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Trial registered on ANZCTR


Registration number
ACTRN12622001447741
Ethics application status
Approved
Date submitted
28/10/2022
Date registered
14/11/2022
Date last updated
14/11/2022
Date data sharing statement initially provided
14/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
AMBLE Trial: Iron Deficiency Anaemia in Major Cardiac, Abdominal and VascuLar surgery patients and Effect on functional outcomes
Scientific title
A two-arm, parallel-group double-blind randomisation controlled trial assessing the effect of of intravenous iron versus placebo administration on haemoglobin concentration in anaemic patients undergoing Major cardiac, abdominal, or vascular surgery
Secondary ID [1] 307911 0
Nil known
Universal Trial Number (UTN)
Trial acronym
AMBLE Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia 327573 0
Iron deficiency 328079 0
Vascular Surgery 328080 0
Abdominal Surgery 328081 0
Cardiac surgery 328120 0
Condition category
Condition code
Surgery 324659 324659 0 0
Other surgery
Blood 325223 325223 0 0
Anaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Active:
Intravenous iron infusion
Ferric carboxymaltose 1000 mg given Intravenously

Perioperative group: Intravenous iron or placebo will be administered once only immediately postoperatively in accordance with local hospital guidelines. Adherence will be monitored in accordance with local hospital guidelines.

Recovery group: Intravenous iron or placebo will be administered once only 4 weeks post-operatively in accordance with local hospital guidelines. Adherence will be monitored in accordance with local hospital guidelines.
Intervention code [1] 324422 0
Treatment: Drugs
Comparator / control treatment
Placebo:
Placebo intravenous infusion (intravenous 0.9% sodium chloride)
Control group
Placebo

Outcomes
Primary outcome [1] 332477 0
Change in Haemoglobin (Hb) concentration on blood sample
Timepoint [1] 332477 0
90 days from Baseline
Secondary outcome [1] 413682 0
Change in Routine Iron markers of: Ferritin & transferrin saturations on blood sample
Timepoint [1] 413682 0
Perioperative Group; Baseline, Post-op days 1, 2 & 4, Discharge (or day 8), 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [2] 413683 0
Changes in Experimental Iron markers including: soluble transferrin receptor (STFR), Hepcidin, Erythroferrone and erythropoietin (EPO) on blood sample
Timepoint [2] 413683 0
Perioperative Group; Baseline, Post-op days 1, 2 & 4, Discharge (or day 8), 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [3] 413685 0
Surgical complication as measured by the Clavien Dindo Scale on medical record review
Timepoint [3] 413685 0
4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [4] 413686 0
Length of hospital stay by medical record review
Timepoint [4] 413686 0
4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline
Secondary outcome [5] 413688 0
Unplanned re-admission to hospital for complications by medical record review
Timepoint [5] 413688 0
4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [6] 413689 0
Days Alive and at Home (DAH) by medical record review
Timepoint [6] 413689 0
4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [7] 413690 0
Change in clinical frailty score
Timepoint [7] 413690 0
Perioperative Group; discharge (or day 8) 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: Baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [8] 413691 0
Changes in Sarcopenia as assessed by quantitative skeletal muscle analysis using dynamometer
Timepoint [8] 413691 0
Perioperative Group; discharge (or day 8) 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: Baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [9] 413692 0
Changes in functional assessments as assessed by Short Physical Performance Battery (composite outcome); 4 metre gait speed, five time sit-stand test, balance test (the balance test is included in the short physical performance battery protocol) Maximal handgrip strength (dynamometer), time to get up and go, or 6-minute walk test.
Timepoint [9] 413692 0
Perioperative Group; discharge (or day 8) 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: Baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [10] 413693 0
Changes in Quality of life measured by Short form survey version 2 (SF-36v2)
Timepoint [10] 413693 0
Perioperative Group; discharge (or day 8) 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: Baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [11] 413694 0
Experimental Inflammatory markers including: CrP, IL6 and other cytokines on blood sample.
Timepoint [11] 413694 0
Perioperative Group; Baseline, Post-op days 1, 2 & 4, Discharge (or day 8), 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: Baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.
Secondary outcome [12] 415704 0
EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire
Timepoint [12] 415704 0
Perioperative Group; discharge (or day 8) 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Randomisation.

Recovery Group: Baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks from Baseline.

