Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000595819
Ethics application status
Approved
Date submitted
18/03/2021
Date registered
19/05/2021
Date last updated
17/03/2023
Date data sharing statement initially provided
19/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
ITHRIVE: Iron and erythropoietin use in anaemic patients in the intensive care
Scientific title
ITHRIVE: Iron and erythropoietin use in anaemic patients in intensive care
Secondary ID [1] 303733 0
Nil KNown
Universal Trial Number (UTN)
Trial acronym
ITHRIVE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia 321174 0
Critical Illness 321175 0
Condition category
Condition code
Blood 318975 318975 0 0
Anaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention group will receive a single dose of 1g intravenous ferric carboxymaltose infusion over two hours in 100ml of 0.9% saline, and a single dose of intravenous Epoetin alfa 40,000 IU (Eprex Janssen-Cilag Pty Ltd, Titusville, NJ, USA). Adherence to the intervention will be checked by observing the co-signed medical record of administration
Intervention code [1] 320045 0
Treatment: Drugs
Comparator / control treatment
The control group will receive the 100ml of 0.9% saline infused over two hours and a 1ml of subcutaneous 0.9% saline. Study drugs will be prepared and administered by a clinical staff member not directly involved in patient care. Study drugs are given once only.
Control group
Placebo

Outcomes
Primary outcome [1] 326887 0
The primary outcome is the number of days alive and at home between randomisation and Day 90 (DAH90). Days spent in rehabilitation or a nursing home are counted as days in hospital. Death prior to discharge from index admission will count as zero DAH90. DAH90 is a validated measure that includes death, duration of hospital stay, need for ongoing rehabilitation and occurrence of hospital readmission
Timepoint [1] 326887 0
Day 90 post randomisation
Primary outcome [2] 326888 0
The proportion of participants that receive their allocated study treatment is equal to or more than 90% of participants. This will be assessed by an audit of the study database. This is a primary outcome for the pilot phase only.
Timepoint [2] 326888 0
End of recruitment and follow up period (90 days post-randomisation)
Primary outcome [3] 326889 0
The proportion of participants lost to follow up is less than 10%.This will be assessed by an audit of the study database.
Timepoint [3] 326889 0
End of recruitment and follow up period (90 days post randomisation)
Secondary outcome [1] 393004 0
post randomisation index icu length of stay, assessed using the patient medical records
Timepoint [1] 393004 0
Day 90 post randomisation
Secondary outcome [2] 393005 0
post randomisation index hospital length of stay, assessed using the patient medical record
Timepoint [2] 393005 0
Day 90 post randomisation
Secondary outcome [3] 393006 0
ICU readmission during index hospitalisation, assessed using the hospital database.
Timepoint [3] 393006 0
Day 90 post randomisation
Secondary outcome [4] 393007 0
Index hospital mortality, assessed using the hospital database
Timepoint [4] 393007 0
Day 90 post randomisation
Secondary outcome [5] 393008 0
Haemoglobin at index hospital discharge, using the most recent blood test
Timepoint [5] 393008 0
Discharge from index hospitalisation
Secondary outcome [6] 393009 0
Proportion of patients who receive at least one red blood cell transfusion to Day 90. This change was made after recruitment of the 40 pilot participants was completed and prior to recommencement of recruitment of the larger clinical trial.
Timepoint [6] 393009 0
Day 90 post randomisation
Secondary outcome [7] 393010 0
Time until hospital readmission, assessed using the patient medical record and by contact with the patient at Day 90 post randomisation via telephone.
Timepoint [7] 393010 0
Day 90 post randomisation
Secondary outcome [8] 393011 0
Duration of hospital readmission, assessed using the patient medical record and contact with the patient via telephone day 90 post randomisation
Timepoint [8] 393011 0
Day 90 post randomisation
Secondary outcome [9] 393012 0
Time to rehabilitation admission, assessed using the patient medical record and telephone contact with the patient day 90 post randomisation.
Timepoint [9] 393012 0
Day 90 post randomisation
Secondary outcome [10] 393013 0
Duration of rehabilitation admission, assessed using the patient medical record and telephone contact with the patient day 90 post randomisation
Timepoint [10] 393013 0
Day 90 post randomisation
Secondary outcome [11] 393014 0
Time to nursing home admission, assessed using the patient medical record and telephone contact with the patient day 90 post randomisation.
Timepoint [11] 393014 0
Day 90 post randomisation
Secondary outcome [12] 393015 0
Overall survival using the patient medical record.
Timepoint [12] 393015 0
Day 90 post randomisation
Secondary outcome [13] 393016 0
Cognitive dysfunction assessed using the Montreal Cognitive Assessment (MOCA-Blind) via telephone contact with the patient. This outcome was prespecified and collected for the pilot phase but was discontinued after completion of recruitment to the pilot phase and prior to commencement of recruitment to the larger clinical trial.
Timepoint [13] 393016 0
Day 90 post randomisation
Secondary outcome [14] 393017 0
quality of life assessed using the EuroQuol EQ- 5D-5L via telephone contact with the patient
Timepoint [14] 393017 0
Day 90 post randomisation
Secondary outcome [15] 393018 0
Minimal clinically important difference (MCID) in DAH90 as reported by trial participants. MCID is the smallest improvement in outcome that a respondent reports as beneficial with respect to the intervention under investigation. This outcome is assessing MCID to determine what difference is important to patients so as to inform the design of a future clinical trial. This will be in person by an investigator to the patient immediately upon enrolment and asked via telephone to participants 90 days after randomisation. Collecting this outcome was prespecified to occur only for the pilot phase and will not be collected in the larger clinical trial.
Timepoint [15] 393018 0
randomisation and Day 90 post randomisation
Secondary outcome [16] 419751 0
Number of patients with at least one serious adverse event, using the hospital medical record
Timepoint [16] 419751 0
day 90 post randomisation
Secondary outcome [17] 419752 0
This is a primary outcome for the pilot phase of the trial which included the first 40 participants: A recruitment rate of greater than or equal to 2 participants per site per month over the course of the recruitment period. This will be assessed by an audit of the study database.
Timepoint [17] 419752 0
Assessed at the end of recruitment of planned sample size of 40 participants. This was prespecified as a primary outcome for the pilot phase and has been moved to the secondary outcomes so that the record is not lost. It will not be reported in the secondary outcomes of the larger clinical phase of 550 participants.

