary outcomes of progression, and the expected absence of loss to follow-up, we will compare the proportions of progression events between the two study arms for each of the factorial randomizations rather than the times to progressions. The primary analysis will use the Z-test for comparison of proportions. Secondary analyses will include adjusting the intervention effect for demographics, exposure characteristics, and severity of disease upon admission, using logistic regression models.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/08/2020
Actual
7/09/2020
Date of last participant enrolment
Anticipated
30/12/2022
Actual
2/12/2022
Date of last data collection
Anticipated
31/03/2023
Actual
2/03/2023
Sample size
Target
500
Accrual to date
Final
446
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 22547 0
Turkey
State/province [1] 22547 0

Funding & Sponsors
Funding source category [1] 305690 0
Charities/Societies/Foundations
Name [1] 305690 0
Rinehart Medical Foundation
Country [1] 305690 0
Australia
Primary sponsor type
Individual
Name
AProf Dr Karin Ried
Address
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn, VIC 3122
Country
Australia
Secondary sponsor category [1] 306101 0
None
Name [1] 306101 0
Address [1] 306101 0
Country [1] 306101 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305968 0
National Institute of Integrative Medicine Human Research Ethics Committee (NIIM HREC)
Ethics committee address [1] 305968 0
Ethics committee country [1] 305968 0
Australia
Date submitted for ethics approval [1] 305968 0
06/05/2020
Approval date [1] 305968 0
18/05/2020
Ethics approval number [1] 305968 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102246 0
A/Prof Karin Ried
Address 102246 0
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn, VIC 3122
Country 102246 0
Australia
Phone 102246 0
+61 3 9912 9545
Fax 102246 0
Email 102246 0
[email protected]
Contact person for public queries
Name 102247 0
Karin Ried
Address 102247 0
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn, VIC 3122
Country 102247 0
Australia
Phone 102247 0
+61 3 9912 9545
Fax 102247 0
Email 102247 0
[email protected]
Contact person for scientific queries
Name 102248 0
Karin Ried
Address 102248 0
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn, VIC 3122
Country 102248 0
Australia
Phone 102248 0
+61 3 9912 9545
Fax 102248 0
Email 102248 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIRole of vitamin C in preventing of COVID-19 infection, progression and severity2022https://doi.org/10.3934/microbiol.2022010
N.B. These documents automatically identified may not have been verified by the study sponsor.