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Trial registered on ANZCTR


Registration number
ACTRN12612001249842
Ethics application status
Approved
Date submitted
26/11/2012
Date registered
26/11/2012
Date last updated
21/11/2018
Date data sharing statement initially provided
21/11/2018
Date results information initially provided
21/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Intravenous iRon or placebO for aNaeMiA in iNtensive care: The Ironman Randomised Controlled Trial
Scientific title
For patients with anaemia admitted to the Intensive Care Unit, does intravenous iron compared with placebo reduce red blood cell transfusion requirement?
Secondary ID [1] 281587 0
Nil
Universal Trial Number (UTN)
Trial acronym
The IRONMAN Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia in critical illness 287869 0
Condition category
Condition code
Blood 288233 288233 0 0
Anaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
intravenous iron 500mg ferric carboxymaltose. Participants in the intervention arm will be redosed with 500mg of ferric carboxymaltose after a minimum of 5 days from the previous dose if they remain in the ICU with a Haemaglobin <100g/L and have no exclusion criteria. The maximum total number of doses will be four doses within thirty days.
Intervention code [1] 286114 0
Treatment: Drugs
Comparator / control treatment
placebo in the form of intravenous 0.9% saline in equal volume to the intervention group (100ml). Participants in the placebo arm will be redosed with 100ml 0.9% saline after a minimum of 5 days from the previous dose if they remain in the ICU with a Haemaglobin <100g/L and have no exclusion criteria. The maximum total number of doses will be four doses within thirty days.
Control group
Placebo

Outcomes
Primary outcome [1] 288424 0
mean number of packed red blood cell units transfused from study enrolment to discharge from hospital. This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [1] 288424 0
hospital discharge
Secondary outcome [1] 300114 0
proportion of patients who receive red blood cell transfusion from enrolment to ICU discharge.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [1] 300114 0
ICU discharge
Secondary outcome [2] 300117 0
Proportion of patients who develop nosocomial infection in ICU including confirmed blood stream infection, ventilator-associated pneumonia, and other infections.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record and clinical assessment and laboratory results.
Timepoint [2] 300117 0
ICU discharge
Secondary outcome [3] 300118 0
Time-weighted Hb on routine morning blood tests from enrolment to ICU discharge.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [3] 300118 0
ICU discharge
Secondary outcome [4] 300119 0
Mean number of RBC units transfused from study enrolment to discharge from the ICU.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [4] 300119 0
ICU discharge
Secondary outcome [5] 300120 0
Proportion of patients who die prior to discharge from hospital.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [5] 300120 0
Hospital discharge
Secondary outcome [6] 300121 0
Duration of admission to ICU.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [6] 300121 0
ICU discharge
Secondary outcome [7] 300122 0
Duration of admission to hospital.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [7] 300122 0
Hospital discharge
Secondary outcome [8] 300123 0
Duration from enrolment to time of first RBC transfusion.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [8] 300123 0
Hospital discharge
Secondary outcome [9] 300124 0
Organ failure support-free days between enrolment and ICU discharge.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.
Timepoint [9] 300124 0
ICU discharge
Secondary outcome [10] 300125 0
Mean Hb, ferritin, transferrin saturation and absolute reticulocyte count fifth daily after study enrolment and on discharge from ICU and hospital.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record and laboratory results.
Timepoint [10] 300125 0
Hospital discharge
Secondary outcome [11] 300126 0
Cost difference between study arms.

This will be assessed by the site investigators and research coordinators retrospectively using the participant medical record, imaging, laboratory results and discharge data.
Timepoint [11] 300126 0
Hospital discharge
Secondary outcome [12] 300127 0
Cost-effectiveness of IV iron.

