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Trial registered on ANZCTR


Registration number
ACTRN12620000285954
Ethics application status
Approved
Date submitted
30/01/2020
Date registered
3/03/2020
Date last updated
3/03/2020
Date data sharing statement initially provided
3/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Iron Repletion in Symptomatic Patients with Atrial Fibrillation (IRON-AF)
Scientific title
A double-blind, randomised, placebo-controlled study to assess the effects of intravenous ferric carboxymaltose on exercise tolerance in patients with atrial fibrillation and iron deficiency.
Secondary ID [1] 299871 0
Nil
Universal Trial Number (UTN)
Trial acronym
IRON-AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial fibrillation 315283 0
Iron deficiency 315284 0
Condition category
Condition code
Cardiovascular 313581 313581 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A total of 84 individuals will be randomised in a 1:1 ratio to ferric carboxymaltose or placebo.

Active Treatment
Ferric carboxymaltose (FCM, Ferinject ®, Vifor Pharma Pty Limited [Melbourne, Australia]) added to 100 mL 0.9% sodium chloride, delivered intravenously over 15 minutes using a volumetric infusion pump, given as a single infusion during each visit at week 0, 1, 4, and 8.

Iron Repletion
For participants in the active treatment group, the total dose of FCM for repletion will be calculated using the Ganzoni formula, rounded to the nearest 100mg. Participants in the active treatment group will receive FCM up to the calculated iron deficit, given over two infusions. The first infusion, given in week 0, will be up to a maximum dose of 1000 mg. The second infusion, given in week 1, will deliver the remainder of the required repletion dose. Patients will be observed during the infusion, and for 30 minutes after its completion. They will have their vital signs taken before the infusion, 5 minutes after the commencement of the infusion, and upon conclusion of the infusion.
Iron Maintenance
At the start of weeks 4 and 8, participants will have iron studies performed. The results of these studies will be reviewed and entered into the web database by an unblinded study coordinator not involved in assessments of efficacy or safety. Participants in the active treatment group will then receive two maintenance infusions of 200 mg FCM, the first during week at the end of week 4 and the second at the end of week 8. In cases of elevated levels of ferritin > 800 ng/L, or ferritin > 500 ng/L when Tsat > 50% or Hb > 160 g/L detected on the iron studies performed the week prior, placebo is to be given instead of FCM during the respective visit.

The primary outcome observed will be the change in VO2peak (mL/min/kg) from baseline to week 12, as measured by cycle ergometer cardiopulmonary exercise testing performed at baseline and week 12.
Intervention code [1] 316137 0
Treatment: Drugs
Comparator / control treatment
100mL 0.9% sodium chloride, delivered intravenously over 15 minutes using a volumetric infusion pump. Participants will receive a single infusion for repletion at week 0 and 1 and maintenance infusions at weeks 5 and 9.
Control group
Placebo

