Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000417987
Ethics application status
Approved
Date submitted
27/03/2020
Date registered
30/03/2020
Date last updated
17/12/2020
Date data sharing statement initially provided
30/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Chloroquine Chemorophylaxis Countermeasure against COVID-19
Scientific title
Multi-Site, Randomized, Open-Label, Parallel-Group, Placebo-Controlled Study to Assess the Chemoprophylactic Efficacy of Chloroquine Against SARS-CoV-2/COVID-19 in Healthcare Workers at High-Risk of Exposure
Secondary ID [1] 300880 0
None
Universal Trial Number (UTN)
Trial acronym
C4
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 Infection 316753 0
Condition category
Condition code
Infection 314978 314978 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral 500mg chloroquine phosphate tablets prophylactic weekly regimen against COVID-19 over 10 week trial period followed with plasma chloroquine levels.
Intervention code [1] 317170 0
Prevention
Intervention code [2] 317171 0
Treatment: Drugs
Comparator / control treatment
Oral 1g (2 x 500mg) Vitamin C tablets weekly regimen used as comparator.
Control group
Placebo

Outcomes
Primary outcome [1] 323288 0
Number of sick days (SDS) during the study period: The number of sick days will be obtained from participants medical records as defined as the number of days deemed 'not fit for duty/work' by their reviewing medical professional, and will be compared between participants randomised to chloroquine and vitamin C.
Timepoint [1] 323288 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.
Secondary outcome [1] 381445 0
Incidence of symptomatic SARS-CoV-2 infections: The incidence of symptomatic SARS-CoV-2 infections will be compared in participants randomised to chloroquine or vitamin C by rt-PCR, serology, medical records, and severity of symptoms as graded by an Investigator in accordance with CTCAE Version 5.0
Timepoint [1] 381445 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.
Secondary outcome [2] 381446 0
Symptom severity of COVID-19: Symptom severity of COVID-19 will be compared between the two groups by rt-PCR, serology, medical records, and severity of symptoms as graded by an Investigator in accordance with CTCAE Version 5.0
Timepoint [2] 381446 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.
Secondary outcome [3] 381447 0
Duration of COVID-19 symptoms: Duration of COVID-19 will be compared between the two groups using a time to clinical improvement score.
Timepoint [3] 381447 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.
Secondary outcome [4] 381448 0
Incidence of asymptomatic infections caused by SARS-CoV-2: The asymptomatic infections caused by SARS-CoV-2 will be determined by comparing baseline and post-prophylactic phase serology samples in the two groups.
Timepoint [4] 381448 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.
Secondary outcome [5] 381449 0
The incidence of specific symptoms of SARS-CoV-2 infections (headache, diarrhoea, abdominal pain, coryzal symptoms, arthralgia, myalgia, dry cough, productive cough, fever, shortness of breath) will be compared in participants randomised to chloroquine or vitamin C. Assessed from patient health records.
Timepoint [5] 381449 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.
Secondary outcome [6] 381451 0
Drug exposure-protection relationship. Whole blood, pre-dose (Day 1), end of Week 5 and Week 12 chloroquine drug concentrations will be correlated with disease protection (if any).
Timepoint [6] 381451 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.
Secondary outcome [7] 381526 0
Angiotension-converting enzyme 2 (ACE2) polymorphisms assessed by genomic analysis will be correlated with frequency of SARS-CoV-2 infection sequelae.
Timepoint [7] 381526 0
12 weeks post-commencement of the IMP. Study to commence Apr 2020.

Eligibility
Key inclusion criteria
Participants eligible for inclusion in this study must fulfill all of the following criteria:
1. Completion of the written informed consent process (signed) with video recording of the verbal consent process;
2. Male or female age 18 to 64 years inclusive, in general good health equivalent to Army Medical Employment Classification J22 or above. Civilian personnel would need to be in good general health as advised by their General Practitioner (GP);
3. Not previously diagnosed with COVID-19;
4. Participant works in/in association with a healthcare facility or other high-risk environment characterised by high level of contact with persons thought likely to be infected with respiratory viruses;
5. Possess an internet enabled smart phone capable of receiving and responding to alerts;
6. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures;
7. Agrees not to self-medicate with chloroquine, hydroxychloroquine or other potential antivirals; and
8. Agree to stay in contact with the study site for the duration of the study and up to 2 weeks following the EOS visit (unless deployed), provide updated contact information as necessary.
Minimum age
18 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants fulfilling any of the following criteria are not eligible for inclusion in this study:
1. History of allergy or intolerance to chloroquine, vitamin C or any excipients.
2. Contraindication to taking chloroquine as chemoprophylaxis e.g. known epileptic, creatinine clearance < 10 mL/min, known prolonged QT syndrome, diabetes.
3. Those having previously received hydroxychloroquine for skin conditions or rheumatological diseases, chloroquine for malaria, tamoxifen, amiodarone or other drugs that may affect the retina within 30 days or 5 half-lives (whichever is longer) of study start.
4. Taking a concomitant medication (abiraterone acetate, agalsidase, amodiaquine, conivaptan, dabrafenib, dacomitinib, dapsone (systemic), enzalutamide, fusidic acid (systemic), idealisib, lanthanum, lumefantrine, mefloquine, MiFEPRIStone, Mitotane, Pimozide, QT-prolonging agents, or stiripentol) which cannot be safely stopped.
5. Participants who, in the opinion of the Investigator, do not have the ability to complete the study.
For other eligibility criteria considerations, the Investigator is referred to the IB (ADFMIDI IB) for detailed information regarding warnings, precautions, contraindications, AEs, and other significant data pertaining to the use of chloroquine.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be assigned to receive either chloroquine or vitamin C in a 1:1 ratio using a permuted block randomization procedure in accordance with a randomization schedule generated by the study biostatistician.

