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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

15/09/2024

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]

None

Universal Trial Number (UTN)

U1111-1236-7757

Trial acronym

INFERR

Linked study record

Health condition

Health condition(s) or problem(s) studied:

anaemia

high ferritin

low transferrin saturation

Liver disease

Kidney disease

Haemodialysis

Condition category

Condition code

Blood

Anaemia

Renal and Urogenital

Kidney disease

Inflammatory and Immune System

Other inflammatory or immune system disorders

Oral and Gastrointestinal

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]

Treatment: Drugs

Comparator / control treatment

Control Treatment Group (Arm B): No iron treatment will be administered

Control group

Active

Outcomes

Primary outcome [1]

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]

From randomisation up to 48 months

Secondary outcome [1]

All-cause mortality

Timepoint [1]

From randomisation up to 48 months

Secondary outcome [2]

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]

From randomisation up to 48 months

Secondary outcome [3]

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]

From randomisation up to 48 months

Secondary outcome [4]

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]

Monthly from randomisation up to 48 months

Secondary outcome [5]

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]

Monthly from randomisation up to 48 months

Secondary outcome [6]

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]

Every 6 months from randomisation up to 48 months

Secondary outcome [7]

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]

Every 6 months from randomisation up to 48 months

Secondary outcome [8]

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]

Monthly from randomisation up to 48 months

Secondary outcome [9]

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]

At randomisation and at the end of the study for the scans.

Secondary outcome [10]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Recruiting

Date of first participant enrolment

Anticipated

15/08/2020

Actual

8/12/2020

Date of last participant enrolment

Anticipated

30/06/2026

Actual

Date of last data collection

Anticipated

31/12/2026

Actual

Sample size

Target

576

Accrual to date

464

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Royal Darwin Hospital - Tiwi

Recruitment hospital [2]

Alice Springs Hospital - Alice Springs

Recruitment postcode(s) [1]

0810 - Tiwi

Recruitment postcode(s) [2]

0870 - Alice Springs

Recruitment postcode(s) [3]

0822 - Tiwi Islands

Recruitment postcode(s) [4]

0810 - Nightcliff

Recruitment postcode(s) [5]

0850 - Katherine

Recruitment postcode(s) [6]

0870 - The Gap

Recruitment postcode(s) [7]

0830 - Palmerston

Recruitment postcode(s) [8]

0870 - Gillen

Recruitment postcode(s) [9]

0872 - Hermannsburg

Recruitment postcode(s) [10]

0860 - Tennant Creek

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

16 Marcus Clarke St,
Canberra ACT 2601

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (EC00153)

Ethics committee address [1]

Menzies School of Health Research
 John Mathews Building (JMB)
 Building 58, Royal Darwin Hospital Campus
 Darwin, NT

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/10/2019

Approval date [1]

18/03/2020

Ethics approval number [1]

HREC 19-3536

Ethics committee name [2]

Central Australian Human Research Ethics Committee (EC00155)

Ethics committee address [2]

Centre for Remote Health
PO Box 4066
Alice Springs NT 0871

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

06/11/2019

Approval date [2]

17/03/2020

Ethics approval number [2]

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

Prof Sandawana William Majoni

Address

Royal Darwin Hospital,
105 Rocklands Drive
Tiwi NT 0810,
P.O Box 41326,
Casuarina, NT 0810

Country

Australia

Phone

+61 8 8922 8888

Fax

[email protected]

Contact person for public queries

Name

Sandawana William Majoni

Address

Royal Darwin Hospital,
105 Rocklands Drive
Tiwi NT 0810,
P.O Box 41326,
Casuarina, NT 0810

Country

Australia

Phone

+61 8 8922 8888

Fax

[email protected]

Contact person for scientific queries

Name

Sandawana William Majoni

Address

Royal Darwin Hospital,
105 Rocklands Drive
Tiwi NT 0810,
P.O Box 41326,
Casuarina, NT 0810

Country

Australia

Phone

+61 8 8922 8888

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
7783	Study protocol			[email protected]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis-a protocol for a prospective open-label blinded endpoint randomised controlled trial.	2021	https://dx.doi.org/10.1186/s13063-021-05854-w

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically