Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000457943
Ethics application status
Approved
Date submitted
7/04/2020
Date registered
8/04/2020
Date last updated
23/10/2020
Date data sharing statement initially provided
8/04/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Hydroxychloroquine for the Community-Based Treatment of COVID-19
Scientific title
A Randomised, Double Blind, Placebo-Controlled Trial of the Efficacy of Hydroxychloroquine for the Community-Based Treatment of Adults With Diagnosed COVID-19
Secondary ID [1] 300953 0
MRINZ/20/01
Universal Trial Number (UTN)
Trial acronym
HCQ Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 316972 0
Condition category
Condition code
Infection 315125 315125 0 0
Other infectious diseases
Respiratory 315152 315152 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral administration of Hydroxychloroquine capsules for five days.
Day 1: 800mg (4 capsules) Hydroxychloroquine stat
Days 2 - 5: 400mg (2 capsules) Hydroxychloroquine once daily
Adherence to trial treatment will be assessed through the study diaries which will require the participant to complete the time of administration and number of tablets taken each day. Participants will not be required to return used study treatments to the research office but encouraged to dispose of any unused medication via their community pharmacy or general practice.
Intervention code [1] 317272 0
Treatment: Drugs
Comparator / control treatment
Oral administration of Placebo capsules for five days.
Day 1: 4 Placebo capsules stat
Days 2 - 5: 2 Placebo capsules once daily
Both the HCQ and placebo capsules contain small amounts of calcium lactate powder, which is used in many food substances and can be found in dietary supplements, so is generally recognised as safe. Calcium lactate powder is the main component of the placebo capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 323403 0
Efficacy of Hydroxychloroquine in the community-based management of COVID-19 assessed by the mean daily InFLUenza Patient-Reported Outcome (FLU-PRO) illness severity score
Timepoint [1] 323403 0
Day 5 of treatment administration
Secondary outcome [1] 381801 0
Severity of symptoms between randomised treatments assessed by the mean daily FLU-PRO illness severity score (total)
Timepoint [1] 381801 0
Daily, from baseline (Day 0) through to Day 28 inclusive
Secondary outcome [2] 381802 0
Severity of symptoms between randomised treatments assessed by the FLU-PRO interference with usual activities five point Likert scale:
How much did your flu symptoms interfere with your usual activities today? (Please select one response only)
1. Not at all
2. A little bit
3. Somewhat
4. Quite a bit
5. Very much
Timepoint [2] 381802 0
Daily, from baseline (Day 0) through to Day 28 inclusive
Secondary outcome [3] 381803 0
Severity of symptoms between randomised treatments assessed by the FLU-PRO physical health rating five point Likert scale:
Overall, how severe were your symptoms today? (Please select one response only)
1. No flu symptoms today
2. Mild
3. Moderate
4. Severe
5. Very severe
Timepoint [3] 381803 0
Daily, from baseline (Day 0) through to Day 28 inclusive
Secondary outcome [4] 381804 0
Severity of COVID-19 specific symptoms between randomised treatments, assessed by mean daily FLU-PRO illness severity score (COVID-19 sub-domains)
Timepoint [4] 381804 0
Daily, from baseline (Day 0) through to Day 28 inclusive
Secondary outcome [5] 381805 0
Duration of symptoms assessed by time from Day 0 until return to usual health as self-reported by participant through completion of the FLU-PRO question: "Have you returned to your usual health today?"
1. Yes
0. No
Outcome deemed to be met once Yes is reported for 2 consecutive days.
Timepoint [5] 381805 0
Daily, from baseline (Day 0) through to Day 28 inclusive
Secondary outcome [6] 381806 0
Duration of symptoms assessed by time from Day 0 to feeling “much better” on the FLU-PRO seven point Likert scale:
Overall, how were your flu symptoms today compared to yesterday? (Please select one response only)
1. Much better
2. Somewhat better
3. A little better
4. About the same
5. A little worse
6. Somewhat worse
7. Much worse
Timepoint [6] 381806 0
Daily, from baseline (Day 0) through to Day 28 inclusive
Secondary outcome [7] 381807 0
Mean tympanic temperature assessed using a thermoscan tympanic thermometer provided to the participant on Day 1
Timepoint [7] 381807 0
Daily, from Day 1 through to Day 28 inclusive
Secondary outcome [8] 381808 0
Mean maximum tympanic temperature assessed using a thermoscan tympanic thermometer provided to the participant on Day 1
Timepoint [8] 381808 0
Daily, from Day 1 through to Day 28 inclusive
Secondary outcome [9] 381809 0
Number of hospital admissions deemed related to COVID-19 assessed via hospital medical records
Timepoint [9] 381809 0
Day 28
Secondary outcome [10] 381810 0
Mortality risk for mild to moderate COVID-19 disease initially managed in the community, assessed by 28 day mortality
Timepoint [10] 381810 0
Day 28
Secondary outcome [11] 381811 0
Mean Treatment Satisfaction Questionnaire for Medication (TSQM II) score
Timepoint [11] 381811 0
Day 14
Secondary outcome [12] 381812 0
Number of COVID-19 diagnoses within participant’s residence, as self-reported by the participant
Timepoint [12] 381812 0
Baseline (Day 0) through to Day 28 inclusive
Secondary outcome [13] 381813 0
Adverse events assessed via telephone calls from an investigator. More commonly reported side effects (affecting between 1% and 10% of people) in long term use of hydroxychloroquine include loss of appetite, nausea, rash, and headache. All adverse events will be collected and assessed for relationship to intervention.
Timepoint [13] 381813 0
Baseline (Day 0) through to Day 28 inclusive
Secondary outcome [14] 381814 0
Qualitative analysis of enablers to treatment and self-isolation that can inform COVID-19 related public health messaging and action, assessed by an optional, anonymous online questionnaire.
Timepoint [14] 381814 0
Day 28
Secondary outcome [15] 381875 0
Qualitative analysis of barriers to treatment and self-isolation that can inform COVID-19 related public health messaging and action, assessed by an optional, anonymous online questionnaire.
Timepoint [15] 381875 0
Day 28