This will be assessed by the site investigators and research coordinators retrospectively using the participant medical record, imaging, laboratory results and discharge data.
Timepoint [12] 300127 0
Hospital discharge

Eligibility
Key inclusion criteria
1. Admitted to an ICU for less than 48 hours
2. Anticipated to require ICU care beyond the next calendar day
3. Hb less than 100 g/L at any time during the preceding 24 hours
4. Age 18 years or greater
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Suspected or confirmed severe sepsis (two or more Systemic Inflammatory Response Syndrome (SIRS) criteria, suspected or confirmed infection, and one or more organ system failure)
2. Serum ferritin greater than 1200ng/ml or transferrin saturation greater than 50%
3. History of haemochromatosis or aceruloplasminaemia
4. Known prior administration of IV iron in the preceding 3 months
5. Jehovah’s Witness or other documented exclusion to receiving blood products
6. Receiving ESA (e.g. epoetin or darbepoeitin) in the 3 months prior to ICU admission
7. Known hypersensitivity to intravenous iron
8. Pregnancy
9. Treatment intent is palliative
10. Death is deemed imminent and inevitable
11. Weight less than 40kg
12. Participating in competing study

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)
Participants will be randomised using a variable box size randomly-derived sequence that is stratified by site. Allocation concealment will be maintained by using sequentially numbered, sealed, opaque envelopes containing the numeric code of the study arm to which the participant has been randomised.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation code will be generated by STATA, a statistical package. Stratification by site only.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/03/2013
Actual
17/06/2013
Date of last participant enrolment
Anticipated
31/12/2015
Actual
4/06/2015
Date of last data collection
Anticipated
1/03/2019
Actual
Sample size
Target
140
Accrual to date
Final
140
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 3678 0
Royal Perth Hospital - Perth
Recruitment hospital [2] 3679 0
Fremantle Hospital and Health Service - Fremantle
Recruitment hospital [3] 3680 0
Joondalup Health Campus - Joondalup
Recruitment hospital [4] 3681 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 6060 0
6000
Recruitment postcode(s) [2] 9508 0
6009 - Crawley
Recruitment postcode(s) [3] 9506 0
6160 - Fremantle
Recruitment postcode(s) [4] 9507 0
6919 - Joondalup

Funding & Sponsors
Funding source category [1] 286384 0
Government body
Name [1] 286384 0
State Health Research Advisory Council, Department of Health, Western Autralia
Country [1] 286384 0
Australia
Funding source category [2] 286385 0
Commercial sector/Industry
Name [2] 286385 0
Vifor Pharma Pty Ltd
Country [2] 286385 0
Australia
Primary sponsor type
Individual
Name
Edward Litton
Address
Department of Intensive Care Medicine
Royal Perth Hospital
Wellington Street
Perth, WA, 6000
Country
Australia
Secondary sponsor category [1] 285172 0
Other Collaborative groups
Name [1] 285172 0
ANZICS CTG
Address [1] 285172 0
10 Levers Tce,
Carlton South
Melbourne VIC 3053
Country [1] 285172 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288454 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 288454 0
South Metropolitan Health Service Human Research Ethics Committee
Fremantle Hospital
Alma Street
Fremantle
WA 6160
Ethics committee country [1] 288454 0
Australia
Date submitted for ethics approval [1] 288454 0
04/12/2012
Approval date [1] 288454 0
07/03/2013
Ethics approval number [1] 288454 0
1/12/0347

Summary
Brief summary
Background
Between 17 and 45% of patients admitted to an Intensive Care Unit (ICU) are reported to receive a red blood cell (RBC) transfusion and these transfusions comprise almost 20% of all RBC use in Australia. Although RBC transfusion may be life-saving in patients with major haemorrhage, the majority of patients transfused in the ICU receive RBCs for other indications including minor haemorrhage, anaemia and augmentation of cardiac output. Observational studies in critical illness identify RBC transfusion as an independent and dose-dependent risk factor for mortality and serious morbidity including transfusion-related lung injury, transfusion-associated circulatory overload, transfusion-related immunomodulation and infection. In addition to the associated risks, transfusion is also costly. The product cost of transfusing a single RBC unit in Western Australia (WA) is $370 and the total cost is $875 and increasing.
There is evidence that current ICU clinical practice complies with the National Health and Medical Research Council (NHMRC) Guidelines on restrictive RBC transfusion thresholds. As such, there is little scope to reduce transfusion through better compliance with existing evidence. Novel interventions to reduce transfusion requirement in critically ill patients are therefore required urgently.