Outcomes
Primary outcome [1] 322035 0
Change in VO2 peak (mL/min/kg) as assessed by cardiopulmonary exercise testing (CPET) performed on a cycle ergometer using a metabolic chart.
Change in ventilatory efficiency, as assessed by cardiopulmonary exercise testing (CPET) performed on a cycle ergometer.
Timepoint [1] 322035 0
12 weeks post baseline
Secondary outcome [1] 377108 0
Change in 36-Item Short Form Survey (SF-36) subscale scores
Timepoint [1] 377108 0
From baseline to weeks 4, 8, 12
Secondary outcome [2] 377109 0
Change in Atrial Fibrillation Effect on Quality-of-Life Questionnaire (AFEQT) overall and subset scores
Timepoint [2] 377109 0
From baseline to weeks 4, 8, 12
Secondary outcome [3] 377110 0
Change in Patient Global Assessment (PGA) score
Timepoint [3] 377110 0
From baseline to weeks 4, 8 and 12
Secondary outcome [4] 377112 0
Change in fatigue score, a 1 – 10 scale designed for this study to describe fatigue, where ‘1’ is ‘no fatigue at all’ and ’10’ is ‘very severe fatigue
Timepoint [4] 377112 0
From baseline to weeks 4, 8 and 12
Secondary outcome [5] 377113 0
Change in New York Heart Association (NYHA) classification
Timepoint [5] 377113 0
From baseline to weeks 4, 8 and 12
Secondary outcome [6] 377114 0
Change in haemoglobin assessed by venous blood assay
Timepoint [6] 377114 0
From baseline to weeks 4, 8 and 12
Secondary outcome [7] 377115 0
Change in 6-minute walk test distance
Timepoint [7] 377115 0
12 weeks post baseline
Secondary outcome [8] 377116 0
Change in ventilatory efficiency, as assessed by cardiopulmonary exercise testing (CPET) performed on a cycle ergometer using a metabolic chart
Timepoint [8] 377116 0
12 weeks post baseline
Secondary outcome [9] 377117 0
Change in resting transthoracic echocardiogram (TTE) parameters. This outcome is exploratory.
Timepoint [9] 377117 0
12 weeks post baseline
Secondary outcome [10] 377119 0
Hospitalisation (total, cardiovascular, heart failure, AF) obtained from self-report, medical records (composite outcome).
Timepoint [10] 377119 0
12 weeks post baseline
Secondary outcome [11] 377120 0
Mortality (total, cardiovascular) obtained from hospital records (composite outcome).
Timepoint [11] 377120 0
12 weeks post baseline
Secondary outcome [12] 379311 0
Change in Atrial Fibrillation Severity Scale (AFSS) severity score
Timepoint [12] 379311 0
Baseline to weeks 4, 8, 12
Secondary outcome [13] 379312 0
Change in AF burden as measured by 4-day Holter monitoring
Timepoint [13] 379312 0
12 weeks post baseline
Secondary outcome [14] 379862 0
Change in stress transthoracic echocardiogram parameters as performed on stationary bicycle exercise (exploratory outcome).
Timepoint [14] 379862 0
12 weeks post baseline
Secondary outcome [15] 379863 0
Change in Atrial Fibrillation Severity Scale (AFSS) burden score
Timepoint [15] 379863 0
Baseline to weeks 4, 8, 12
Secondary outcome [16] 379864 0
Change in serum ferritin
Timepoint [16] 379864 0
From baseline to weeks 4, 8 and 12
Secondary outcome [17] 379865 0
Change in transferrin saturation assessed by serum assay
Timepoint [17] 379865 0
From baseline to weeks 4, 8 and 12
Secondary outcome [18] 379866 0
Change in erythrocyte sedimentation rate assessed by venous blood assay.
Timepoint [18] 379866 0
From baseline to weeks 4, 8 and 12
Secondary outcome [19] 379867 0
Change in C-reactive protein levels assessed by serum assay.
Timepoint [19] 379867 0
From baseline to weeks 4, 8 and 12
Secondary outcome [20] 379868 0
Change in brain-natriuretic peptide levels assessed by serum assay
Timepoint [20] 379868 0
From baseline to weeks 4, 8 and 12

Eligibility
Key inclusion criteria
• At least 18 years of age
• Paroxysmal or persistent atrial fibrillation
• Stable medical therapy in the 4 weeks prior to enrolment with no dose changes of atrial fibrillation drugs in the last 2 weeks
• Haemoglobin < 150g/L
• Serum ferritin < 100 ug/L or serum ferritin < 300 ug/L if Tsat < 20%
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Known hypersensitivity to parenteral iron preparations
• History of primary or secondary haemochromatosis
• Known haemoglobinopathy or haemolytic anaemia
• History of erythropoietin-stimulating agent, intravenous iron therapy, and / or blood transfusion in the 6 weeks prior to randomisation
• Requiring treatment with blood transfusion in the next 3 months
• Requiring surgery with anticipated moderate or severe blood loss in the next 3 months
• Oral iron therapy at doses > 80 mg/day (of elemental iron) in the 1 week prior to randomisation (note: ongoing use of multivitamins containing <= 80 mg/day is permitted)
• Planned cardioversion, catheter ablation, AV nodal ablation with pacemaker insertion or surgical ablation within the next 3 months
• Body weight <= 35 kg
• Exercise training program(s) in the 3 months prior to screening, or planned in the next 3 months
• Ongoing blood loss
• Current active autoimmune or systemic inflammatory diseases
• Current active systemic infection or bacteraemia
• Known chronic liver disease, hepatitis B or hepatitis C infection, or screening AST / ALT above three times the upper limit of normal range
• Known active malignancy, with the exception of squamous cell and basal cell carcinoma of the skin, and cervical intraepithelial neoplasia
• Currently receiving systemic chemotherapy and/or radiotherapy
• Known chronic kidney disease
• History of dialysis, current dialysis or dialysis planned within the next 3 months
• Currently pregnant, breastfeeding, or trying to conceive within the next 3 months
• Acute myocardial infarction, transient ischaemic attack, or stroke in the 3 months prior to randomisation
• Coronary artery bypass graft, percutaneous intervention, or major surgery (including thoracic and cardiac surgery) within the last 3 months (diagnostic catheterisations are allowed)
• Subject is unable to perform exercise testing, either according to the Investigator’s judgement, or due to the following conditions:
o Severe lower limb musculoskeletal or neurological conditions
o Unstable angina
o Severe valvular or left ventricular outflow tract obstruction requiring intervention
• Subject is currently enrolled in, or is within 30 days of completion of, another interventional study
• Subject has previously been randomised to this study (subjects may be rescreened if they previously did not meet the eligibility criteria)
• Subject will not be available for completion of all assessments as per the study protocol

