Clinical trial NCT02642562: Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency: IRONMAN
Official title: Effectiveness of Intravenous Iron Treatment vs Standard Care in Patients With Heart Failure and Iron Deficiency: a Randomised, Open-label Multicentre Trial (IRONMAN)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Heart Failure
Iron Deficiency
Left Ventricular Systolic Dysfunction
Keywords: Intravenous iron
PROBE design
Lead sponsor: University of Glasgow
Sponsor class: OTHER
Collaborators: name: NHS Greater Glasgow and Clyde
name: Pharmacosmos A/S
name: British Heart Foundation
First posted: 2015-12-30
Enrollment: 1160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will address whether the additional use of Intravenous (IV) iron on top of standard care will improve the outlook for patients with heart failure and iron deficiency. One group of participants will receive treatment with iron injections and the other group will not receive any iron injections.

Detailed description: Chronic heart failure (CHF) is a very common medical problem. Despite improvements in treatment, many patients suffer limiting symptoms of shortness of breath and fatigue. Hospitalisation for CHF is common and life expectancy reduced. Many patients with CHF have a deficiency of iron (low iron levels or cannot use iron properly), and this is associated with poorer outcomes. Some small research studies have suggested that giving patients intravenous iron improves symptoms in the short term. It is unknown, however, whether correcting iron deficiency is beneficial to patients with CHF in the long term and whether it improves life expectancy and keeps them out of hospital. This study will help us answer these key questions.

This study will address whether the additional use of Intravenous (IV) iron on top of standard care will improve the outlook for patients with heart failure and iron deficiency. One group of participants will receive treatment with iron injections and the other group will not receive any iron injections.

The study will take place in about 70 secondary care sites (hospitals) across the UK. Participants will be recruited over a period of about five years and will be followed up for a minimum of three months (average duration of about four years per participant). After the initial visits, participants will be seen every four months.

Eligibility criteria: Inclusion criteria

1. Age ≥18 years
2. LVEF ≤45% within the prior two years using any conventional imaging modality (this should be the most recent assessment of LVEF)
3. New York Heart Association (NYHA) class II - IV
4. Iron deficient - defined as TSAT \<20% and/or ferritin \<100 ug/L
5. Evidence of being in a higher risk HF group: (a) Current (with the expectation that patient will survive to discharge) or recent (within 6 months) hospitalisation for HF, OR (b) Out-patients with NT-proBNP \>250 ng/L in sinus rhythm or \>1,000 ng/L in atrial fibrillation (or BNP of \> 75 pg/mL or 300 pg/mL, respectively)
6. Able and willing to provide informed consent

Exclusion criteria

1. Haematological criteria: ferritin \>400ug/L; haemoglobin \<9.0, or \>13 g/dL in women or \>14g/dL in men; (B12 or folate deficiency should be corrected but do not exclude the patient)
2. MDRD/CKD-EPI estimated glomerular filtration rate (eGFR) \<15ml/min/1.73m2
3. Already planned to receive IV iron
4. Likely to need or already receiving erythropoiesis stimulating agents (ESA)
5. Any of the following apply: (a) planned cardiac surgery or revascularisation; (b) within 3 months of any of the following: a primary diagnosis of type 1 myocardial infarction (excluding small troponin elevations in the context of heart failure admissions), cerebrovascular accident (CVA), major CV surgery or percutaneous coronary intervention (PCI), or blood transfusion; (c) on active cardiac transplant list; (d) left ventricular assist device implanted.
6. Any of the following comorbidities: active infection (if the patient is suffering from a significant ongoing infection as judged by the investigator recruitment should be postponed until the infection has passed or is controlled by antibiotics), other disease with life expectancy of \<2 years, active clinically relevant bleeding in the investigator's opinion, known or suspected gastro-intestinal malignancy
7. Pregnancy, women of childbearing potential (i.e. continuing menstrual cycle) not using effective contraception (see Appendix 3) or breast-feeding women
8. Contra-indication to IV iron in the investigator's opinion according to current approved Summary of Product Characteristics: hypersensitivity to the active substance, to Monofer® or any of its excipients (water for injections, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment)); known serious hypersensitivity to other parenteral iron products; non-iron deficiency anaemia (e.g. haemolytic anaemia); iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis); decompensated liver disease.
9. Participation in another intervention study involving a drug or device within the past 90 days (co-enrolment in observational studies is permitted)

