Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000805875
Ethics application status
Approved
Date submitted
31/03/2021
Date registered
25/06/2021
Date last updated
15/04/2024
Date data sharing statement initially provided
25/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Paramedic Randomized Trial of Noradrenaline Versus Adrenaline in the Initial Management of Patients with Cardiogenic Shock: The PANDA Trial
Scientific title
Paramedic Randomized Trial of Noradrenaline Versus Adrenaline in the Initial Management of Patients with Cardiogenic Shock: Investigating the effect on 28-day mortality
Secondary ID [1] 303819 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PANDA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiogenic Shock 321335 0
Condition category
Condition code
Cardiovascular 319115 319115 0 0
Coronary heart disease
Cardiovascular 319116 319116 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible patients will be randomised in a 1:1 fashion to receive EITHER Noradrenaline (trial agent) or Adrenaline (control).

While the trial agent is being prepared, metaraminol 0.5-1.0mg (intravenous) can be administered at 2 minute intervals to maintain perfusion.

Noradrenaline Intravenous Infusion:
• Prepare 3mg noradrenaline diluted to 50mL with 5% dextrose or normal saline
• Commence at 5mcg/min
• Titrate up to 250mcg/min, aiming to achieve SBP greater than or equal to 100mmHg
• Increases or decreases in dosage should be at a rate of 5-10mcg/min
Intervention code [1] 320124 0
Treatment: Drugs
Comparator / control treatment
The comparator arm will be the current Ambulance Victoria clinical practice guideline for the management of inadequate perfusion - Adrenaline infusions are commenced and titrated to achieve a systolic blood pressure of greater than or equal to 100mmHg.

While the control agent is being prepared, metaraminol 0.5-1.0mg (intravenous) can be administered at 2 minute intervals to maintain perfusion.

Adrenaline Intravenous Infusion:
• Prepare 3mg adrenaline diluted to 50mL with 5% dextrose or normal saline
• Commence at 5mcg/min
• Titrate up to 250mcg/min, aiming to achieve SBP greater than or equal to 100mmHg
• Increases or decreases in dosage should be at a rate of 5-10mcg/min
Control group
Active

Outcomes
Primary outcome [1] 327005 0
All-cause mortality determined through assessment of the patient medical records.
Timepoint [1] 327005 0
Assessed at 28 days post-randomisation
Primary outcome [2] 327006 0
The primary safety end-point is the development of refractory shock determined by review of Ambulance Victoria patient care records. This is defined as requiring >100mcg/min of the assigned agent despite adequate fluid resuscitation to maintain a SBP of >100mmHg, for a period of greater than 10-minutes.
Timepoint [2] 327006 0
Handover of care to Emergency Department by review of Ambulance Victoria patient records
Secondary outcome [1] 397366 0
Composite end point of the proportion of patients with all-cause 28-day mortality, initiation of renal replacement therapy, refractory shock during transport to hospital, or arrhythmia requiring intervention during transport to hospital.
Timepoint [1] 397366 0
28 days following randomisation

Eligibility
Key inclusion criteria
• Adult (aged 18 years or older)
• Evidence of shock with an indication to commence vasoactive infusion as per Ambulance Victoria Clinical Practice Guidelines and systolic blood pressure <=90mmHg despite adequate filling.
• Suspected cardiac aetiology.

Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Suspected traumatic, anaphylactic or asthmatic aetiology of shock
• Heart rate < 50 beats per minute
• Transferred from another healthcare facility
• Cardiac arrest with greater than or equal to 30 minutes of cardiopulmonary resuscitation prior to return of spontaneous circulation.
• Patient dependent on others for activities of daily living
• Female who is known or suspected to be pregnancy
• Receiving vasoactive infusion prior to randomisation

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)
Ambulance Victoria MICA paramedics will be provided with randomisation envelopes. Half in each pack will contain instructions for administering intravenous adrenaline and half will contain instructions for administering noradrenaline as per study protocol. The envelopes will be randomised by computer-generated code into blocks of six, numbered externally, and then sealed within an opaque envelope that conceals the treatment designation. After each patient is enrolled, a new envelope will be placed on vehicle at the earliest convenient time from the remaining envelopes held at the ambulance station.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Envelopes will be randomised by computer-generated code into blocks of six as previously undertaken by Ambulance Victoria
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data analyses will be performed by an independent biostatistician using the statistical package SPSS version 23 (IBM Corporation, Armonk, NY, USA). Variables that approximate a normal distribution will be summarised as mean ± standard deviation, and groups compared using T-Tests. Non-normally distributed variables will be summarised as median and first and third quartiles (Q1, Q3), and groups compared using Mann-Whitney Rank sum tests with exact inference. Binomial variables will be expressed as proportions and 95% confidence intervals (exact binomial) and groups compared by Chi-Squared tests.

