Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001566820p
Ethics application status
Submitted, not yet approved
Date submitted
18/09/2021
Date registered
18/11/2021
Date last updated
18/11/2021
Date data sharing statement initially provided
18/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
NEt ultrafiltration Prescription and Targeting versus Usual NEt ultrafiltration during continuous renal replacement therapy
Scientific title
A multi-centre, cluster cross-over, phase 3 randomised clinical trial of the clinical efficacy of targeted net ultrafiltration rate compared to usual care in critically ill patients receiving continuous renal replacement therapy
Secondary ID [1] 303031 0
None
Universal Trial Number (UTN)
Trial acronym
NEPTUNE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute kidney injury 323670 0
Continuous renal replacement therapy 323671 0
Condition category
Condition code
Renal and Urogenital 321211 321211 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Continuous renal replacement therapy (CRRT) involves removal of solutes and fluid via an extracorporeal circuit. Intensity of solute removal is described by the 'exchange volume'. Intensity of fluid removal is described by the 'net ultrafiltration (NUF) rate'.

The study treatment for this trial is a targeted NUF rate of between 1.01 and 1.75 mL/kg/h. NUF rate will be calculated using actual body weight, capped at extremes of 50 and 120 kg. This will be administered by the bedside ICU nurse who controls the CRRT settings. The duration of the intervention will be for the length of time that the patient remains on CRRT. As a crossover study, centres will be allocated to intervention or control arms for a period of 6 months each, with a 2 month washout period occurring in between the two periods. Other elements of the CRRT prescription including the modality of CRRT and choice of anticoagulation will be at the discretion of the clinician. Compliance will be monitored by audit of patient medical records
Intervention code [1] 321753 0
Treatment: Other
Comparator / control treatment
The comparator treatment is a NUF rate prescribed according to the discretion of the clinician (i.e. usual care). Observational analyses suggest that, as part of usual care, the NUF rate is <1.01 mL/kg/h in 1/3 of patients and >1.75 mL/kg/h in 1/3 of patients.

The duration of the control treatment will be for the length of time that the patient remains on CRRT. As a crossover study, centres will be allocated to intervention or control arms for a period of 6 months each, with a 2 month washout period occurring in between the two periods.
Control group
Active

Outcomes
Primary outcome [1] 328995 0
The time to renal recovery, defined as the number of hours between the initiation and discontinuation of renal replacement therapy (RRT). This will be assessed by accessing the patient medical record
Timepoint [1] 328995 0
Assessed from time of commencement of RRT to time of discontinuation, or up to a maximum of 28 days post-intervention commencement
Secondary outcome [1] 401093 0
Recruitment rate, as determined by an audit of the study database
Timepoint [1] 401093 0
End of trial
Secondary outcome [2] 401094 0
Compliance with NUF prescription, defined as the number of hours of CRRT spent within target NUF range divided by the total number of hours of CRRT. This will be assessed by accessing the patient medical record
Timepoint [2] 401094 0
Upon discontinuation of CRRT
Secondary outcome [3] 401096 0
ICU mortality. This will be assessed by accessing the patient medical record
Timepoint [3] 401096 0
At time of discharge from ICU, or up to a maximum of 28 days post-intervention commencement
Secondary outcome [4] 401097 0
In-hospital mortality. This will be assessed by accessing the patient medical record
Timepoint [4] 401097 0
At time of discharge from hospital.
Secondary outcome [5] 401098 0
28-day mortality. This will be assessed by accessing the patient medical record
Timepoint [5] 401098 0
28 days post-intervention commencement
Secondary outcome [6] 401099 0
90-day mortality. This will be assessed by accessing the patient medical record
Timepoint [6] 401099 0
90 days post-intervention commencement
Secondary outcome [7] 401100 0
ICU-free survival. This will be assessed by accessing the patient medical record
Timepoint [7] 401100 0
From time of discharge from ICU to 90 days post-ICU discharge
Secondary outcome [8] 401101 0
Hospital-free survival. This will be assessed by accessing the patient medical record
Timepoint [8] 401101 0
From time of discharge from hospital to 90 days post-hospital discharge
Secondary outcome [9] 401102 0
ICU length of stay. This will be assessed by accessing the patient medical record
Timepoint [9] 401102 0
From time of admission to ICU to time of discharge
Secondary outcome [10] 401103 0
Hospital length of stay. This will be assessed by accessing the patient medical record
Timepoint [10] 401103 0
From time of admission to hospital to time of discharge
Secondary outcome [11] 401104 0
Proportion of patients who are RRT-dependent at ICU discharge. This will be assessed by accessing the patient medical record
Timepoint [11] 401104 0
At time of discharge from ICU
Secondary outcome [12] 401105 0
Proportion of patients who are RRT-dependent at 28 days. This will be assessed by accessing the patient medical record
Timepoint [12] 401105 0
28 days post-intervention commencement
Secondary outcome [13] 401106 0
Proportion of patients who are RRT-dependent at 90 days. This will be assessed by accessing the patient medical record
Timepoint [13] 401106 0
90 days post-intervention commencement
Secondary outcome [14] 401107 0
Cumulative ICU fluid balance. This will be assessed by accessing the patient medical record
Timepoint [14] 401107 0
At time of discharge from ICU up to a maximum of 28 days
Secondary outcome [15] 401108 0
Major adverse kidney event (defined as the composite of death or dialysis). This will be assessed by accessing the patient medical record
Timepoint [15] 401108 0
30 days post-intervention commencement
Secondary outcome [16] 401109 0
Duration of mechanical ventilation at day 28 . This will be assessed by accessing the patient medical record
Timepoint [16] 401109 0
28 days post-intervention commencement
Secondary outcome [17] 401110 0
Duration of vasopressor therapy at day 28 . This will be assessed by accessing the patient medical record
Timepoint [17] 401110 0
28 days post-intervention commencement
Secondary outcome [18] 401111 0
Mean peak daily noradrenaline-equivalent dose to day 7. This will be assessed by accessing the patient medical record
Timepoint [18] 401111 0
7 days post-intervention commencement
Secondary outcome [19] 401112 0
Hypophosphatemia (<0.60 mmol/L). This will be assessed by accessing the patient medical record
Timepoint [19] 401112 0
28 days post-intervention commencement
Secondary outcome [20] 401113 0
Hypokalaemia (<3.0 mmol/L). This will be assessed by accessing the patient medical record
Timepoint [20] 401113 0
28 days post-intervention commencement
Secondary outcome [21] 401114 0
Hypomagnesemia (<0.60 mmol/L). This will be assessed by accessing the patient medical record
Timepoint [21] 401114 0
28 days post-intervention commencement
Secondary outcome [22] 401115 0
Kidney failure (defined as the requirement for chronic dialysis). This will be assessed by accessing the patient medical record
Timepoint [22] 401115 0
1 year post-intervention commencement
Secondary outcome [23] 401116 0
Mortality. This will be assessed by accessing the patient medical record
Timepoint [23] 401116 0
1 year post-intervention commencement

