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Trial registered on ANZCTR


Registration number
ACTRN12620000731998p
Ethics application status
Not yet submitted
Date submitted
5/06/2020
Date registered
13/07/2020
Date last updated
13/07/2020
Date data sharing statement initially provided
13/07/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Will treating the overwhelming patient response with medications affect COVID-19 mortality?
Scientific title
Safety and efficacy of a pharmacological strategy using Losartan in hospital patients with COVID-19
Secondary ID [1] 301296 0
Nil Known
Universal Trial Number (UTN)
U1111-1252-6251
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 317629 0
Condition category
Condition code
Respiratory 315710 315710 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 315711 315711 0 0
Other inflammatory or immune system disorders
Infection 315712 315712 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multisite, 3 stage inpatient study of the Angiotensin II Receptor Blocker Losartan for treatment of COVID-19. The three stages will be recruited sequentially.

In the first stage, 9 participants will be allocated to the active treatment. The first intervention studied will be Losartan 25mg tablet once daily, for 7 days, or their entire admission (whichever is longer).

Following complete recruitment to the first stage, participants will be allocated to the second stage of the study. In the second stage, 9 participants will start at 25mg Losartan. If hemodynamically stable after 24 hours, they will increase dose to 25mg twice daily for 7 days, or their entire admission (whichever is longer).
If not (clinical decision) the participant will stay on 25mg daily for 7 days, or the remainder of for their admission (whichever is longer).

Following complete recruitment to the first and second stages, participants will be allocated to the third stage of the study. In the third stage, 9 participants will start on 25 mg Losartan daily. If hemodynamically stable after 24 hours, they will increase dose to 25mg twice daily. Then, if hemodynamically stable after further 24 hours, they will increase dose again to 25mg morning and 50mg night. After a further 24 hours, and if the participant is hemodynamically stable, they will increase dose to 50mg twice daily for 7 days, or the remainder of for their admission (whichever is longer).

For all stages, the dose will be held if the blood pressure systolic reading is less than 100mmHg, and/or a renal function decrease of greater than 30% from baseline is observed, or serum potassium greater than permitted by the institutional upper limit of normal (ULN) occurs.

Losartan will be restarted at the previous dose level (or 25 mg if Stage 1) if resolution of the symptoms which caused the dose to be held, i.e. the Patient no longer has a blood pressure systolic reading less than 100mmHg, and/or a renal function decrease of greater than 30% from baseline, or serum potassium greater than permitted by the institutional ULN, is seen within 24 hours (when the next dose of drug due) for 7 days, or the remainder of their entire admission (whichever is longer). If not resolved, drug will not be reinstated and the participant will be withdrawn.

Adherence to this treatment plan will be monitored by checking the administered interventions and observations recorded in patient medical records.

Participants will also cease Losartan if they develop of any new grade 4 AE, not present at baseline, possibly or probably attributable to Losartan.

Intervention code [1] 317677 0
Treatment: Drugs
Comparator / control treatment
For this study, 9 participants will be allocated to a comparator/control Arm (3 participants per stage), No treatment beyond usual supportive care, defined as treating clinicians standard approach will be given. The duration of treatment in the comparator/control group is the remainder of their entire admission.
Control group
Active