Eligibility
Key inclusion criteria
Perioperative group and Recovery group

Patients who meet the following criteria at the start of treatment are eligible for the study:
1. Adults (greater than or equal to 18 years)
2. Undergoing planned or unplanned (elective/expedited or emergent) cardiac surgery (bypass or valve), abdominal surgery (open or laparoscopic) or vascular surgery (open or hybrid) of the lower limb
3. Anaemia (Hb <130g/L in males and <120g/L) in females
4. Willing and able to undergo follow-up visits
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Perioperative group and Recovery group

Patients who, at the start of treatment, meet any of the following criteria are not eligible for the study:
1. Blood transfusion at operation or blood transfusion in previous 3 months
2. Erythropoietin or intravenous iron in the previous 4 weeks
3. Known hypersensitivity to (ferric carboxymaltose or equivalent) or its excipients
4. Active infection on therapeutic antibiotics
5. Known chronic liver disease
6. Known other cause for anaemia (eg. untreated B12 or folate deficiency or myelodysplasia)
7. Known family history of haemochromatosis or Transferrin saturation (TSATS) >50%
8. Pregnancy or lactation
9. Unable to provide written informed consent

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random allocation will be performed using a computer-generated code, access via a web-based service.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Other
Other design features
'Perioperative group' and 'Recovery group' will be randomised to receive the intervention or placebo within these groups
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2022
Actual
Date of last participant enrolment
Anticipated
1/08/2024
Actual
Date of last data collection
Anticipated
1/12/2024
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 23156 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 38516 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 312198 0
Government body
Name [1] 312198 0
South Metropolitan Health Service
Country [1] 312198 0
Australia
Primary sponsor type
Government body
Name
South Metropolitan Health Service
Address
Administration Building, Fiona Stanley Hospital, 14 Barry Marshall Parade
Murdoch WA 6150
Country
Australia
Secondary sponsor category [1] 313770 0
None
Name [1] 313770 0
Address [1] 313770 0
Country [1] 313770 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311573 0
South Metropolitan Health Service
Ethics committee address [1] 311573 0
Level 2, Education Building, Fiona Stanley Hospital 14 Barry Marshall Parade
Murdoch WA 6150
Ethics committee country [1] 311573 0
Australia
Date submitted for ethics approval [1] 311573 0
26/07/2022
Approval date [1] 311573 0
09/09/2022
Ethics approval number [1] 311573 0
RGS0000005557

Summary
Brief summary
Iron deficiency is the commonest nutritional deficiency globally, affecting 2 billion people and is the leading cause of anaemia. Iron deficiency anaemia makes people tired and unwell as well as impacting physical function, it is a WHO top 10 leading cause for disability. Anaemia is common in patients undergoing major surgery and associated with worse patient outcomes and increased post operative mortality.

The aim of this trial is to explore the mechanisms of iron deficiency over the perioperative time period in patients undergoing cardiac, abdominal and vascular surgery and the response to intravenous iron therapy that bypasses the normal Hepcidin mediated iron pathways. Secondary aims include to assess the efficacy of intravenous iron and measuring potential effects on patients’ physical recovery.

AMBLE will be a prospective, parallel-group, double blinded, randomised, multi-centre trial designed to investigate the effects of intravenous iron therapy on disease progression in cardiac, abdominal, and vascular surgery patients.

Two separate groups of patients will be assessed:
The Perioperative group of patients included if about to undergo major cardiac, abdominal and vascular surgery to assess the mechanisms of iron deficiency in the perioperative period.
The Recovery group of patients included 4 weeks after hospital discharge following major cardiac, abdominal and vascular surgery to assess recovery of physical function and anaemia.

The outcomes of this research will generate a better understanding of the mechanism of iron deficiency anaemia in surgical patients as well as how this affects post operative recovery. By better understanding the aetiology of iron metabolism in surgery we can determine what intervention (iron +/- EPO) may improve patient outcomes and the administration timing thereof. As a result, more informed decisions will be made regarding iron supplementation and therapy in these patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121570 0
Prof Toby Richards
Address 121570 0
Department of Vascular Surgery
Fiona Stanley Hospital
11 Robin Warren Dr, Murdoch WA 6150
Country 121570 0
Australia
Phone 121570 0
+610861511178
Fax 121570 0
Email 121570 0
[email protected]
Contact person for public queries
Name 121571 0
Toby Richards
Address 121571 0
Department of Vascular Surgery
Fiona Stanley Hospital
11 Robin Warren Dr, Murdoch WA 6150
Country 121571 0
Australia
Phone 121571 0
+610861511178
Fax 121571 0
Email 121571 0
[email protected]
Contact person for scientific queries
Name 121572 0
Toby Richards
Address 121572 0
Department of Vascular Surgery
Fiona Stanley Hospital
11 Robin Warren Dr, Murdoch WA 6150
Country 121572 0
Australia
Phone 121572 0
+610861511178
Fax 121572 0
Email 121572 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data collected during the trial, after de-identification will be available upon request to the Principal Investigator.
When will data be available (start and end dates)?
After publication of main trial findings, no end date
Available to whom?
Case-by-case basis
Available for what types of analyses?
For meta-analyses and case-by-case basis on request with data-sharing agreement.
How or where can data be obtained?
Subject to approvals by Principal Investigator. Data requests can be emailed to [email protected]


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
No additional documents have been identified.