Eligibility
Key inclusion criteria
1. Adult patient who has required ICU-level care for more than 48 hours
2. The treating clinician has determined that ICU discharge is appropriate or is likely to be appropriate in the next 24 hours
3. Haemoglobin <100g/L on the most recent usual care measurement within the last 24 hours
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Received IV iron therapy or ESA therapy in the last three months
2. Active cancer+
3. The treating clinician believes that trial participation is not in the best interests of the patient
4. The treating clinician believes death during this hospital admission is inevitable
5. Any history of adverse reaction to IV iron or ESA therapy, or therapies derived from mammalian cells
6. Blood products are contraindicated
7. Receiving antibiotic therapy with a planned total therapy duration >10 days^
8. Thromboembolism chemoprophylaxis is contraindicated
9. Resident in a nursing home or high-level chronic care facility
10. Pregnancy or breast feeding
11. Weight less than 50 kg
12. Porphyria
13. Previously enrolled in ITHRIVE

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 concealment will be maintained by using sequentially numbered, sealed, opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block randomisation schedule with variable block size will be developed by the study statistician, stratified by site.
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 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Pilot phase of initial 40 participants: All analyses will be conducted on an intention-to-treat basis. No imputation will be made for missing data. The co-primary outcomes (recruitment rate is greater than or equal to 2 participants per site per month, received study drug, followed up), will be reported as number (%). Secondary outcomes will be reported as number (%), mean (+-SD) or median (IQR) with between-group differences analysed using Chi square, students t test or the Wilcoxon ran-sum test as appropriate. Ordinal logistic regression will be used to analyse the individual domains of EQ5D5L. Linear regression on transformed continuous outcomes will be used for MOCA-Blind and EQ5D5L summary score.
Secondary outcomes will only be analysed in aggregate, not by group. This is to preserve the ability to include these participants in an analysis of patient-centered outcomes in a larger trial
Larger 550 participant clinical trial: All analyses will be conducted on an intention-to-treat basis. The between-group primary outcome of DAH will be analysed using quantile regression with treatment arm as the independent variable and DAH as the dependent variable. No assumptions will be made for missing data. A sensitivity analyses of the primary outcome will be conducted using multiple imputation to handle missing data. The The main analysis method for the primary objective will be repeated for the duration of index hospital admission. Other secondary outcomes will be reported descriptively by treatment arm as:
- Count and percentages for dichotomous variables
- Means and corresponding 95% CIs and medians and IQRs for continuous valued variables
- Kaplan-Meier product limit curves and their corresponding 95% CIs using Greenwood’s method for time to event variables.
Differences between treatment arms will be analysed using Fisher’s exact test for dichotomous variables, linear regression for continuous valued variables and Cox proportional hazards regression for time to event variables. Point estimates of the test statistics and their 95% CIs will be reported. Test assumptions will be assessed as appropriate.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
9/08/2021
Actual
1/10/2021
Date of last participant enrolment
Anticipated
20/02/2026
Actual
Date of last data collection
Anticipated
20/11/2026
Actual
Sample size
Target
550
Accrual to date
39
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment hospital [1] 18945 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [2] 18946 0
Footscray Hospital - Footscray
Recruitment hospital [3] 18947 0
Sunshine Hospital - St Albans