Eligibility
Key inclusion criteria
• Aged 18 to 75 years.
• Laboratory confirmed SARS-CoV2 infection.
• Advised to self-manage COVID-19 in the community by the regional public health team.
• In the Investigator’s opinion, is able and willing to comply with all trial requirements.
• Baseline Flu PRO score >1.3
• Able to receive and commence randomised treatment via courier the day after consent was obtained.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Known pregnancy or planning to become pregnant during the study period
• Currently breastfeeding
• Known maculopathy or retinal disorder.
• Known cardiac disease/dysrhythmia or prolonged QTc
• Know renal disease
• Known hepatic disease
• Known hypomagnesaemia or hypokalaemia.
• Currently using hydroxychloroquine or any 4-aminoquinoline.
• Use of medications prolonging QTc including: Class IA (quinidine, procainamide, disopyramide) and III (amiodarone, sotalol, ibutilide, dofetilide) antiarrythmics, macrolides, methadone, fluoroquinolones, domperidone, fluconazole, ondansetron, tacrolimus, tramadol, anti-retrovirals.
• Current use of tamoxifen, digoxin, tricyclics, SSRIs, antipsychotics, halfantrine, cyclosporin and anti-epileptic medications
• Current use of oral hypoglycaemics including glipizide, glyburide, gliclazide, glimepiride, repaglinide, nateglinide, metformin, rosiglitazone, pioglitazone, acarbose, miglitol, voglibose, sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, dapagliflozin, canagliflozin, bromocriptine.
• Sensitivity or allergy to 4-aminoquinilone compounds or any excipients used in the study
• Unable to access digital consent forms or maintain remote contact with the study team
• Have any other condition which, at the investigator’s discretion, is believed may present a safety risk or impact the feasibility of the study or the study results.

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 done in the study database using the inbuilt randomisation module. Investigators will not have access to the randomisation schedule.
Where participants are allocated treatment according to the index participant randomisation outcome, investigators will not have access to the outcome beforehand, they are required to contact the holder of the allocation schedule who will be located at the central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary outcome variable is mean illness severity measured by FLU-PRO 5 days after randomisation. The FLU-PRO has been evaluated in influenza-like illness (Powers et al,, 2018). The difference between ‘Severe and very severe’ and ‘Moderate’ was 0.56 units and between ‘Moderate’ and ‘Mild’ was 0.47 units. This can be interpreted that an important difference in scores is likely to be 0.5 units. The standard deviation (SD) reported associated with these differences was about 0.5 units. In order to detect a difference of 0.5 units with an SD of 0.5 units, an intraclass correlation coefficient (ICC) of 0.1 with 90% power needs 26 participants per arm, total 52. Typically, in primary care-based studies ICCs for questionnaires are of the order of 0.05, so an ICC of 0.1 is a reasonable assumption for a continuous measurement made in the same individuals within a household. We are unsure of the non-completion rate of the instrument, but assuming this is 25% we plan to recruit 70 participants. Because this instrument has not been used in patients with COVID-19 we will evaluate the SD after 20 participants have been recruited and re-estimate the sample size required.

The primary outcome will be an ‘intention to treat’ analysis. The ITT group will be participants that receive randomised treatment. The primary analysis will be a mixed linear model, similar to ANCOVA with baseline FLU-PRO score as a continuous co-variate and randomised treatment as a fixed effect, with the addition of a random effect for household to account for the correlated measurements within households i.e. the cluster randomisation, and an interaction term between treatment and treatment delay (as an indicator variable).

