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Trial registered on ANZCTR


Registration number
ACTRN12620000454976
Ethics application status
Approved
Date submitted
7/04/2020
Date registered
8/04/2020
Date last updated
8/04/2020
Date data sharing statement initially provided
8/04/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Can intravenous high dose zinc improve clinical outcomes in patients with COVID-19 infection?
Scientific title
High-dose intravenous zinc (HDIVZn) as adjunctive therapy in COVID-19 positive critically ill patients: A pilot randomized controlled trial
Secondary ID [1] 300959 0
Protocol Number DT 62996/2020
Universal Trial Number (UTN)
Trial acronym
ZINC COVID study
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
COVID-19 infection 316977 0
Acute respiratory distress syndrome 316978 0
Condition category
Condition code
Infection 315142 315142 0 0
Other infectious diseases
Respiratory 315143 315143 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
COVID-19 symptomatic confirmed hospitalized adult patients will be enrolled as soon as possible after fulfilling the criteria for randomisation. Patients will be allocated in a 1:1 ratio to either the treatment group receiving intravenous zinc chloride (0.5mg/kg/d) or to control group, receiving saline placebo alone.
Pharmaceutical grade Zinc Chloride stock solution obtained from an Australian company (Phebra Pty Ltd) will be diluted in 250ml of normal saline and infused, resulting in a final dosage of 0.5mg/kg/d. Patients will be administered zinc for seven days. To standardise administration time, zinc infusions will commence around 9am but anywhere between 8am to 12pm in the morning is adequate. Zinc chloride will be administered via central venous or peripheral access over 3-6 hrs.
We will monitor fidelity to the intervention by review of nursing documentation in the intravenous fluid given section of the electronic fluid balance chart. Note will be made of what was given, time commenced, volume given, time completed.
Intervention code [1] 317280 0
Treatment: Drugs
Comparator / control treatment
Control is placebo in the form of normal saline 250ml bag infused daily over 3-6 hours.
Control group
Placebo

Outcomes
Primary outcome [1] 323411 0
In non-ventilated patients- Mean change in the worst (highest) level of oxygenation (oxygen flow in litres/min). This will be assessed by the nursing documentation in the participant's electronic record of the flow rate of oxygen delivered and the delivery method (ie nasal prongs, Hudson mask, or non-breather mask).
In ventilated patients- Mean change in the worst (lowest) PaO2 /FiO2 ratio (in mmHg). This will be assessed by nursing documented PaO2 and FiO2 levels in the patient chart.
Timepoint [1] 323411 0
Worst recorded level of oxygenation during the 7 days of intervention.
Primary outcome [2] 323416 0
Feasibility will be assesses by the following measures:
• The primary assessment of our ability to blind treatment of the HDIVZn in a 250-ml saline preparation
• Drug availability from supplier, storage and timely delivery to a patient
• Good clinical practice documentation of drug prescription on Cerner (an electronic medical record), delivery to ICU by project research officer, double signing by nursing staff
• Appropriate preparation of drug- onsite refrigeration storage, preparation with SOPs, maintenance of sterile conditions, protocol compliance, breaches, and variation, documentation processes including patient retention and follow-up rates
• Determine the per-patient cost to estimate subsequent pivotal trial costs
• Assess the process for efficient and effective data entry and analysis
These will be assessed by our research investigators on a regular basis and data collected in the case report forms.
Timepoint [2] 323416 0
During 7 days of intervention
Secondary outcome [1] 381857 0
Mortality
Timepoint [1] 381857 0
28 days
Secondary outcome [2] 381858 0
Duration of mechanical ventilation.
This will be assessed by nursing and medical documentation in the ICU electronic medical record of when ventilation was ceased (in relation to commencement of the trial intervention.)
Timepoint [2] 381858 0
28 days
Secondary outcome [3] 381859 0
Duration of oxygen therapy.
This will be assessed by nursing and medical documentation in the ward or ICU electronic medical record. Note will be made of when therapeutic oxygen delivery was ceased.
Timepoint [3] 381859 0
28 days