Outcomes
Primary outcome [1] 323923 0
To determine the incidence of any treatment emergent AE, using using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Targeted toxicities include hypotension, skin rash. These will be coded at all timepoints by both the clinician and the clinical trial manager in terms of causality.
Timepoint [1] 323923 0
CTCAE v5.0 will be completed and assessed daily until the patient is no longer on trial, that is 7 days or until discharge, whichever is longer. The primary endpoint will be assessed days 1-7, but in this study all time points will be assessed during analysis.
Primary outcome [2] 323924 0
Incidence of Blood Pressure toxicity, defined as systolic BP readings < 100mmHg that do not return to baseline within 24 hours will be measured as per standard local hospital practice (digital or manual sphygmomanometer), and required to be measured at least daily (once in 24 hours).
Timepoint [2] 323924 0
The incidence will be assessed daily until patient no longer on trial, that is 7 days or until discharge, whichever is longer. The primary endpoint will be assessed days 1-7, but in this study all time points will be assessed during analysis.
Secondary outcome [1] 383344 0
A Sequential Organ Failure Assessment Score (SOFA) will be completed daily by the treating clinician.
Timepoint [1] 383344 0
The score will be assessed daily until patient no longer on trial, that is 7 days or until discharge, whichever is longer. In this study, all time points will be assessed during analysis.
Secondary outcome [2] 383345 0
ICU admission - yes/no. This will be collected from the patients medical records - either admitted or not. This information will be collected only once, after discharge..
Timepoint [2] 383345 0
ICU admission - yes/no. This will be collected from the patients medical records - either admitted or not. This information will be collected only once, aafter discharge.
Secondary outcome [3] 383346 0
Intubation - yes/no. This will be collected from the patients medical records - either intubated or not and if yes how many hours. collected once from medical records at completion of study.
Timepoint [3] 383346 0
intubation - yes/no. This will be collected from the patients medical records - either intubated or not and if yes how many hours. collected once from medical records at completion of study.
his information will be collected only once, after the completion of the study.
Secondary outcome [4] 383347 0
The total time of in hospital will be assessed until patient no longer on trial, that is 7 days or until discharge, whichever is longer. In this study, all time points will be assessed during analysis, which will occur once from medical records, after discharge, at completion of study
Timepoint [4] 383347 0
The total time of in hospital will be assessed until patient no longer on trial, that is 7 days or until discharge, whichever is longer. In this study, all time points will be assessed during analysis, which will occur once from medical records, after discharge, at completion of study
Secondary outcome [5] 383348 0
exploratory analysis - The level of proinflammatory markers will be measured by daily blood samples taken and sent for analysis.
Timepoint [5] 383348 0
exploratory. The level of proinflammatory markers will be assessed daily, with other routine bloods including potassium, until patient no longer on trial, that is 7 days or until discharge, whichever is longer. In this study, all time points will be assessed during analysis.
Secondary outcome [6] 383780 0
The length of ICU admission (calculated from the time of admission to the time of discharge) will be collected from the patients medical records,
Timepoint [6] 383780 0
The length of ICU admission will be assessed once, from the medical records post discharge.
This information will be collected only once, after the completion of the study.
Secondary outcome [7] 383781 0

The total time a participant is intubated (calculated from the time intubation is started to the time ceased) will be collected from the patients medical records.

This information will be collected only once, after the completion of the study.
Timepoint [7] 383781 0
The total time a participant is intubated (calculated from the time intubation is started to the time ceased) will be collected from the patients medical records.

This information will be collected only once, after the completion of the study.
Secondary outcome [8] 383782 0
The concentration of Angiotensin II will be measured by daily blood samples taken and sent for analysis.
Timepoint [8] 383782 0
The samples will be taken daily until discharge or for 7 days, whichever is longer. They will be assessed post trial in a batch.
Secondary outcome [9] 383783 0
The COVID-19 Viral load (quantitative) will be measured by daily blood samples taken and sent for analysis.
Timepoint [9] 383783 0
The samples will be taken daily until discharge or for 7 days, whichever is longer. They will be assessed post trial in a batch.

Eligibility
Key inclusion criteria
Confirmed SARS-CoV-2 infection by any method
Current admission as inpatient to hospital ward for management of COVID-19
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Current use of RAS agent
Known contra-indication to any RAS agent
Participation in another clinical trial for COVID-19 or SARS-CoV-2
Current or previous admission to ICU for COVID-19 management

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)
Allocation of participants is concealed through the need to contact the external holder of the sequence generator software, Sequence generator only occurs after consent is obtained and it is determined the subject is eligible.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation will be performed using a computer generated random code based on the 3:1 allocation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Descriptive analyses including clinical correlations will be generated, with all variables explored and will focus on safety and efficacy endpoints.