Recruitment hospital [4] 24302 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [5] 24303 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 33453 0
6150 - Murdoch
Recruitment postcode(s) [2] 33454 0
3011 - Footscray
Recruitment postcode(s) [3] 33455 0
3021 - St Albans
Recruitment postcode(s) [4] 39849 0
6009 - Nedlands
Recruitment postcode(s) [5] 39850 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 308140 0
Hospital
Name [1] 308140 0
Fiona Stanley Hospital
Country [1] 308140 0
Australia
Funding source category [2] 313416 0
Government body
Name [2] 313416 0
National Health and Medical Research Council Investigator Grant (GNT2017081)
Country [2] 313416 0
Australia
Funding source category [3] 313417 0
Government body
Name [3] 313417 0
Future Health Research Fund WA Department of Health (2022/000278)
Country [3] 313417 0
Australia
Funding source category [4] 313418 0
Charities/Societies/Foundations
Name [4] 313418 0
Intensive Care Foundation of Australia and New Zealand (2105)
Country [4] 313418 0
Australia
Primary sponsor type
Hospital
Name
Fiona Stanley Hospital
Address
11 Robin Warren Drive
Murdoch 6150
WA
Country
Australia
Secondary sponsor category [1] 308903 0
None
Name [1] 308903 0
Address [1] 308903 0
Country [1] 308903 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308126 0
South Metropolitan Health Service
Ethics committee address [1] 308126 0
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch 6150
WA
Ethics committee country [1] 308126 0
Australia
Date submitted for ethics approval [1] 308126 0
01/10/2020
Approval date [1] 308126 0
08/12/2020
Ethics approval number [1] 308126 0
RGS0000004354

Summary
Brief summary
The primary objective of this trial is to determine the feasibility of a pivotal clinical trial of intravenous iron and erythropoietin in adult survivors of critical illness requiring treatment in the intensive care unit.

The hypothesis of the pilot phase of the trial is that a clinical trial of intravenous iron and erythropoietin is feasible based on the capacity of the study investigators to enrol sufficient eligible participants and deliver the study medications and follow up the patients appropriately. Demonstrating this would provide evidence that a trial with a much larger number of patients should be undertaken to assess safety and efficacy.
The primary objective of the clinical phase of this trial is to determine the safety and efficacy of intravenous iron and erythropoietin in adult survivors of critical illness requiring treatment in the intensive care unit.
In both phases the trial is parallel group, placebo-controlled, blinded, randomised trial that will allocate patients who are recovering in an ICU after an episode of critical illness and who are anaemic, in a 1:1 ratio, to intravenous iron and intravenous erythropoietin alfa in addition to standard care, or placebo in addition to standard care. The pilot phase was conducted at a single centre, the larger clinical trial is planned to be multicentre.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109630 0
A/Prof Edward Litton
Address 109630 0
Intensive Care Unit
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch 6150
WA
Country 109630 0
Australia
Phone 109630 0
+61415293281
Fax 109630 0
Email 109630 0
[email protected]
Contact person for public queries
Name 109631 0
A/Prof Edward Litton
Address 109631 0
Intensive Care Unit
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch 6150
WA
Country 109631 0
Australia
Phone 109631 0
+61415293281
Fax 109631 0
Email 109631 0
[email protected]
Contact person for scientific queries
Name 109632 0
A/Prof Edward Litton
Address 109632 0
Intensive Care Unit
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch 6150
WA
Country 109632 0
Australia
Phone 109632 0
+61415293281
Fax 109632 0
Email 109632 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
Consent documents do not contain provisions for sharing individual data


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11060Study protocol  [email protected]
11061Statistical analysis plan  [email protected]
11062Informed consent form  [email protected]
11063Clinical study report  [email protected]
11418Ethical approval  [email protected]



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.