If the participant is determined to be eligible, site personnel who are authorized to randomize participants and who have completed training for the IWRS, will log onto the system and provide the pre-assigned unique participant number. The IWRS provides the randomized group kit number and assigns the participant to one of the two interventions. If the participant is randomized and is never dispensed study drug, then the participant will be considered a randomization failure and an additional participant will be randomized with the next randomization sequence at the time he/she is randomized at that site. Likewise, if the participant was randomized and then is determined to not be eligible for the study, and never received study drug, then another participant will be randomized such that the total numbers of participants who were eligible, randomized, and dispensed study drug meet the enrollment goals. All efforts will be made to retain participants and reasons for withdrawal may include withdrawal of consent or lost to follow-up or evidence of substance abuse that may affect the participant’s capacity to complete the study in the Investigator’s opinion. The reason(s) that a participant was considered a randomization failure or screen failure will be documented in source documents and eCRF.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Centralised randomisation will be performed using the electronic data management system (EDMS), (IBM eClinical), that contains a randomization module. The EDMS is available for randomization of participants 24 hours per day, 7 days per week from any computer using a web browser.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary endpoint is the number of days SDS due to SARS-CoV-2 infection during the study period which coincides with the Australian winter months. Days SDS due to SARS-CoV-2 infection can be treated as count data. A negative binomial regression will be used to compare days SDS between groups administered chloroquine or vitamin C. Sample size estimation is based on the primary endpoint.

The anticipated days SDS for participants taking vitamin C is assumed to be 5 days per 10 weeks. Assuming a dispersion parameter of 0.5 for the negative binomial model, a sample size of 612 subjects (306 per group) will be sufficient to provide 90% power to detect a 20% reduction in event rates (chloroquine vs. vitamin C) at the significance level of 0.05. Allowing for 10% early withdrawal, this study will recruit a total of 680 participants (340 participants per group).

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
The C4 Trial was stopped early due to lack of community transmission of SARS-CoV-2
Date of first participant enrolment
Anticipated
30/03/2020
Actual
3/04/2020
Date of last participant enrolment
Anticipated
15/10/2020
Actual
14/04/2020
Date of last data collection
Anticipated
28/09/2020
Actual
Sample size
Target
680
Accrual to date
Final
44
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 29691 0
4051 - Enoggera
Recruitment postcode(s) [2] 29692 0
4306 - Amberley
Recruitment postcode(s) [3] 29693 0
4275 - Canungra
Recruitment postcode(s) [4] 29697 0
4401 - Oakey

Funding & Sponsors
Funding source category [1] 305299 0
Government body
Name [1] 305299 0
Defence Materiel Technology Centre (DMTC)
Country [1] 305299 0
Australia
Primary sponsor type
Government body
Name
Australian Defence Force Malaria and Infectious Disease Institute
Address
Weary Dunlop Drive, Gallipoli Barracks, Enoggera QLD 4051
Country
Australia
Secondary sponsor category [1] 305669 0
None
Name [1] 305669 0
Address [1] 305669 0
Country [1] 305669 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305638 0
Department of Defence and Veterans' Affairs Human Research Ethics Committee
Ethics committee address [1] 305638 0
Ethics committee country [1] 305638 0
Australia
Date submitted for ethics approval [1] 305638 0
22/03/2020
Approval date [1] 305638 0
25/03/2020
Ethics approval number [1] 305638 0
241-20

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

Contacts
Principal investigator
Name 101046 0
Dr Christopher Moller
Address 101046 0
Australian Defence Force Malaria and Infectious Disease Institute
Weary Dunlop Drive, Gallipoli Barracks, Enoggera QLD 4051
Country 101046 0
Australia
Phone 101046 0
+61 404491621
Fax 101046 0
Email 101046 0
[email protected]
Contact person for public queries
Name 101047 0
Christopher Moller
Address 101047 0
Australian Defence Force Malaria and Infectious Disease Institute
Weary Dunlop Drive, Gallipoli Barracks, Enoggera QLD 4051
Country 101047 0
Australia
Phone 101047 0
+61 404491621
Fax 101047 0
Email 101047 0
[email protected]
Contact person for scientific queries
Name 101048 0
Dennis Shanks
Address 101048 0
Australian Defence Force Malaria and Infectious Disease Institute
Weary Dunlop Drive, Gallipoli Barracks, Enoggera QLD 4051
Country 101048 0
Australia
Phone 101048 0
+61 7 3332 4801
Fax 101048 0
Email 101048 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
EmbaseCoronavirus disease and the cardiovascular system: A narrative review of the mechanisms of injury and management implications.2021https://dx.doi.org/10.21037/cdt-20-779
N.B. These documents automatically identified may not have been verified by the study sponsor.