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Trial registered on ANZCTR


Registration number
ACTRN12620000620921
Ethics application status
Approved
Date submitted
26/05/2020
Date registered
28/05/2020
Date last updated
28/05/2020
Date data sharing statement initially provided
28/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Angiotensin II Infusion in COVID-19-Associated Vasodilatory Shock: A multinational, multicentre registry
Scientific title
Angiotensin II Infusion in COVID-19-Associated Vasodilatory Shock: A multinational, multicentre registry
Secondary ID [1] 301382 0
Nil known
Universal Trial Number (UTN)
Trial acronym
ACES
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 317639 0
Condition category
Condition code
Respiratory 315720 315720 0 0
Other respiratory disorders / diseases
Infection 315728 315728 0 0
Other infectious diseases
Public Health 315729 315729 0 0
Epidemiology

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
2
Target follow-up type
Months
Description of intervention(s) / exposure
The ACES Partnership represents a novel, coordinated effort to create a high-quality, detailed, prospective registry of COVID-19 patients requiring angiotensin II or other novel therapy worldwide. All patients will be followed until hospital discharge.
- Data collection
The ACES Study Registry is a clinical registry designed to measure the quality of care and develop patient-centred approaches for patient with COVD-19 receiving angiotensin II or novel therapy. It will collect valuable health information during hospital admission for the purpose of ensuring excellence in care delivery in this highly specific patient group.

Retrospective data
Data on patients who have left the ICU or have died will be included under a waiver of consent. During this COVID-19 pandemic the investigators believe that it is not recommended to contact patients that have already left the ICU as:
• It would add an extra emotional stress and burden to the patients and their family;
• Their involvement in this registry is not a high risk;
• It is not an interventional study;
• Patients would not be able to breach isolation and return to the hospital to complete consent documents;
• Postal deliveries are not functioning or are non-existent; and
• In this period of world-wide high COVID-19 mortality a waiver for data collected retrospectively is warranted.

Prospective data
COVID-19 patients who are in ICU and require angiotensin II or a novel therapy are critically unwell and will be unconscious. Patients and families involved in this disease are under a great deal of stress and in many institutions families or decision makers will not be available due to isolation practices of those units. The Investigators believe it is vital that all patients administered angiotensin II or novel therapy (and matched patients) are included in the registry to accurately describe the population and gain a quick response to the best management of patients receiving angiotensin II or novel therapy. For these reasons the investigators believe all prospectively involved patients should also be included in the ACES registry under a waiver of consent.

The data will be collected at ICU admission, daily until day 3, and ICU and hospital discharge.

Intervention code [1] 317687 0
Not applicable
Comparator / control treatment
Control patients will be adults who are diagnosed with COVID-19 but not receiving angiotensin II infusion or novel therapy. In the case of angiotensin II patients will be matched by date of ICU admission, age, respiratory support needed at ICU admission, presence of hypertension, and use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. Patients will be excluded if they are less than 18 years of age.
Control group
Active

Outcomes
Primary outcome [1] 323929 0
Time until being discharged alive from the intensive care unit (ICU) (defined as the time from ICU admission until ICU discharge alive, assessed by the date of admission and date of discharge retrieved from medical records)
Timepoint [1] 323929 0
Until ICU discharge
Secondary outcome [1] 383359 0
Survival to ICU discharge
Timepoint [1] 383359 0
Until ICU discharge
Secondary outcome [2] 383360 0
Survival to hospital discharge
Timepoint [2] 383360 0
Until hospital discharge
Secondary outcome [3] 383361 0
Duration of mechanical ventilation (assessed by the date of admission and date of discharge retrieved from medical records)
Timepoint [3] 383361 0
28 days post ICU admission
Secondary outcome [4] 383362 0
Change in oxygenation in the first 3 days (assessed by daily assessment of respiratory support, defined as low flow oxygen, high flow oxygen, non-invasive ventilation or invasive mechanical ventilation, and retrieved from medical records)
Timepoint [4] 383362 0
First 3 days after ICU admission
Secondary outcome [5] 383363 0
ICU length of stay
Timepoint [5] 383363 0
Until ICU discharge
Secondary outcome [6] 383364 0
Hospital length of stay
Timepoint [6] 383364 0
Until hospital discharge
Secondary outcome [7] 383365 0
Need of additional support (defined as need of ECMO, renal replacement therapy, tracheostomy, use and dose of other vasopressors and/or prone positioning, retrieved from medical records)
Timepoint [7] 383365 0
Until ICU discharge
Secondary outcome [8] 383366 0
Clinician reported complications considered attributable to angiotensin II infusion or other novel therapy (retrieved from medical records)
Timepoint [8] 383366 0
Until ICU discharge