Univariate analysis, T-tests or the corresponding non-parametric tests, will be used to test for differences in change in active treatment and control group.

If the active treatment is shown to be a potentially safe and effective treatment over the control group, subsequent studies will be designed and undertaken to determine the particular dose and frequency required.

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)
NSW,SA
Recruitment hospital [1] 16759 0
John Hunter Hospital - New Lambton
Recruitment hospital [2] 16760 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 16761 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [4] 16762 0
Nepean Hospital - Kingswood
Recruitment postcode(s) [1] 30384 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 30382 0
2305 - New Lambton
Recruitment postcode(s) [3] 30385 0
2747 - Kingswood
Recruitment postcode(s) [4] 30383 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 305739 0
Self funded/Unfunded
Name [1] 305739 0
Address [1] 305739 0
Country [1] 305739 0
Primary sponsor type
Government body
Name
NSW Health via the Hunter New England Local Health District
Address
Hunter New England Local Health District
Lookout Road
New Lambton NSW 2305
Country
Australia
Secondary sponsor category [1] 306165 0
None
Name [1] 306165 0
Address [1] 306165 0
Country [1] 306165 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 306014 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 306014 0
Bellberry Ltd.
123 Glen Osmond Rd
Eastwood
SA 5063
Ethics committee country [1] 306014 0
Australia
Date submitted for ethics approval [1] 306014 0
30/07/2020
Approval date [1] 306014 0
Ethics approval number [1] 306014 0

Summary
Brief summary
There are many current health and social needs in the COVID pandemic. From both a health and and economic perspective, the best population policy is to vaccinate. However, in the absence of a vaccine, a combination of minimizing exposure and using proven therapies to prevent flulike symptoms becoming lung failure requiring ventilation and ICU beds is the only strategy.

The key to respiratory illness is the viral attack on the pulmonary Renin Angiotensin System (RAS), which drives a substantial inflammatory process. This has reached a zenith with SARS-CoV-2, which comprehensively dysregulates the pulmonary RAS processes by targeting a vital RAS component, the angiotensin-converting enzyme 2 (ACE2). It is this enzyme that becomes the molecular target or receptor for SARS-CoV-2 (COVID) infection with the concurrent loss of its role in physiologically countering RAS induced inflammation.

We aim to study in an open label randomised trial the safety of a range of identifed, currently used ARB and ACEI's. The first compound selected is Losartan, a drug that interferes with the renin angiotensin system. Many retrospective studies have now reported significant mortality benefits for patients who are on RAS drugs when admitted to hospital. We aim to undertake a prospective study in patients not usually on such drugs to describe the safety, tolerability and efficacy of adding Losartan to the treatment regime in Australian hospitalised COVID patients
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102422 0
Prof Jennifer Martin
Address 102422 0
Head of Clinical Pharmacology, University of Newcastle.
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 102422 0
Australia
Phone 102422 0
+61 2 40420908
Fax 102422 0
Email 102422 0
jen.martin@newcastle.edu.au
Contact person for public queries
Name 102423 0
Prof Jennifer Martin
Address 102423 0
Head of Clinical Pharmacology, University of Newcastle.
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 102423 0
Australia
Phone 102423 0
+61 2 40420908
Fax 102423 0
Email 102423 0
jen.martin@newcastle.edu.au
Contact person for scientific queries
Name 102424 0
Prof Jennifer Martin
Address 102424 0
Head of Clinical Pharmacology, University of Newcastle.
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 102424 0
Australia
Phone 102424 0
+61 2 40420908
Fax 102424 0
Email 102424 0
jen.martin@newcastle.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
What supporting documents are/will be available?
No other documents available
Summary results
No Results