Intravenous (IV) iron has been shown to be effective for the management of iron-restricted erythropoiesis, reducing RBC transfusion, in multiple well conducted RCTs in a number of patient groups. If IV iron reduces transfusion requirement in patients admitted to the ICU it will represent a promising candidate intervention to also reduce mortality and serious morbidity. However, its clinical and cost-effectiveness in patients who are critically ill in the ICU is uncertain.

Aim
The primary aim of the study is to determine if the administration of IV iron compared with placebo to patients admitted to an ICU and who are anaemic reduces RBC transfusion prior to hospital discharge.
The secondary aim is to determine if a phase III RCT of IV iron is warranted with such a trial having the aim of determining whether IV iron, compared to placebo, results in improved patient-centred outcomes.

Objectives
To determine whether the administration of IV iron in patients who are admitted to an ICU and are anaemic will:
1. Reduce the mean number of transfused RBC units
2. Improve clinical outcomes including mortality at hospital discharge and duration of admission to hospital and ICU
3. Be cost-effective

Methods
The proposed study will be a blinded, parallel group, phase II randomised trial comparing IV iron with placebo in patients admitted to the ICU and who are anaemic. Participants will be eligible if they are within 48 hours of admission to the ICU, have had one or more measurements of Hb <100g/L within the preceding 24 hours, are expected to require ICU care beyond the next calendar day, and fulfil none of the exclusion criteria. Participants will be randomised in a 1:1 ratio to the intervention or placebo group. Participants randomised to the IV iron group will receive 500mg of ferric carboxymaltose. Participants who are randomised to the control group will receive an equivalent volume of IV 0.9% saline. The intervention will be blinded to study staff and clinical staff caring for the patient. The study will be conducted in 4 metropolitan ICUs in Perth WA comprising Fremantle Hospital, Joondalup Hospital, Royal Perth Hospital, and Sir Charles Gairdner Hospital.

Outcomes
The primary end-point is the mean number of RBC units transfused. The study will also investigate the effect of intravenous iron on mortality and major morbidity as well as the costs and cost-effectiveness of IV iron.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 389 389 0 0
/AnzctrAttachments/363305-CV 2014 IRONMAN Protocol CC&R.pdf

Contacts
Principal investigator
Name 34983 0
Dr Edward Litton
Address 34983 0
Intensive Care Unit
Royal Perth Hospital
Wellington St
Perth
WA
6000
Country 34983 0
Australia
Phone 34983 0
+61892242244
Fax 34983 0
Email 34983 0
ed_litton@hotmail.com
Contact person for public queries
Name 18230 0
Dr Ed Litton
Address 18230 0
Department of Intensive Care Medicine
Royal Perth Hospital
Wellington Street
Perth WA, 6000
Country 18230 0
Australia
Phone 18230 0
+61892242244
Fax 18230 0
Email 18230 0
ed_litton@hotmail.com
Contact person for scientific queries
Name 9158 0
Dr Ed Litton
Address 9158 0
Department of Intensive Care Medicine
Royal Perth Hospital
Wellington Street
Perth, WA, 6000
Country 9158 0
Australia
Phone 9158 0
+61892242244
Fax 9158 0
Email 9158 0
ed_litton@hotmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Individual requests to be made to the study management committee for consideration


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Litton E, Baker S, et al. Intravenous iron or plac... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseIntravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial: A randomized trial of IV iron in critical illness.2016https://dx.doi.org/10.1007/s00134-016-4465-6
EmbaseIron supplementation to treat anaemia in adult critical care patients: A systematic review and meta-analysis.2016https://dx.doi.org/10.1186/s13054-016-1486-z
EmbaseThe IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia.2014
N.B. These documents automatically identified may not have been verified by the study sponsor.