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Trial registered on ANZCTR


Registration number
ACTRN12620000705987
Ethics application status
Approved
Date submitted
11/05/2020
Date registered
29/06/2020
Date last updated
29/06/2020
Date data sharing statement initially provided
29/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
INFERR - Iron Infusion in Haemodialysis Study: Effect of Intravenous Iron Polymaltose on survival and hospitalisation rates for Indigenous Patients with High Ferritin Levels on Haemodialysis
Scientific title
INFERR - Iron Infusion in Haemodialysis Study: Effect of Intravenous Iron Polymaltose on survival and hospitalisation rates for Indigenous Patients with High Ferritin Levels on Haemodialysis
Secondary ID [1] 299497 0
None
Universal Trial Number (UTN)
U1111-1236-7757
Trial acronym
INFERR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
anaemia 314743 0
high ferritin 314744 0
low transferrin saturation 314745 0
Liver disease 317226 0
Kidney disease 317570 0
Haemodialysis 317571 0
Condition category
Condition code
Blood 313074 313074 0 0
Anaemia
Renal and Urogenital 313075 313075 0 0
Kidney disease
Inflammatory and Immune System 315367 315367 0 0
Other inflammatory or immune system disorders
Oral and Gastrointestinal 315654 315654 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention Treatment Group (Arm A): 400 mg of Iron Polymaltose administered intravenously by the dialysis nurse at the renal unit divided equally (200 mg) over two haemodialysis sessions monthly for up to 48 months

Adherence to the treatment will be monitored by attendance for haemodialysis as the treatment is routinely given by the nurses during dialysis. The rates of non-adherence are anticipated to be very low because for this reason.
Intervention code [1] 315754 0
Treatment: Drugs
Comparator / control treatment
Control Treatment Group (Arm B): No iron treatment will be administered
Control group
Active

Outcomes
Primary outcome [1] 321620 0
Differences according to treatment allocation in risk of hospitalisation with all-cause infection or death.
The primary outcome is a composite outcome measure with
1. All-cause death
2. Hospitalisation with all-cause infection

Outcome data will be collected from patient medical records. The data will also be entered into the CRFs during each follow up visit. Blinded outcomes adjudication will be performed by adjudicators independent of the study.
Timepoint [1] 321620 0
From randomisation up to 48 months
Secondary outcome [1] 375609 0
All-cause mortality
Timepoint [1] 375609 0
From randomisation up to 48 months
Secondary outcome [2] 375610 0
Risk of hospitalisation
Outcome data will be collected from patient medical records. The data will also be entered into the CRFs during each follow up visit. Blinded outcomes adjudication will be performed by adjudicators independent of the study.
Timepoint [2] 375610 0
From randomisation up to 48 months
Secondary outcome [3] 375611 0
All-cause infection
Outcome data will be collected from patient medical records. The data will also be entered into the CRFs during each follow up visit. Blinded outcomes adjudication will be performed by adjudicators independent of the study.
Timepoint [3] 375611 0
From randomisation up to 48 months
Secondary outcome [4] 375612 0
Differences in haemoglobin level (a normally distributed continuous outcome) at 3 months, as this measures the efficacy of iron therapy, using analysis of covariance (ANCOVA), with adjustment for baseline haemoglobin level

Routine care blood tests will be performed every month including hemoglobin levels. These results will be directly transferred from the laboratory results repositories onto the CRF's at each study follow up visit.
Timepoint [4] 375612 0
Monthly from randomisation up to 48 months
Secondary outcome [5] 375613 0
Causes and explanation of high serum ferritin concentrations : Comparison and multivariable regression analyses to assess the cross-sectional association between serum ferritin concentrations and the following will be performed :
other measures of iron status (serum hepcidin, Tranferrin Saturation (TSAT), soluble transferrin receptor, percentage hypochromic red cells, reticulocyte haemoglobin content, liver iron).
Outcome data will be collected from patient medical records. The data will also be entered into the CRFs during each follow up visit. Blinded outcomes adjudication will be performed by adjudicators independent of the study.
Timepoint [5] 375613 0
Monthly from randomisation up to 48 months

Secondary outcome [6] 375614 0
Serious adverse events: all serious adverse events, hospital admissions, frequency of infections associated with hospitalisation and mortality will be compared between the groups. The difference between the groups will be assessed using the chi-squared test for binary outcomes, Kaplan-Meier survival curves with log rank statistic for time to event and Student’s t test or analysis of covariance (or non-parametric methods if appropriate) for continuous outcomes. Pre-specified analyses according to baseline ferritin strata will be performed (less than or equal to 1200 microgram per liter and greater than 1200microgram per liter).

