Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000309785
Ethics application status
Approved
Date submitted
14/02/2022
Date registered
18/02/2022
Date last updated
23/03/2023
Date data sharing statement initially provided
18/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
International ALLIANCE Study of Therapies to prevent progression of COVID-19, a randomized trial - Stage 2
Scientific title
Therapies to prevent progression of COVID-19, including Quercetin, Zinc, high dose Vitamin D with or without Intravenous Vitamin C, a multi-centre, international, randomized trial: The International ALLIANCE Study - Stage 2
Secondary ID [1] 306425 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record
Sub-study of ACTRN12620000557932

Health condition
Health condition(s) or problem(s) studied:
COVID-19 325259 0
Condition category
Condition code
Infection 322659 322659 0 0
Other infectious diseases
Respiratory 322660 322660 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 2: In and Outpatients in Turkey
Arm 1) Quercetin plus zinc plus Vit D3
Arm 2) Quercetin plus zinc plus Vit D3 plus intravenous (IV) Vitamin C

Trial Arm 1:
Quercetin : 500mg oral twice a day for 7 day
Zinc Citrate: 30mg elemental zinc oral daily for 7 days
Vitamin D3 high dose: 600,000 IU intra-muscular bolus once on day 1 after Vitamin D level blood test, followed up by 50,000IU orally weekly for 4 weeks

Trial Arm 2:
Quercetin : 500mg oral twice a day for 7 day
Zinc Citrate: 30mg elemental zinc oral daily for 7 days
Vitamin D3 high dose: 600,000 IU intra-muscular bolus once on day 1 after Vitamin D level blood test, followed up by 50,000IU orally weekly for 4 weeks
Plus
IV Vitamin C (Sodium Ascorbate): 30g /day for 4 days;
equivalent to 50mg/kg every 6hrs on day 1 followed by 100mg/kg every 6hrs (4x day, 400mg/kg/day) for 4 days (average 28g/day; maximum dose of 50g/24hrs for those weighing more than 125kg).

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] 322862 0
Treatment: Other
Comparator / control treatment
No Vit C in comparator group.
Stage 2: Both groups receive Quercetin plus zinc plus high dose Vit D3.
In both groups, outcomes will be compared to population data on outcomes of standard care.
Control group
Active

Outcomes
Primary outcome [1] 330456 0
mortality within 15 days from enrolment assessed by data linkage to patient medical records
Timepoint [1] 330456 0
daily for 15 days from enrolment
Primary outcome [2] 330457 0
Composite: Change in severity and duration of symptoms, assessed by data linkage to patient medical records
Timepoint [2] 330457 0
at 7 days, 15, 30 and 45 days since enrolment / baseline = admission to hospital
Primary outcome [3] 330458 0
length of hospital stay = days discharge since hospital admission assessed by data linkage to patient medical records
Timepoint [3] 330458 0
days in hospital since admission at hospital discharge
Secondary outcome [1] 406280 0
Need for and number of days for humidified high-flow oxygen assessed by linkage to patient medical records
Timepoint [1] 406280 0
at day 7, 15, 30 and 45 since enrolment
Secondary outcome [2] 406281 0
Admission to ICU assessed by data linkage to patient medical records
Timepoint [2] 406281 0
at day 7, 15, 30 and 45 since enrolment
Secondary outcome [3] 406282 0
Days in hospital assessed by data linkage to patient medical records
Timepoint [3] 406282 0
at day 7, 15, 30 and 45 since enrolment
Secondary outcome [4] 406283 0
Days in ICU assessed by data linkage to patient medical records
Timepoint [4] 406283 0
at day 7, 15, 30 and 45 since enrolment
Secondary outcome [5] 406284 0
required additional therapy, including anti-biotic, i.e. Azithromycin; anti-coagulalent, or steroid assessed by data linkage to patient medical records
Timepoint [5] 406284 0
at day 7, 15, 30 and 45 since enrolment
Secondary outcome [6] 406285 0
Need for and days of renal replacement therapy assessed by data linkage to patient medical records
Timepoint [6] 406285 0
at day 7, 15, 30 and 45 since enrolment
Secondary outcome [7] 406286 0
Need for and days of extracorporeal support assessed by data linkage to patient medical records
Timepoint [7] 406286 0
at day 7, 15, 30 and 45 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 quercetin 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 quercetin, or 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

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.

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. Continuous variables will be analysed by Student-t test and repeated measures ANOVA, and categorical variables will be analysed by Chi-Square test. Subgroup analyses by gender, BMI, vaccination status, vitamin D levels will be explored.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
21/03/2022
Actual
Date of last participant enrolment
Anticipated
17/02/2023
Actual
Date of last data collection
Anticipated
31/03/2023
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment outside Australia
Country [1] 24579 0
Turkey
State/province [1] 24579 0

Funding & Sponsors
Funding source category [1] 310774 0
Charities/Societies/Foundations
Name [1] 310774 0
Rinehart Medical Foundation
Country [1] 310774 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] 312012 0
None
Name [1] 312012 0
Address [1] 312012 0
Country [1] 312012 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310349 0
National Institute of Integrative Medicine Human Research Ethics Committee (NIIM HREC)
Ethics committee address [1] 310349 0
Ethics committee country [1] 310349 0
Australia
Date submitted for ethics approval [1] 310349 0
06/05/2020
Approval date [1] 310349 0
18/05/2020
Ethics approval number [1] 310349 0
0068N_2020

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

Contacts
Principal investigator
Name 117334 0
A/Prof Karin Ried
Address 117334 0
National Institute of Integrative Medicine 21 Burwood Rd Hawthorn VIC 3122
Country 117334 0
Australia
Phone 117334 0
+61 3 9912 9545
Fax 117334 0
Email 117334 0
karinried@niim.com.au
Contact person for public queries
Name 117335 0
Karin Ried
Address 117335 0
National Institute of Integrative Medicine 21 Burwood Rd Hawthorn VIC 3122
Country 117335 0
Australia
Phone 117335 0
+61 3 9912 9545
Fax 117335 0
Email 117335 0
karinried@niim.com.au
Contact person for scientific queries
Name 117336 0
Karin Ried
Address 117336 0
National Institute of Integrative Medicine 21 Burwood Rd Hawthorn VIC 3122
Country 117336 0
Australia
Phone 117336 0
+61 3 9912 9545
Fax 117336 0
Email 117336 0
karinried@niim.com.au

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
No additional documents have been identified.