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Trial registered on ANZCTR


Registration number
ACTRN12622001105730p
Ethics application status
Submitted, not yet approved
Date submitted
1/08/2022
Date registered
10/08/2022
Date last updated
10/08/2022
Date data sharing statement initially provided
10/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The Fatigue after Infusion or Transfusion (FIT) Pilot Trial and Feasibility Study
Scientific title
The FIT Pilot Trial and Feasibility Study: a three-armed randomised pilot trial of intravenous iron versus blood transfusion for the treatment of moderate-to-severe postpartum anaemia and feasibility surveys.
Secondary ID [1] 307687 0
Nil known
Universal Trial Number (UTN)
Trial acronym
FIT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
postpartum anaemia 327234 0
Condition category
Condition code
Blood 324372 324372 0 0
Anaemia
Reproductive Health and Childbirth 324373 324373 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Women will be randomised to one of three groups. Arm B and Arm C are the intervention arms:

Arm B. Red blood cell transfusion (RBC-T). The number of units of RBCs to be determined by the responsible clinician and given within 24 hours of randomisation.

Arm C. Intravenous iron (IV-iron) and RBC-T. Single dose of 1000mg dose of ferric carboxymaltose (FCM) and RBC-T with the number of units of RBCs to be determined by the responsible clinician. IV-iron and RBC-T to be administered within 24 hours of of randomisation.

Interventions will be administered by registered midwives and nurses, as per the normal standard of care.

FCM will be administered intravenously as an infusion according to local hospital protocol. Manufacturer instructions recommend it should be diluted in 250mL of sterile 0.9% sodium chloride solution and infused over 15 minutes. Vital signs of women should be closely monitored and documented before, during, and after FCM administration according to local hospital policy.

The total iron requirements for FCM have been shown to be less than or equal to 1600mg for approximately 90% of postpartum women, therefore a fixed single 1000mg dose of FCM has been chosen (1). This dose selection is supported by Medsafe advice of a single FCM not exceeding 1000mg, or up to a maximum of 20mg/kg body weight (2).

RBC-T should be administered with appropriate monitoring as per each hospital protocol.

Relevant concomitant care permitted or prohibited: Oral iron supplementation may be prescribed according to local hospital guidelines, as determined by the responsible clinician. Where local guidance is not available, it is recommended that oral iron should not given in addition to the study interventions. When oral iron is given, data regarding the prescription and use of oral iron will be collected.

A study-specific log will be kept for each participant to monitor adherence to the intervention.
Where a clinician prescribes an additional intervention (IV-iron or RBC-T) contrary to randomisation allocation this will be considered a protocol violation (by the Lead Investigator or Senior Supervising Investigator). Data regarding the use of additional IV-iron and RBC-T will be collected along with the reasons why, to inform future trial planning or the likelihood of protocol violation/crossover of treatment.

(1) Seid MH, Butcher AD, Chatwani A. Ferric Carboxymaltose as Treatment in Women with Iron-Deficiency Anemia. Anemia. 2017;2017.
(2) Medsafe M. Ferinject New Zealand Data Sheet. 2021; Available from: https://www.medsafe.govt.nz/profs/Datasheet/f/ferinjectinj.pdf
Intervention code [1] 324162 0
Treatment: Drugs
Intervention code [2] 324192 0
Treatment: Other
Comparator / control treatment
Arm A. Single dose of 1000mg IV-iron FCM

IV-iron will be administered by registered midwives and nurses, as per the normal standard of care.
Control group
Active