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated web-based randomisation schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We anticipate that randomisation of 70 patients will provide robust statistical power to detect plausible and clinically relevant proportional improvement in VO2max of 2ml/min/kg with 80% power and 2-sided alpha level of 0.05. Power calculation assumptions are based on prior randomised and observational studies in heart failure and AF populations suggesting that iron deficient and replete individuals exhibit at least a clinically relevant 2mL/min/kg difference in VO2max with standard deviation of 3ml/min/kg. Taking the above into account, we plan to recruit 84 patients in total (42 patients per group) to allow for a 15% discontinuation rate.

Continuous variables will be reported as mean and standard deviation, or median and interquartile range, as appropriate to distribution. Count variables will be reported as number and percentage. The primary analysis will be an unpaired comparison of the changes in VO2max between the treatment arms using the Student t test. Paired changes from baseline to week 12 will be assessed using paired t tests. Summary statistics will include the point estimates of week 12 VO2max, the change from baseline to week 12, and the estimates and 2-sided 95% confidence intervals (CI) for the difference between least squares means of the 2 treatment arms. Other continuous end points will be analysed in a similar fashion. Categorical variables will be evaluated using a chi-square or Fisher exact test as appropriate. All statistical tests will be two-sided, and a p value of <0.05 will be considered significant. All analyses will be undertaken using Stata 13.0 (Stata Corporation).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 15276 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 28586 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 304332 0
University
Name [1] 304332 0
University of Adelaide
Address [1] 304332 0
North Terrace, Adelaide, SA 5000
Country [1] 304332 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
North Terrace, SA 5000
Country
Australia
Secondary sponsor category [1] 304577 0
None
Name [1] 304577 0
Address [1] 304577 0
Country [1] 304577 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304783 0
Central Adelaide Health Network HREC
Ethics committee address [1] 304783 0
Royal Adelaide Hospital
Port Road, SA 5000
Ethics committee country [1] 304783 0
Australia
Date submitted for ethics approval [1] 304783 0
06/01/2020
Approval date [1] 304783 0
28/01/2020
Ethics approval number [1] 304783 0
HREC/20/CALHN/6

Summary
Brief summary
The study aims to determine the efficacy and safety of iron supplementation in patients with atrial fibrillation and iron deficiency. Participants will be individuals with symptomatic atrial fibrillation who meet the inclusion and exclusion criteria. After providing consent, patients will have a blood tests to identify those with iron deficiency. Those with iron deficiency will continue their involvement in the study and will be asked to complete a set of health questionnaires, and undergo a cardiac ultrasound, exercise testing, and heart rhythm monitoring.
Participants will be randomised to one of two treatment groups (in a 1:1 ratio) of either placebo or ferric carboxymaltose (iron) delivered through an infusion over 15 minutes. Patients will have follow-up visits at week 4 and 8, and will undergo final testing at week 12. The trial will recruit 84 patients.
It is expected that participants who receive the supplementation of iron will improve their exercise tolerance after 12 weeks compared to those who receive the placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98186 0
Dr Chris Wong
Address 98186 0
Cardiovascular Investigation Unit
Royal Adelaide Hospital
Port Road, Adelaide, SA 5000
Country 98186 0
Australia
Phone 98186 0
+61 8 8313 9000
Fax 98186 0
Email 98186 0
c.wong@adelaide.edu.au
Contact person for public queries
Name 98187 0
Dr Chris Wong
Address 98187 0
Cardiovascular Investigation Unit
Royal Adelaide Hospital
Port Road, Adelaide, SA 5000
Country 98187 0
Australia
Phone 98187 0
+61 8 8313 9000
Fax 98187 0
Email 98187 0
c.wong@adelaide.edu.au
Contact person for scientific queries
Name 98188 0
Dr Chris Wong
Address 98188 0
Cardiovascular Investigation Unit
Royal Adelaide Hospital
Port Road, Adelaide, SA 5000
Country 98188 0
Australia
Phone 98188 0
+61 8 8313 9000
Fax 98188 0
Email 98188 0
c.wong@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results