Improved Recovery by Iron Following Surgery With Blood Loss, the IRIS-trial

Study Overview
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Brief Summary
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The aim of the study is to investigate if iv iron formulation improve recovery after surgery with blood loss. Post-operative anaemia is a common debilitating condition after major surgery due to a combination of preoperative iron deficiency anaemia (IDA) and per-operative blood loss. Median blood loss following hepatopancreatobiliary (HPB) and complex aortic surgery typically range between 500-1000 ml. Bioavailability of iron may be a rate limiting factor in erythropoiesis in anaemia secondary to blood loss. For the IRIS trial, it is hypothesized that intravenously (iv) administered Ferric Carboxymaltose after a per-operative blood loss of 400-4000 ml, improves post-operative recovery and reduces the RBC transfusion. Patients scheduled for elective HPB surgery or complex aortic surgery will be screened for eligibility and recruited into the study. By the end of the surgical procedure, if blood loss is estimated to 400-4000 ml, the patient is randomized 1:1 to iv 1000 mg Ferric Carboxymaltose or placebo. The primary endpoint is a composite of death, number of RBC transfusions, post-operative severe anemia (Hb <80 g/L) and FACT-An Quality of life (QoL) five weeks after surgery, assessed by win ratio. The trial will also examine effects on; a) levels of Hb; b) markers of erythropoiesis and iron bioavailability; c) post-operative complications; d) post-operative recovery; e) performance status; f) subgroups based on type of surgery and degree of anemia and iron deficiency; g) re-admissions; h) long term outcome based on patient medical records and i) how post-operative recovery differs between those with low (<400 ml), high (400-4000 ml) and very high (>4000 ml) per-operative blood loss. Recruitment will continue until 338 patients are randomized or 304 have completed the five week follow up The coordinating center of the trial is the Department of Surgery at Uppsala University Hospital. Participating sites are also Linköping University Hospital and Lund University Hospital, all in Sweden. Other sites may be added.

Official Title
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Improved Recovery by Iron Following Surgery With Blood Loss, a Double-blind Multi-centre Randomized Controlled Phase III Drug Trial (the IRIS-trial)

Conditions
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Surgery, Liver Metastases, Liver Cancer, Pancreas Cancer, Aortic Aneurysm

Intervention / Treatment
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* Drug: Ferric carboxymaltose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent Male and female patients Weight > 50 kg > 18 years of age Scheduled for complex aortic surgery, liver resection or pancreatic resection Exclusion Criteria: Short expected survival (less than six months) Intra-venous iron therapy within one month prior to surgery Severe anaemia (B-Hb <80 mg/L) prior to surgery Contraindication to Ferric Carboxymaltose according to SmPC Iron overloading disorder, i.e. hemochromatosis Risk of small for size future liver remnant Pre-operative renal replacement therapy Enrolled in another drug or medical device study within 30 days prior to enrolment of the current study Another planned major surgical procedure before the five week follow up Unsuitable for inclusion according to the investigator Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: At end of surgery, peri-operative blood loss is determined and if 400-4000 ml, the patient is randomised to iv Ferric Carboxymaltose 1000 mg or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Iv Iron<br>Ferric Carboxymaltose, single dose, Intra venous 1000 mg in 100 ml 0.9% NaCl | Drug: Ferric carboxymaltose<br>* Active drug<br>|
| Placebo Comparator: Placebo<br>Placebo, single dose, Intra venous 0.9% NaCl 100 ml | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recovery after iv Iron | To examine if 1000 mg iv Ferric Carboxymaltose administered immediately following hepatic or pancreatic resection or complex aortic surgery with 400 - 4000 ml perioperative blood loss affect a composite of death, number of RBC transfusions, prevalence of post-operative severe anaemia (Hb < 80 g/L) and change in FACT-An QoL questionnaire score at five weeks after surgery compared to pre-operative baseline score. The composite endpoint is assessed by win ratio in the following order: Alive at five weeks (yes/no); number of RBC transfusions from surgery until five weeks; severe anaemia with Hb <80 g/L any time after surgery until five weeks (yes/no); FACT-An score (score at five weeks minus score at baseline) | Five weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hb | Assess if effects of the intervention are linked to increased post operative Hb (g/L) | One to five weeks | 
| Complications | To assess if the intervention reduce post operative complications measured by the comprehensive complication index | One to five weeks | 
| Recovery | To assess if the intervention affect recovery measured by the post operative morbidity survey | One to five weeks | 
| Performance status | To assess if the intervention affect performance assessed by Karnofsky performance status | Five weeks |