Outcomes
Primary outcome [1] 332166 0
The number of women consenting to take part in the FIT Pilot Trial (randomised trial) by audit of the study recruitment log.
Timepoint [1] 332166 0
Upon completion of recruitment.
Primary outcome [2] 332167 0
Trial approached recruitment rate: the number of participants randomised/the number of women approached and invited to participate by audit of the study recruitment log.
Timepoint [2] 332167 0
Upon completion of recruitment.
Primary outcome [3] 332168 0
Overall recruitment rate: this will be estimated from the number of participants randomised/the number of women birthing in the same period with Hb 65-79 g/L; assessed by audit of the study recruitment log, and by accessing hospital records.
Timepoint [3] 332168 0
Upon completion of recruitment.
Secondary outcome [1] 412455 0
The proportion of Maori or Pacific women recruited compared to the proportion of Maori or Pacific women in the local and national population of women who have given birth; assessed by audit of the study recruitment log, and by accessing hospital records.
Timepoint [1] 412455 0
Upon completion of recruitment.
Secondary outcome [2] 412456 0
The completion rate of haemoglobin measurements, by audit of the study database.
Timepoint [2] 412456 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [3] 412457 0
The completion rate of ferritin measurement, by audit of the study database.
Timepoint [3] 412457 0
At baseline and at follow-up visits at 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [4] 412458 0
The completion rate of MFI measurements, by audit of the study database.
Timepoint [4] 412458 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [5] 412459 0
The completion rate of EPDS measurements, by audit of the study database.
Timepoint [5] 412459 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [6] 412460 0
The completion rate of baby-feeding code measurements, assessed by audit of the study database.
Timepoint [6] 412460 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [7] 412461 0
Differences in physical fatigue scores between each intervention arm, at each time-point. Physical fatigue is measured on a sub-scale of the validated Multidimensional Fatigue Inventory (MFI).
Timepoint [7] 412461 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention
Secondary outcome [8] 412462 0
Differences in mean change in haemoglobin blood sample concentrations from baseline, between each intervention arm, at each time-point..
Timepoint [8] 412462 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [9] 412463 0
Changes in ferritin levels assessed using a blood sample.
Timepoint [9] 412463 0
At baseline and at follow-up visits at 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [10] 412607 0
Changes in the Edinburgh Postnatal Depression Score.
Timepoint [10] 412607 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [11] 412629 0
Changes in babyfeeding codes at all time-points from baseline, assessed by audit of study-specific log for each participant..
Timepoint [11] 412629 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [12] 412630 0
The number and type of treatment related adverse events and reactions from the administration of interventions until completion of the study.

Known serious adverse reactions (SARs) for RBC-T include transfusion related acute lung injury, severe allergic reactions, and haemolytic reactions. The most known SAR for FCM is anaphylactic reaction.

Adverse events and reactions will be assessed by physical examination and by participant self-reporting, and defined in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0)

https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf
Timepoint [12] 412630 0
From baseline to completion of the study at 12 weeks post-intervention.
Secondary outcome [13] 412631 0
The enablers and barriers to recruitment for women, assessed by a semi-structured study-specific questionnaire.
Timepoint [13] 412631 0
For women randomised to the trial enablers and barriers will be assessed at baseline.

For women who decline randomisation, but consent to a questionnaire, enablers and barriers will be assessed following the invitation to participate.
Secondary outcome [14] 412632 0
The enablers and barriers to recruitment for healthcare professionals or research personnel, including acceptable inclusion and exclusion criteria for recruitment to the future definitive FIT Trial; assessed by a semi-structured study-specific questionnaire.
Timepoint [14] 412632 0
From commencement of the the study to completion of follow-up in all participants.
Secondary outcome [15] 412633 0
The number of sites that are willing to participate assessed by audit of the study database.
Timepoint [15] 412633 0
From commencement of the the study to completion of follow-up in all participants.
Secondary outcome [16] 412644 0
The prescription and use of oral iron, assessed by audit of study-specific log for each participant.
Timepoint [16] 412644 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [17] 412645 0
The use of additional IV-iron and RBC-T (protocol violation), assessed by audit of study-specific log for each participant.
Timepoint [17] 412645 0
At baseline and at follow-up visits at 1 week (± 2 days), 6 weeks (± 3 days), and 12 weeks (± 1 week) post-intervention.
Secondary outcome [18] 412646 0
The number of women who are ineligible to participate because they have already received IV-iron or RBC-T, assessed by audit of the study database.
Timepoint [18] 412646 0
From commencement of the the study to completion of recruitment in all participants.