As part of the adverse event reporting for the study data will be collected and recorded in the CRF. This data will include final diagnosis, alive status on discharge, details of procedures, measures of inflammatory markers (C-reactive protein,Tumour Necrosis Factor alpha, Interleukin 1 and Interleukin 6), other abnormal blood results, abnormal ECG results, any additional comorbidities and any other clinical details such as skin reactions, anaphylaxis and infection episodes noted on the discharge summary

Data for adverse events will be collected from awareness of the adverse event, this could be during review of medical records or as a report from a treating clinicians or from the study participant directly. The data will be entered into the CRFs after collection.
Timepoint [6] 375614 0
Every 6 months from randomisation up to 48 months
Secondary outcome [7] 375615 0
Cost analysis: an analysis of the financial costs of the treatment will be performed assessing the costs of erythropoieses stimulating agents (ESA), iron, hospital admissions and procedures for the duration of follow-up among all patients assigned to intravenous iron compared to no iron treatment.

Outcome data will be collected from patient medical records and entered into CRFs during follow-up visits. This will include administration of erythropoieses stimulating agents (ESA) and iron, additional data will be collected on hospital admissions and procedures that occur whilst on the study.
Timepoint [7] 375615 0
Every 6 months from randomisation up to 48 months
Secondary outcome [8] 383467 0
Explanation of high serum ferritin concentrations: An analysis will be performed to assess the potential causes of the high ferritin by assessing any potential relationship with inflammatory markers such as C-reactive protein, Tumour Necrosis Factor alpha, IL1 and IL6

Data will be collected from medical records and laboratory blood results of the inflammatory markers. The data will be collected and aggregated onto CRF's in preparation for analysis.
Timepoint [8] 383467 0
Monthly from randomisation up to 48 months
Secondary outcome [9] 383630 0
Liver iron stores using ferriscans

Ferriscans will be performed by the radiology department and results will be entered in the patients' medical records and transferred to the CRF's
Timepoint [9] 383630 0
At randomisation and at the end of the study for the scans.
Secondary outcome [10] 384125 0
Liver fibrosis or cirrhosis using liver ultrasound scans and fibroscans

The ultrasound scan and fibroscans will be performed by 2 of the investigators. The data will be transferred directly onto CRFs.
Timepoint [10] 384125 0
At randomisation and at the end of the study for the scans.

Eligibility
Key inclusion criteria
1. Male or female aged less than or equal to 18 years
2. Identify as Aboriginal and/or Torres Strait Islander
3. On maintenance haemodialysis for greater than or equal to 3 months
4. Clinical laboratory results:
a. haemoglobin less than or equal 115 gram per liter,
b. ferritin levels greater than or equal to 700 microgram per liter & less than or equal to 2000 microgram per liter
c. Transferrin Saturation (TSAT) less than 40%
d. C-reactive protein (CRP) less than 50 milligram per liter
5. Willing to join the study and can provide informed consent
6. On adequate Erythropoietin Stimulating Agents (ESA) therapy
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of known allergic or adverse or hypersensitivity reactions to iron polymaltose or parenteral iron products;
2. Already receiving iron unless they have stopped the iron therapy for greater than or equal to 4 weeks at the time of recruitment;
3. Has received blood transfusion within the last 4 weeks;
4. Known iron overload, haemochromatosis, haemoglobinopathy, haemolytic anaemia, aplastic anaemia, lymphoproliferative disease or cancer or on current cancer treatment
5. Participant’s primary clinician unwilling to enrol
6. Severe asthma, eczema or allergies;
7. Not planning to remain resident in the Northern Territory for the next 12 months;
8. Patients who frequently miss haemodialysis which, in the opinion of the Investigator, would make the participant unsuitable for the study or would prevent compliance with study protocol.
9. Ferritin greater than 2000 microgram per liter
10. Tranferrin Saturation (TSAT) greater than or equal to 40%
11. Life expectancy less than 12 months per the judgement of the investigator
12. Living-donor transplant scheduled within 12 months
13. Scheduled to switch to peritoneal dialysis

Temporary Exclusion Criteria:
Participant may not enter the trial at any given time if:
1. Fever greater than 38 degrees Celsius, or has evidence of active bacterial infection, or C-reactive protein (CRP) greater than or equal to 50 milligram per liter

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible Patients will be randomised 1:1. Randomisation will be stratified by site and according to baseline ferritin levels (less than or equal to 1200 microgram per liter and greater than 1200 microgram per liter) in permuted blocks of variable sizes.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The recruitment target is 576 participants. Average planned follow-up in the study will be up to a maximum of 48 months (4 years). The 2-year rate of admission with first episode of infection or death in patients on maintenance haemodialysis from 2000-2014 was 60%. In order to achieve a study power >80% at 5% significance level in detecting a 30% reduction in time to the first hospitalisation with all-cause infection or death, using the log-rank test (time to event modelling), assuming a 5% drop-out rate, 576 participants will be randomised 1:1 into each arm with a hazard ratio of 0.70 for standard over active treatment(i.e. 30% reduction in time to first hospitalisation for people receiving iron). The study also has > 90% power at 5% significance level of detecting a difference in haemoglobin of 5 gram per liter and standard deviation of 11.3 gram per liter based on published data. The sample size also provides enough power to determine differences within the ferritin strata.