Eligibility
Key inclusion criteria
Adult patients who are diagnosed with COVID-19 and receiving angiotensin II infusion or novel therapy. Control patients will be adults who are diagnosed with COVID-19 but not receiving angiotensin II infusion and novel therapies.
Angiotensin II group
1. Patients who are admitted to a participating centre; and
2. Diagnosed with COVID-19; and
3. Receive angiotensin II infusion.
Control group
1. Patients who are admitted to a participating centre; and
2. Diagnosed with COVID-19; and
3. Not receive angiotensin II infusion; and
4. Receiving vasopressor infusion; and
5. Matched to a patient from the angiotensin II group by:
a. Date of ICU admission (range of ± 2 days); and
b. Age (range of ± 2 years); and
c. Respiratory support at ICU admission (no support or only oxygen or non-invasive ventilation/high flow nasal cannula or invasive ventilation); and
d. History of hypertension (yes or no); and
e. Use of ACEIs or ARBs (use or not).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they are less than 18 years of age.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Convenience sample
Timing
Both
Statistical methods / analysis
It is expected that each centre will recruit an average of 15 consecutive patients per month who fulfil the inclusion criteria. Assuming recruitment at 7 sites over three months, a sample size of 315 patients will be recruited over the first three months. This project is designed to obtain data to assist in the planning of definitive trials that will test the hypothesis that angiotensin II influences survival. The power of this type of observational study relates to the confidence about how close an observed point estimate for a proportion is to the true proportion. A sample size of 250 patients (45 days) would have 90% power to identify that the point estimate was within 5% of the true value for an event, for example the chance of being discharged alive from the ICU.
Comparisons will be performed using chi-square tests for equal proportion, Student’s t-tests for parametric data and Wilcoxon rank sum tests otherwise, with results presented as median (interquartile range), means (standard deviation) and number (%), respectively. Multivariable analysis will be performed using hierarchical regression adjusting for known covariates and baseline imbalances, with patients nested within sites. Survival outcomes will be assessed using Cox-proportional hazards regression and reported as hazard ratios (95% confidence interval). Data will be analysed using R version 3.6.3 (The R Project for Statistical Computing). A two-sided P-value of 0.05 will be used to indicate significance.
Objective, reliable co-variates for risk adjustment will be determined to enable factors outside the control of clinicians to be taken into account by using appropriate statistical adjustments.

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,VIC
Recruitment hospital [1] 16763 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 16764 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 16765 0
The Alfred - Melbourne
Recruitment hospital [4] 16766 0
Campbelltown Hospital - Campbelltown
Recruitment postcode(s) [1] 30389 0
2560 - Campbelltown
Recruitment postcode(s) [2] 30388 0
3004 - Melbourne
Recruitment postcode(s) [3] 30386 0
3084 - Heidelberg
Recruitment postcode(s) [4] 30387 0
3168 - Clayton
Recruitment outside Australia
Country [1] 22576 0
Italy
State/province [1] 22576 0
Country [2] 22577 0
United Kingdom
State/province [2] 22577 0
Country [3] 22578 0
Germany
State/province [3] 22578 0
Country [4] 22579 0
Canada
State/province [4] 22579 0
Country [5] 22580 0
Belgium
State/province [5] 22580 0