Eligibility
Key inclusion criteria
Postpartum women with liveborn babies less than or equal to 20 weeks gestation, regardless of mode of birth, at participating sites.

Inclusion criteria
• Within one week (less than or equal to 7 days) of birth
• Any Hb 65-79 g/L
• Clinically stable as determined by the treating clinician
• Suitable to receive either IV-iron and/or RBC-T as determined by treating clinician
• Able to provide informed consent
Minimum age
16 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
• Ongoing heavy bleeding
• Already received IV-iron and/or RBC-T as a treatment for peripartum and/or PPA
• Aged <16 years
• Religious, cultural or other objections to RBC-T or IV-iron
• IV-iron in preceding month
• History of anaemia other than iron-deficiency anaemia i.e. thalassemia or other haemoglobinopathies
• Haemochromatosis
• Known contraindications and precautions to IV-iron: history of hypersensitivity to IV-iron; iron overload (or disturbance in utilisation of iron), bacteremia, hypophosphataemia or hepatic or renal impairment
• Renal impairment, history of cardiac or respiratory failure, heart surgery, organ transplant.
• RBC-T contraindicated i.e. history of previous serious reaction to RBC-T

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 computer-generated randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The block method of restricted randomisation using block sizes of 3,6 and 9.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
A formal sample size calculation is not required for pilot trials and feasibility studies, as per CONSORT guidelines (1). The sample size will be determined by the study duration of three months.

The data analysis is pre-specified. All of the data will be analysed as a single group, except for the secondary outcomes of comparing physical fatigue, haemoglobin and ferritin levels which will be analysed by intervention arm.

The primary outcome will be considered as an overall recruitment rate and of those approached, with a secondary outcome assessing recruitment rates for Maori and Pacific women.

Descriptive analyses will be used to summarise the demographic data, obstetric data, baseline data and follow-up data including haemoglobin and ferritin levels, MFI, EPDS and babyfeeding codes.

The primary outcome of pilot trial recruitment rate will be calculated based on the number of recruited participants/the number of women approached or referred to participate. The overall estimated recruitment rate will be calculated based on the number of participants recruited/the number of broadly eligible (Hb 65-79 g/L) women birthing in the same study period within 1 week of birth, at the participating site.

Secondary outcome analyses for physical fatigue will be made by repeated measures of fatigue scores in analysis of variance (ANOVA) over each time-point; with baseline physical fatigue as the covariate. If a significant difference is found among the intervention arms a multiple comparison, or pairwise comparison, will be undertaken as a post-hoc test. Significance will be set at an alpha level of 0.05.

For analyses of the secondary outcome of haemoglobin, repeated measures of haemoglobin levels will be analysed in ANOVA over each time-point, with baseline haemoglobin as the covariate. If a significant difference is found, post-hoc multiple comparisons will be undertaken. For haemoglobin, the primary end-point for potential effectiveness of the study intervention will be assessed as the mean change from baseline to the six-week time-point.

Data will be analysed using IBM SPSS (Version 28) statistical software.

(1) Eldridge S, Chan C, Campbell M, Bond C, Hopewell S, Thabane L, et al. CONSORT extension for Pilot and Feasibility Trials Checklist. Vol. 355, Bmj. 2016.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/09/2022
Actual
Date of last participant enrolment
Anticipated
30/11/2022
Actual
Date of last data collection
Anticipated
22/02/2023
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment outside Australia
Country [1] 24928 0
New Zealand
State/province [1] 24928 0

Funding & Sponsors
Funding source category [1] 311957 0
Government body
Name [1] 311957 0
Health Research Council of New Zealand
Country [1] 311957 0
New Zealand
Primary sponsor type
University
Name
Liggins Institute, University of Auckland
Address
85 Park Road
Grafton
Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 313443 0
None
Name [1] 313443 0
NA
Address [1] 313443 0
NA
Country [1] 313443 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311388 0
Southern Health and Disability Ethics Committees
Ethics committee address [1] 311388 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 311388 0
New Zealand
Date submitted for ethics approval [1] 311388 0
08/07/2022
Approval date [1] 311388 0
Ethics approval number [1] 311388 0