Secondary outcomes: Time to event data will be analysed by Cox Proportional Hazards. Hospital admission rates and other dichotomous variables will be estimated by standard binomial methods. The distribution of the levels of interference with usual activities and physical health rating will be examined using ordinal regression. Other continuous variables (temperature, TSQM II score) will be analysed by ANCOVA. Age or sex modifiers to treatment responses will be analysed using a mixed linear model, similar to ANCOVA with baseline FLU-PRO score as a continuous co-variate and randomised treatment as a fixed effect, and the addition of a random effect for household to account for the correlated measurements within households and an interaction term between treatment and age (as a continuous variable), sex and treatment delay.
Basic descriptive statistics will be used for data generated from tick box questions. Data from free text questions will be analysed inductively within QSR International's NVivo 12 software to create themes within the reported enablers and barriers to treatment and self-isolation.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Safety concerns
Other reasons/comments
Other reasons
Due to emerging safety data around Hydroxychloroquine use in COVID-19 and the lack of COVID-19 cases in the NZ community we decided to withdraw this trial.
Date of first participant enrolment
Anticipated
14/04/2020
Actual
Date of last participant enrolment
Anticipated
1/01/2021
Actual
Date of last data collection
Anticipated
29/01/2021
Actual
Sample size
Target
70
Accrual to date
Final
Recruitment outside Australia
Country [1] 22471 0
New Zealand
State/province [1] 22471 0
N/A

Funding & Sponsors
Funding source category [1] 305398 0
Other
Name [1] 305398 0
Medical Research Institute of New Zealand
Country [1] 305398 0
New Zealand
Primary sponsor type
Other
Name
Medical Research Institute of New Zealand
Address
Level 7, CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country
New Zealand
Secondary sponsor category [1] 305777 0
None
Name [1] 305777 0
Address [1] 305777 0
Country [1] 305777 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305722 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 305722 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 305722 0
New Zealand
Date submitted for ethics approval [1] 305722 0
02/04/2020
Approval date [1] 305722 0
17/04/2020
Ethics approval number [1] 305722 0
20/NTB/73

Summary
Brief summary
The COVID-19 pandemic continues to escalate in terms of morbidity and mortality worldwide. Evidenced-based treatment strategies are lacking and currently focused on managing severe disease in hospitalised patients. With most infected patients self-managing in the community there is potential to minimise symptoms, viral load and transmissibility of COVID-19 through effective interventions in this setting. Hydroxychloroquine (HCQ) is an affordable, available and safe drug with demonstrable inhibitory effect in vitro against the virus causing COVID-19. Participants will administer HCQ or placebo for five days, completing daily diary entries to assess their symptoms as well as measuring tympanic temperature twice daily.
This national, randomised, placebo-controlled trial of hydroxychloroquine in the community-based management of confirmed COVID-19 patients will provide evidence of efficacy and inform a definitive study to assess high priority clinical outcomes such as relative reduction in hospital admission rates and mortality.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101354 0
Dr Alex Semprini
Address 101354 0
Medical Research Institute of New Zealand
Level 7, CSB Building,
Wellington Hospital,
Newtown
Wellington 6021
Country 101354 0
New Zealand
Phone 101354 0
+64 4 805 0260
Fax 101354 0
Email 101354 0
[email protected]
Contact person for public queries
Name 101355 0
Dr Alex Semprini
Address 101355 0
Medical Research Institute of New Zealand
Level 7, CSB Building,
Wellington Hospital,
Newtown
Wellington 6021
Country 101355 0
New Zealand
Phone 101355 0
+64 4 805 0260
Fax 101355 0
Email 101355 0
[email protected]
Contact person for scientific queries
Name 101356 0
Dr Alex Semprini
Address 101356 0
Medical Research Institute of New Zealand
Level 7, CSB Building,
Wellington Hospital,
Newtown
Wellington 6021
Country 101356 0
New Zealand
Phone 101356 0
+64 4 805 0260
Fax 101356 0
Email 101356 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices)
When will data be available (start and end dates)?
18-24 months after publication until a minimum of 5 years after publication
Available to whom?
Researchers who provide a methodologically sound proposal that has been approved by the study steering committee
Available for what types of analyses?
To achieve the aims outlined in the approved proposal
How or where can data be obtained?
Through a signed data sharing agreement and by emailing the principal investigator ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7528Study protocol  [email protected]
7529Statistical analysis plan  [email protected]
7530Informed consent form  [email protected]
7531Ethical approval  [email protected]
7532Analytic code  [email protected]



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
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