Funding & Sponsors
Funding source category [1] 305822 0
University
Name [1] 305822 0
ANZIC-RC, Monash University
Address [1] 305822 0
Department of Epidemiology and Preventive Medicine
Monash University
Level 3
553 St Kilda Road
Melbourne VIC 3004
Country [1] 305822 0
Australia
Primary sponsor type
Individual
Name
Rinaldo Bellomo
Address
Intensive Care Unit
Austin Health
145 Studley Rd,
Heidelberg
VIC 3084
Australia
Country
Australia
Secondary sponsor category [1] 306265 0
None
Name [1] 306265 0
Address [1] 306265 0
Country [1] 306265 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306090 0
The Alfred
Ethics committee address [1] 306090 0
55 Commercial Rd,
Melbourne
VIC 3004
Australia
Ethics committee country [1] 306090 0
Australia
Date submitted for ethics approval [1] 306090 0
20/04/2020
Approval date [1] 306090 0
04/05/2020
Ethics approval number [1] 306090 0
63720

Summary
Brief summary
In December 2019, several cases of atypical pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported in Wuhan, China. This novel virus has now become responsible for a pandemic (COVID-19). In most of cases, COVID-19 is a self-limited lower respiratory tract illness. However, in some patients, it causes acute respiratory distress syndrome (ARDS), shock, myocardial injury, acute kidney injury, and multiorgan failure develop. A significant proportion of mechanically ventilated patients with COVID-19 infection require vasopressor support. Conventional and recommended agents used for such support include norepinephrine and vasopressin.
Angiotensin II may be a suitable agent in patients with COVID-19 because of its potential nephroprotective effect, its potentially ability to specifically assist in patients recently exposed to angiotensin converting enzyme inhibitors (ACEIs), and because of its potential to affect the internalization and downregulation of angiotensin converting enzyme 2 (ACE2). This is relevant to COVID-19-associated critical illness because ACE is both the protein responsible for the break-down of angiotensin II to Angiotensin 1-7 and is the receptor for the viral entry into the cells. The primary aim is to generate an international, multicentre network of integrated care for patients with COVID-19 treated with angiotensin II or other novel therapy to monitor safety and to monitor outcomes. The hypothesis is that, in patients with COVID-19 receiving angiotensin II or novel therapy, additional evidence of benefit or harm can be identified, improved and used to guide further research in the field with the implementation of an international angiotensin II registry.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102666 0
Prof Rinaldo Bellomo
Address 102666 0
Austin Health
Intensive Care Unit
145 Studley Rd,
Heidelberg
VIC 3084
Country 102666 0
Australia
Phone 102666 0
+61 400360537
Fax 102666 0
Email 102666 0
Rinaldo.BELLOMO@austin.org.au
Contact person for public queries
Name 102667 0
Mr Tony Trapani
Address 102667 0
Australian and New Zealand Intensive Care-Research Centre (ANZIC-RC)
Monash University
Level 3,
553 St Kilda Road
Melbourne,
VIC 3004
Country 102667 0
Australia
Phone 102667 0
+61 409798892
Fax 102667 0
Email 102667 0
tony.trapani@monash.edu
Contact person for scientific queries
Name 102668 0
Dr Ary Serpa Neto
Address 102668 0
Australian and New Zealand Intensive Care-Research Centre (ANZIC-RC)
Monash University
Level 3,
553 St Kilda Road
Melbourne,
VIC 3004
Country 102668 0
Australia
Phone 102668 0
+61 432749435
Fax 102668 0
Email 102668 0
ary.serpaneto@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All individual de-identified data collected during the study
When will data be available (start and end dates)?
After the publication of the first paper of the collaboration and available for 5 years after publication
Available to whom?
Scientific investigators interested in the field
Available for what types of analyses?
Secondary analyses defined in discussion with the Steering Committee of the study
How or where can data be obtained?
After contact with the principal investigator and study coordinator (ary.serpaneto@monash.edu)
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 8084 0
Study protocol
Citation [1] 8084 0
Link [1] 8084 0
Email [1] 8084 0
ary.serpaneto@monash.edu
Other [1] 8084 0
Attachment [1] 8084 0
Summary results
No Results