Primary outcomes:
measure: CV mortality or hospitalisation for worsening heart failure (analysis will include first and recurrent hospitalisations)
timeFrame: Minimum of 3 months follow-up from last patient recruited
Secondary outcomes:
measure: Hospitalisation for worsening heart failure (recurrent events)
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: CV hospitalisation (first event)
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: CV death or hospitalisation for heart failure analysed as time to first event
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: Overall Score from Minnesota Living with Heart Failure
timeFrame: At 4 months
measure: Cardiovascular mortality
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: Overall EQ-5D VAS
timeFrame: At 4 months
measure: Overall EQ-5D index
timeFrame: At 4 months
measure: CV mortality or hospitalisation for major CV event (stroke, MI, heart failure) (first event)
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: All-cause mortality
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: All-cause hospitalisation (first event)
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: Combined all-cause mortality or first all-cause unplanned hospitalisation
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: Physical domain of QoL (Minnesota Living With Heart Failure)
timeFrame: At 4 months
measure: Physical domain of QoL (Minnesota Living With Heart Failure)
timeFrame: At 20 months
measure: Overall EQ-5D VAS
timeFrame: At 20 months
measure: Overall EQ-5D index
timeFrame: At 20 months
measure: Overall Score from Minnesota Living With Heart Failure
timeFrame: At 20 months
measure: Days dead or hospitalised
timeFrame: At 36 months
measure: Quality-adjusted days alive and out of hospital
timeFrame: At 12 months
measure: 6 minute walk test
timeFrame: At 4 months
measure: 6 minute walk test
timeFrame: At 20 months
measure: Death due to infection
timeFrame: Minimum of 3 months follow-up from last patient recruited
measure: Hospitalisation primarily for infection (first event)
timeFrame: Minimum of 3 months follow-up from last patient recruited
Other outcomes:
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Airdrie
country: United Kingdom
facility: University Hospital Monklands
city: Antrim
country: United Kingdom
facility: Antrim Area Hospital
city: Ashington
country: United Kingdom
facility: Wansbeck General Hospital
city: Barnet
country: United Kingdom
facility: Barnet Hospital
city: Basildon
country: United Kingdom
facility: Basildon University Hospital
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital
city: Belfast
country: United Kingdom
facility: Royal Victoria Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
city: Bridgend
country: United Kingdom
facility: Princess of Wales Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal Hospital
city: Chichester
country: United Kingdom
facility: St. Richard's Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Croydon
country: United Kingdom
facility: Croydon University Hospital
city: Darlington
country: United Kingdom
facility: Darlington Memorial Hospital
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Dundonald
country: United Kingdom
facility: Ulster Hospital
city: Eastbourne
country: United Kingdom
facility: Eastbourne District General Hospital
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: Glasgow
country: United Kingdom
facility: Golden Jubilee National Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Harefield
country: United Kingdom
facility: Harefield Hospital
city: High Wycombe
country: United Kingdom
facility: Wycombe General Hospital
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Isleworth
country: United Kingdom
facility: West Middlesex University Hospital
city: Kilmarnock
country: United Kingdom
facility: University Hospital Crosshouse
city: Kingston upon Thames
country: United Kingdom
facility: Kingston Hospital
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital
city: Larbert
country: United Kingdom
facility: Forth Valley Royal Hospital
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool Heart and Chest Hospital
city: Llandough
country: United Kingdom
facility: University Hospital Llandough
city: Llantrisant
country: United Kingdom
facility: Royal Glamorgan Hospital
city: London
country: United Kingdom
facility: Guy's and St. Thomas' Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital (Imperial College)
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: North Middlesex University Hospital
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Newport
country: United Kingdom
facility: Royal Gwent Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
city: Oldham
country: United Kingdom
facility: Royal Oldham Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
city: Poole
country: United Kingdom
facility: Poole Hospital
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
city: Sheffield
country: United Kingdom
facility: Northern General Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
city: Southend
country: United Kingdom
facility: Southend University Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Sunderland
country: United Kingdom
facility: City Hospitals Sunderland
city: Swansea
country: United Kingdom
facility: Morriston Hospital
city: Swindon
country: United Kingdom
facility: Great Western Hospital
city: Tooting
country: United Kingdom
facility: St. George's Hospital
city: Torquay
country: United Kingdom
facility: Torbay Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Watford
country: United Kingdom
facility: Watford General Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
Study officials:
affiliation: Chair of Steering Committee (Retired)
name: Nicholas Boon
role: STUDY_CHAIR
References:
citation: Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, Ahmed FZ, Al-Mohammad A, Cowburn PJ, Foley PWX, Graham FJ, Japp AG, Lane RE, Lang NN, Ludman AJ, Macdougall IC, Pellicori P, Ray R, Robertson M, Seed A, Ford I; IRONMAN Study Group. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022 Dec 17;400(10369):2199-2209. doi: 10.1016/S0140-6736(22)02083-9. Epub 2022 Nov 5.
citation: Kalra PR, Cleland JG, Petrie MC, Ahmed FZ, Foley PW, Kalra PA, Lang NN, Lane RE, Macdougall IC, Pellicori P, Pope MTB, Robertson M, Squire IB, Thomson EA, Ford I. Rationale and design of a randomised trial of intravenous iron in patients with heart failure. Heart. 2022 Nov 24;108(24):1979-1985. doi: 10.1136/heartjnl-2022-321304.