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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 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]

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

Condition category

Condition code

Blood

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]

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]

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]

hospital discharge

Secondary outcome [1]

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]

ICU discharge

Secondary outcome [2]

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]

ICU discharge

Secondary outcome [3]

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]

ICU discharge

Secondary outcome [4]

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]

ICU discharge

Secondary outcome [5]

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]

Hospital discharge

Secondary outcome [6]

Duration of admission to ICU.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.

Timepoint [6]

ICU discharge

Secondary outcome [7]

Duration of admission to hospital.

This will be assessed by the site investigators and research coordinators prospectively using the participant medical record.

Timepoint [7]

Hospital discharge

Secondary outcome [8]

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]

Hospital discharge

Secondary outcome [9]

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]

ICU discharge

Secondary outcome [10]

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]

Hospital discharge

Secondary outcome [11]

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]

Hospital discharge

Secondary outcome [12]

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]

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?

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)

Recruitment hospital [1]

Royal Perth Hospital - Perth

Recruitment hospital [2]

Fremantle Hospital and Health Service - Fremantle

Recruitment hospital [3]

Joondalup Health Campus - Joondalup

Recruitment hospital [4]

Sir Charles Gairdner Hospital - Nedlands

Recruitment postcode(s) [1]

6000

Recruitment postcode(s) [2]

6160 - Fremantle

Recruitment postcode(s) [3]

6919 - Joondalup

Recruitment postcode(s) [4]

6009 - Crawley

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

State Health Research Advisory Council, Department of Health, Western Autralia

Address [1]

Level 2, C Block
189 Royal Street
East Perth
WA 6004

Country [1]

Australia

Funding source category [2]

Commercial sector/Industry

Name [2]

Vifor Pharma Pty Ltd

Address [2]

Level 8, 80 Dorcas Street, Southbank
Melbourne VIC 3006

Country [2]

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]

Other Collaborative groups

Name [1]

ANZICS CTG

Address [1]

10 Levers Tce,
Carlton South
Melbourne VIC 3053

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

South Metropolitan Health Service Human Research Ethics Committee

Ethics committee address [1]

South Metropolitan Health Service Human Research Ethics Committee
Fremantle Hospital
Alma Street
Fremantle 
WA 6160

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/12/2012

Approval date [1]

07/03/2013

Ethics approval number [1]

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]

/AnzctrAttachments/363305-CV 2014 IRONMAN Protocol CC&R.pdf

Contacts

Principal investigator

Name

Dr Edward Litton

Address

Intensive Care Unit
Royal Perth Hospital
Wellington St
Perth
WA
6000

Country

Australia

Phone

+61892242244

Fax

ed_litton@hotmail.com

Contact person for public queries

Name

Ed Litton

Address

Department of Intensive Care Medicine
Royal Perth Hospital
Wellington Street
Perth WA, 6000

Country

Australia

Phone

+61892242244

Fax

ed_litton@hotmail.com

Contact person for scientific queries

Name

Ed Litton

Address

Department of Intensive Care Medicine
Royal Perth Hospital
Wellington Street
Perth, WA, 6000

Country

Australia

Phone

+61892242244

Fax

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

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia.	2014
Embase	Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial: A randomized trial of IV iron in critical illness.	2016	https://dx.doi.org/10.1007/s00134-016-4465-6
Embase	Iron supplementation to treat anaemia in adult critical care patients: A systematic review and meta-analysis.	2016	https://dx.doi.org/10.1186/s13054-016-1486-z

N.B. These documents automatically identified may not have been verified by the study sponsor.

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