Eligibility
Key inclusion criteria
• Consenting adult patients adult male or female, age 18 years or older. Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or another commercial or public health assay
• Hospitalized with a SARS-CoV-2 infection of any duration
• Ability to provide informed consent signed by study patient or legally acceptable representative
• Willingness and ability to comply with study-related procedures/assessments
• Have an oxygen saturation (SaO2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) (Pao2: Fio2) at or below 300 mg Hg.
• No chronic kidney disease (CKD) defined by stage II or higher using the Kidney Disease Improving Global Outcomes (KDIGO) classification
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Age less than 18yo or pregnant or lactating female
• Allergy to Zn
• Severe hepatic impairment defined as Child C liver disease.
• eGFR equal to or less than 30 mL/min/1.73 m2 (defined using CKD-EPI SCr formula)
• History of any organ transplant which requires active immunosuppressive treatment which can interfere with kidney function
• If a patient required cardiopulmonary resuscitation (CPR) within 14 days
• DNR (do not resuscitate) DNI (do not intubate) orders
• Death is deemed imminent or inevitable during this admission, and either the attending physician, patient or substitute decision-maker is not committed to active treatment
• Already receiving dialysis (either acute or chronic) or imminent need of dialysis at the time of enrolment
• Patients with known HIV infection
• Patients with a known or suspected history of oxalate nephropathy or hyperoxaluria, scurvy, chronic iron overload, G-6PD deficiency
• Clinician expects to prescribe Zinc for another indication
• Patients with known haemochromatosis.

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)
This pilot study will be conducted as a randomised double-blinded placebo-control study. The trial study nurses will use the randomisation module in Research Electronic Data Capture (REDCap) hosted by Austin Health, which is a secure web application for managing online data collection. The trial nurses will then maintain a separate database on a password protected computer of treatment allocation. These nurses are responsible for intervention preparation of zinc or placebo in 250ml saline bags labeled with the participant's details and then distributed to the treating medical team for administration. No other members of the treating or research team will have access to the treatment allocation or preparation of interventions.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block randomisation method with variable block sizes of 2, 4 and 6 will be used to allocate eligible patients to either the treatment group, receiving HDIVZn or to the control group in a 1:1 ratio. Randomisation will be performed by the randomisation module in Research Electronic Data Capture (REDCap), which is a secure web application for managing online data collection.
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 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Power:
The primary outcome of this study is related to the effect of zinc therapy on the level of oxygenation expressed either as worst (highest) oxygen flow (in litres/min) in non-ventilated patients or worst (lowest) PaO2 (in mmHg)/FiO2 (as a fraction of 1) ratio in ventilated patients. We hypothesize that zinc therapy will decrease the worst level of oxygenation during the first week (of the treatment period) by 20% compared to placebo from a mean worst value of 10L/min (placebo) to a mean of 8L/min (zinc) or from a mean worst value of 150 (placebo) to a mean worst value of 180 (zinc). If patients transition from non-ventilated to ventilated during the study period, the PaO2/FiO2 ratio will be used.
To have an 80% power to see such an effect at an alpha of 0.05 in non-ventilated patients, assuming a standard deviation (SD) for O2 flow of 4L/min 28 patients would have to be randomized in each arm. In ventilated patients, to have an 80% power to see such an effect at an alpha of 0.05, assuming an SD for the PaO2/FiO2 ratio of 60, 49 patients would have to randomized in each arm.
Rounding off the first group to 30 per arm and the second group to 50 per arm to account for withdrawals, we estimate that a study of 160 patients would provide a suitable sample size to test our primary hypothesis.