All patients allocated to each group will be considered as comprising the intention-to treat population for all primary and secondary analyses. Owing to the emergent situation at the time of recruitment, we anticipate that a proportion of patients will be randomised without receiving a study drug. Accordingly, we will perform pre-specified secondary analyses for patients meeting inclusion criteria for cardiogenic and non-cardiogenic shock who subsequently receive a study drug. Differences in the primary outcome will be analysed with the use of an unadjusted chi-square test. Kaplan-Meir curves for estimated survival will be compared with the use of a log-rank test. A Cox proportional-hazard regression model will be used to evaluate the influence of potential confounding factors on the outcome (factors will be selected and included in the model if the p-value in the univariate analysis is <0.20).

Pre-defined subgroups analysis of the primary outcome will be conducted according to the type of shock (septic, cardiogenic, post cardiac arrest, or hypovolaemia). A test for interaction will be performed and presented as a forest plot.

Analysis will be performed by an independent biostatistician. Both the study statistician and investigators will be unaware of the patients’ treatment assignment while they are performing the analyses.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
28/02/2024
Actual
28/02/2024
Date of last participant enrolment
Anticipated
23/02/2026
Actual
Date of last data collection
Anticipated
23/08/2026
Actual
Sample size
Target
1155
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 308217 0
Charities/Societies/Foundations
Name [1] 308217 0
National Heart Foundation - Vanguard grant
Country [1] 308217 0
Australia
Primary sponsor type
Government body
Name
Ambulance Victoria
Address
31 Joseph Street Blackburn North
Victoria
3130
Country
Australia
Secondary sponsor category [1] 309002 0
None
Name [1] 309002 0
None
Address [1] 309002 0
N/A
Country [1] 309002 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308198 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 308198 0
55 Commercial Rd,
Melbourne VIC, 3004
Ethics committee country [1] 308198 0
Australia
Date submitted for ethics approval [1] 308198 0
07/04/2021
Approval date [1] 308198 0
04/06/2021
Ethics approval number [1] 308198 0
HREC/73653/Alfred-2021
Ethics committee name [2] 315123 0
Monash University Human Research Ethics Committee
Ethics committee address [2] 315123 0
https://www.monash.edu/researchoffice/ethics
Ethics committee country [2] 315123 0
Australia
Date submitted for ethics approval [2] 315123 0
18/10/2022
Approval date [2] 315123 0
18/10/2022
Ethics approval number [2] 315123 0
36199

Summary
Brief summary
Shock is a clinical syndrome which is characterised by cellular and tissue hypoxia due to either inadequate oxygen delivery, increased oxygen demand, or a combination of these processes. It may present on a clinical spectrum ranging from occult hypoperfusion (with preserved blood pressure) to fulminant circulatory collapse. Prompt haemodynamic support of patients with shock is vital to prevent and potentially reverse multi-organ dysfunction. In addition to treating the underlying disease process, intravenous fluid administration constitutes an essential part of the initial management. However, often fluid resuscitation is insufficient and hypotension persists. In this clinical setting vasopressor and/or inotropic medications can be considered. The efficacy of these drugs has largely been assessed though their impact on haemodynamic end-points. Head-to-head comparison between these agents assessing for major clinical outcomes, such as mortality, is limited. However, in small studies of cardiogenic shock, noradrenaline appears to be superior to adrenaline. We aim to compare the efficacy of noradrenaline and adrenaline in the pre-hospital setting in a population experiencing cardiogenic shock
Trial website
NA
Trial related presentations / publications
NA
Public notes

Contacts
Principal investigator
Name 109898 0
Prof Dion Stub
Address 109898 0
Alfred Hospital Heart Centre, Level 3
55 Commercial Rd
Melbourne
Victoria
3004
Country 109898 0
Australia
Phone 109898 0
+613 90763263
Fax 109898 0
Email 109898 0
[email protected]
Contact person for public queries
Name 109899 0
Prof Dion Stub
Address 109899 0
Alfred Hospital Heart Centre, Level 3
55 Commercial Rd
Melbourne
Victoria
3004
Country 109899 0
Australia
Phone 109899 0
+613 90763263
Fax 109899 0
Email 109899 0
[email protected]
Contact person for scientific queries
Name 109900 0
Prof Dion Stub
Address 109900 0
Alfred Hospital Heart Centre, Level 3
55 Commercial Rd
Melbourne
VIC
3004
Country 109900 0
Australia
Phone 109900 0
+613 90763263
Fax 109900 0
Email 109900 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
Individual participant data will be aggregated in the analysis and de-identified. As such individual participant data will not be available.


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
No additional documents have been identified.