Summary
Brief summary
Currently, the treatment options for clinically stable women with moderate-to-severe postpartum anaemia (PPA, haemoglobin (Hb) <90 g/L) are largely between intravenous iron (IV-iron), red blood cell transfusion (RBC-T), or a combination of both. Our recent observational study found regional variation in the management of moderate-to-severe PPA, including by ethnicity. Overall, Maori and Pacific women had more anaemia before and after birth, and received more IV-iron and less RBC-T than European women. A lack of high-quality evidence on the comparative effectiveness and risks of treatment approaches for women with moderate-to-severe PPA is likely to be a significant contributor to the inconsistency in clinical management. This lack of high-quality evidence includes women-centred outcomes linked to PPA, such as fatigue, postnatal depression and breastfeeding, as well as haematological outcomes. These outcomes are important because the impact of fatigue, postnatal depression and impaired breastfeeding may have long-term consequences for mothers and babies.

To create gold-standard evidence to direct future practice, an appropriately powered randomised trial is needed and should explore outcomes of importance to women, as well as to healthcare practitioners and service providers. However, there are indications that recruitment to a randomised trial may be challenging.

We are therefore planning the FIT Pilot Trial and Feasibility Study to further understand the enablers and barriers to participation and to optimise the success of a larger, future FIT Trial. We have applied a health equity lens in the planning of the FIT Pilot Trial, to maximise participation for all women with PPA especially those who currently have less advantage in this area.

The research aim is to assess the feasibility of the FIT Trial and to optimise future study design by undertaking the FIT Pilot Trial and Feasibility Study. The research question is: Can we recruit women and health care professionals to participate in a three-armed trial of IV iron alone, IV-iron and RBC-T in combination, or RBC-T alone, for clinically stable women with moderate-to-severe PPA?

The primary objective is to determine the number of women willing to be recruited, and the recruitment rate, to a three-armed randomised trial of IV-iron, IV-iron and RBC-T or RBC-T.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120918 0
Ms Esther Caljé
Address 120918 0
Liggins Institute, The University of Auckland
Level 2, Building 503
85 Park Road, Grafton, Auckland 1023
Private Bag 92019, Auckland 1142
Country 120918 0
New Zealand
Phone 120918 0
+64 09 9236691
Fax 120918 0
Email 120918 0
[email protected]
Contact person for public queries
Name 120919 0
Esther Caljé
Address 120919 0
Liggins Institute, The University of Auckland
Level 2, Building 503
85 Park Road, Grafton, Auckland 1023
Private Bag 92019, Auckland 1142
Country 120919 0
New Zealand
Phone 120919 0
+64 09 9236691
Fax 120919 0
Email 120919 0
[email protected]
Contact person for scientific queries
Name 120920 0
Esther Caljé
Address 120920 0
Liggins Institute, The University of Auckland
Level 2, Building 503
85 Park Road, Grafton, Auckland 1023
Private Bag 92019, Auckland 1142
Country 120920 0
New Zealand
Phone 120920 0
+64 09 9236691
Fax 120920 0
Email 120920 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 underlying published results only.
When will data be available (start and end dates)?
Beginning immediately following publication and ending 10 years following publication of main results
Available to whom?
Published data will only be available to approved researchers under specific data-sharing arrangements as provided by the Clinical Data Research Hub, based at the Liggins Institute, University of Auckland (https://wiki.auckland.ac.nz/researchhub).
Available for what types of analyses?
Data will be made available for research on postpartum anaemia, including IPD analysis.
How or where can data be obtained?
Published data will only be available to approved researchers under specific data-sharing arrangements as provided by the Clinical Data Research Hub, based at the Liggins Institute, University of Auckland (https://wiki.auckland.ac.nz/researchhub).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16785Study protocol  [email protected] 384465-(Uploaded-01-08-2022-13-27-58)-Study-related document.docx



Results publications and other study-related documents

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