Statistical Methods To Be Undertaken:
The descriptive analysis of the data will include the calculation of means, standard deviations, and absolute and relative frequencies of the baseline and follow-up data. Randomisation will be checked by suitable two-sided statistical tests (Chi-Square, or Fisher’s exact test for categorical data, Student’s t-Test or Mann-Whitney-U tests for continuous data). If normality of the data is not given, non-parametric methods will be used. Potentially confounding factors will be checked for using multivariable logistic regression analysis. All renal dysfunction data well be analysed according to the intention-to-treat principle. Continuous data will be tested for normal distribution using histograms. Between-group comparisons for continuous data will be performed with the use of the Student’s t-test or the Mann-Whitney U test and for categorical data with the use of Fisher’s exact test or chi-square test where appropriate. A p-value 0.05 will indicate statistical significance. A full model with clinical relevant covariates (e.g. sex, age, previous heart surgery, preoperative creatinine) will be used for a stepwise backward variable selection procedure to identify independent risk factors for AKI. Secondary endpoints will be analysed in the ITT collective using Fishers’ exact test, or chi-square tests for categorical data, Student’s t-tests and Mann-Whitney-U tests for continuous data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 16396 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 29941 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 305405 0
Other
Name [1] 305405 0
Australian Urologic Cancer Research Trust
Address [1] 305405 0
Suite 5/210 Burgundy St
Heidelberg
VIC 3084
Country [1] 305405 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Rd
Heidelberg
VIC 3084
Country
Australia
Secondary sponsor category [1] 305788 0
University
Name [1] 305788 0
University of Melbourne
Address [1] 305788 0
Gratten St
Parkville
VIC 3010
Country [1] 305788 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305727 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 305727 0
Austin Health HREC
Level 8, HSB
145 Studley Rd
Heidelberg
VIC 3084
Ethics committee country [1] 305727 0
Australia
Date submitted for ethics approval [1] 305727 0
24/03/2020
Approval date [1] 305727 0
06/04/2020
Ethics approval number [1] 305727 0
HREC/62996/Austin-2020

Summary
Brief summary
An outbreak of a new virus called novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to the health of people worldwide and the global economy. There are no vaccines for this virus, and there is no specific treatment for people infected with the virus. In severe cases, COVID-19 virus can spread to the lungs and cause extreme difficulty with their breathing. We call this acute respiratory distress syndrome (ARDS).

Zinc is a naturally occurring essential metal required for the normal function of the body. Numerous studies have been done showing the potential of zinc to inhibit viral infections (including the common cold) in clinical trials and experiments.

It is our study hypothesis that zinc will reduce the severity of COVID-19 infection and improve the clinical outcomes of patients with COVID-19 infection.

Therefore, we plan to perform a study to test whether zinc (given as Zn chloride) is effective and safe in subjects with COVID-19 infection and to work out whether giving zinc to patients can make them get better quicker.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101374 0
A/Prof Joseph Ischia
Address 101374 0
Department of Surgery
University of Melbourne, Austin Health
Level 8, LTB
Studley Rd
Heidelberg, VIC 3084
Country 101374 0
Australia
Phone 101374 0
+61 03 9496 3676
Fax 101374 0
Email 101374 0
jjischia@unimelb.edu.au
Contact person for public queries
Name 101375 0
A/Prof Joseph Ischia
Address 101375 0
Department of Surgery
University of Melbourne, Austin Health
Level 8, LTB
Studley Rd
Heidelberg, VIC 3084
Country 101375 0
Australia
Phone 101375 0
+61 03 9496 3676
Fax 101375 0
Email 101375 0
jjischia@unimelb.edu.au
Contact person for scientific queries
Name 101376 0
A/Prof Joseph Ischia
Address 101376 0
Department of Surgery
University of Melbourne, Austin Health
Level 8, LTB
Studley Rd
Heidelberg, VIC 3084
Country 101376 0
Australia
Phone 101376 0
+61 03 9496 3676
Fax 101376 0
Email 101376 0
jjischia@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Patients are being treated for a severe medical condition and their privacy is of utmost importance. Consent will be sought to share data with other research collaborators for the purpose of the trial only.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 7550 0
Study protocol
Citation [1] 7550 0
Link [1] 7550 0
Email [1] 7550 0
Other [1] 7550 0
Type [2] 7551 0
Statistical analysis plan
Citation [2] 7551 0
Link [2] 7551 0
Email [2] 7551 0
Other [2] 7551 0
Type [3] 7552 0
Informed consent form
Citation [3] 7552 0
Link [3] 7552 0
Email [3] 7552 0
Other [3] 7552 0
Type [4] 7553 0
Ethical approval
Citation [4] 7553 0
Link [4] 7553 0
Email [4] 7553 0
Other [4] 7553 0
Summary results
No Results