Eligibility
Key inclusion criteria
1. Clinician-based decision that the patient has a requirement for CRRT
2. Acute kidney injury (AKI), as defined by stage 2 or greater KDIGO criteria
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age <18 years
2. Pregnancy
3. Death is deemed to be imminent or inevitable during this admission, and either the attending physician, patient or substitute decision-maker is not committed to active treatment
4. Prior exposure to CRRT or intermittent renal replacement therapy (IRRT) this admission or previous enrolment in this study
5. Chronic haemodialysis or peritoneal dialysis
6. Concurrent extracorporeal membrane oxygenation

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)
A centralised, web-based system (REDCap) will be employed, allowing 24-hour enrolment and random allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The random allocation sequence will be generated using a computer software program and embedded into the REDCap system. Site investigators, site research coordinators, and study participants will not have access to the allocation sequence.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All analyses for outcomes will use individual patient-level data. All models will consider the ICU as the cluster unit (random effect) and will include a fixed effect for the treatment group. A covariate adjustment for the order of administration of the treatment is planned to account for the order and secular time effect. The primary outcome will be assessed in a clustered semi-competing risk model as described in the sample size calculation section. Death in the study period will be treated as a semi-competing risk since death prior to CRRT discontinuation prevents CRRT discontinuation, but death may still occur after CRRT discontinuation.

All statistical analyses will be conducted on an intention-to-treat basis, reported according to the CONSORT extension for cluster trials, with patients analysed according to their assigned treatment arms, unless otherwise indicated. No or minimal losses to follow–up for the primary and secondary outcomes are anticipated. Complete–case analysis will be carried out for all the outcomes. An interim analysis for efficacy is planned after the first 6 month period is complete. Hypothesis tests will be two–sided with a significance level of 0.05. Analyses will be performed using the R v.4.0.2 (R Core Team, 2016, Vienna, Austria) program. A full statistical analysis plan will be made available before the locking of the database.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2022
Actual
Date of last participant enrolment
Anticipated
30/04/2023
Actual
Date of last data collection
Anticipated
30/04/2024
Actual
Sample size
Target
1500
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC

Funding & Sponsors
Funding source category [1] 307445 0
Hospital
Name [1] 307445 0
Austin Health
Country [1] 307445 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australia and New Zealand Intensive Care Society Research Centre
Address
Level 3, 553 St Kilda Road, Melbourne, 3004, VIC
Country
Australia
Secondary sponsor category [1] 308119 0
Individual
Name [1] 308119 0
Prof Rinaldo Bellomo
Address [1] 308119 0
Austin Health
145 Studley Road, Heidelberg, 3084, VIC
Country [1] 308119 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307523 0
Austin Health
Ethics committee address [1] 307523 0
Ethics committee country [1] 307523 0
Australia
Date submitted for ethics approval [1] 307523 0
31/07/2021
Approval date [1] 307523 0
Ethics approval number [1] 307523 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107542 0
Dr Emily See
Address 107542 0
Austin Health
145 Studley Road, Heidelberg, 3084, VIC
Country 107542 0
Australia
Phone 107542 0
+61 3 9496 5992
Fax 107542 0
+61 3 9496 3932
Email 107542 0
[email protected]
Contact person for public queries
Name 107543 0
Emily See
Address 107543 0
Austin Health
145 Studley Road, Heidelberg, 3084, VIC
Country 107543 0
Australia
Phone 107543 0
+61 3 9496 5000
Fax 107543 0
+61 3 9496 3932
Email 107543 0
[email protected]
Contact person for scientific queries
Name 107544 0
Emily See
Address 107544 0
Austin Health
145 Studley Road, Heidelberg, 3084, VIC
Country 107544 0
Australia
Phone 107544 0
+61 3 9496 5000
Fax 107544 0
+61 3 9496 3932
Email 107544 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
Ethics approval not sought for sharing of patient data


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.