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)
NT
Recruitment hospital [1] 14941 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [2] 14942 0
Alice Springs Hospital - Alice Springs
Recruitment postcode(s) [1] 28216 0
0810 - Tiwi
Recruitment postcode(s) [2] 28217 0
0870 - Alice Springs
Recruitment postcode(s) [3] 28219 0
0822 - Tiwi Islands
Recruitment postcode(s) [4] 28220 0
0810 - Nightcliff
Recruitment postcode(s) [5] 28221 0
0850 - Katherine
Recruitment postcode(s) [6] 28222 0
0870 - The Gap
Recruitment postcode(s) [7] 28223 0
0830 - Palmerston
Recruitment postcode(s) [8] 28224 0
0870 - Gillen
Recruitment postcode(s) [9] 28225 0
0872 - Hermannsburg
Recruitment postcode(s) [10] 28226 0
0860 - Tennant Creek

Funding & Sponsors
Funding source category [1] 303996 0
Government body
Name [1] 303996 0
National Health and Medical Research Council
Address [1] 303996 0
16 Marcus Clarke St,
Canberra ACT 2601
Country [1] 303996 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Menzies School of Health Research
Address
PO Box 41096
Casuarina NT 0811
Country
Australia
Secondary sponsor category [1] 304178 0
None
Name [1] 304178 0
Address [1] 304178 0
Country [1] 304178 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304489 0
Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (EC00153)
Ethics committee address [1] 304489 0
Menzies School of Health Research
John Mathews Building (JMB)
Building 58, Royal Darwin Hospital Campus
Darwin, NT
Ethics committee country [1] 304489 0
Australia
Date submitted for ethics approval [1] 304489 0
09/10/2019
Approval date [1] 304489 0
18/03/2020
Ethics approval number [1] 304489 0
HREC 19-3536
Ethics committee name [2] 304499 0
Central Australian Human Research Ethics Committee (EC00155)
Ethics committee address [2] 304499 0
Centre for Remote Health
PO Box 4066
Alice Springs NT 0871
Ethics committee country [2] 304499 0
Australia
Date submitted for ethics approval [2] 304499 0
06/11/2019
Approval date [2] 304499 0
17/03/2020
Ethics approval number [2] 304499 0
Ca-19-3567

Summary
Brief summary
The Iron Infusion in Haemodialysis Study – Intravenous iron polymaltose versus no iron in maintenance haemodialysis (MHD): a prospective open-label blinded endpoint randomised controlled trial – will assess the safety and effectiveness of intravenous iron treatment among Indigenous MHD patients with anaemia, high ferritin and low transferrin saturation. All patients 18 years or older on MHD for greater than or equal to 3 months will be eligible for screening and recruitment. We will randomise 576 patients across the Northern Territoy to achieve study power of greater than 80% in detecting a 30% reduction in time to the first of hospitalisation with infection or death. Secondary outcomes will be all serious adverse events, hospital admissions, infection rates, differences in haemoglobin levels over 6 to 12 months, and death. A cost analysis will be performed looking at the costs of treatment, hospital admissions and procedures between the intervention arm versus the control.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97126 0
A/Prof Sandawana William Majoni
Address 97126 0
Royal Darwin Hospital,
105 Rocklands Drive
Tiwi NT 0810,
P.O Box 41326,
Casuarina, NT 0810
Country 97126 0
Australia
Phone 97126 0
+61 8 8922 8888
Fax 97126 0
Email 97126 0
William.Majoni@nt.gov.au
Contact person for public queries
Name 97127 0
A/Prof Sandawana William Majoni
Address 97127 0
Royal Darwin Hospital,
105 Rocklands Drive
Tiwi NT 0810,
P.O Box 41326,
Casuarina, NT 0810
Country 97127 0
Australia
Phone 97127 0
+61 8 8922 8888
Fax 97127 0
Email 97127 0
William.Majoni@nt.gov.au
Contact person for scientific queries
Name 97128 0
A/Prof Sandawana William Majoni
Address 97128 0
Royal Darwin Hospital,
105 Rocklands Drive
Tiwi NT 0810,
P.O Box 41326,
Casuarina, NT 0810
Country 97128 0
Australia
Phone 97128 0
+61 8 8922 8888
Fax 97128 0
Email 97128 0
William.Majoni@nt.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
In partnership with the INFERR trial Indigenous Reference Group, and consistent with principles of Indigenous data sovereignty, the trial management committee will develop a process and framework for consideration of requests for sharing of individual participant-level data. At this stage, we will commit to sharing summary of data underlying published results only.
The trial management committee will be the custodians of the final INFERR trial dataset. No-one outside the trial management committee will be given access to the data without the permission of the trial management committee.



What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 7783 0
Study protocol
Citation [1] 7783 0
Link [1] 7783 0
Email [1] 7783 0
william.majoni@menzies.edu.au
Other [1] 7783 0
Attachment [1] 7783 0
Summary results
No Results