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Trial registered on ANZCTR


Registration number
ACTRN12621001239853
Ethics application status
Approved
Date submitted
13/07/2021
Date registered
14/09/2021
Date last updated
14/09/2021
Date data sharing statement initially provided
14/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women in their third trimester: REVAMP-TT
Scientific title
Effectiveness of intravenous iron administered during the third trimester in Malawian women in the management of anaemia: a 4-year, multicentre, parallel-group, two-arm, open-label randomised controlled superiority trial
Secondary ID [1] 304755 0
Nill
Universal Trial Number (UTN)
Trial acronym
REVAMP-TT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia 322795 0
Iron-deficiency 322796 0
Hypophosphataemia 322797 0
Foetal anaemia 322798 0
Infection 322799 0
Child development 322800 0
Maternal depression 322801 0
Condition category
Condition code
Blood 320388 320388 0 0
Anaemia
Mental Health 320389 320389 0 0
Depression
Reproductive Health and Childbirth 320390 320390 0 0
Other reproductive health and childbirth disorders
Infection 320787 320787 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Intravenous Ferric Carboxymaltose (1000 mg for bodyweight > 50 Kg, or 20 mg/Kg for bodyweight < 50 Kg) given once at enrolment as a single infusion over 15 min.

Intervention code [1] 321136 0
Treatment: Drugs
Comparator / control treatment
Arm 2: Oral iron tablets containing 200 mg Ferrous Sulphate (approx. 65 mg of elemental iron) twice daily for 90 days or the duration of pregnancy, whichever is shorter.

Women randomised to the oral iron arm of the study will be encouraged to provide any remaining iron tablets so that a pill count can be done to assess their adherence to the treatment.
Control group
Active

Outcomes
Primary outcome [1] 328223 0
Proportion of women with pre-delivery anaemia (defined as a venous haemoglobin value < 11 g/dL).

This will be determined by a Sysmex haematology analyser.
Timepoint [1] 328223 0
36-weeks gestation
Secondary outcome [1] 398135 0
The proportion of women with maternal iron deficiency (ferritin<15 mg/L, sTfR/Ferritin index).

Iron indices will be measured in an accredited laboratory using serum samples in automated platforms (e.g. Modular P800 and Modular Analytics E170 systems (Roche))
Timepoint [1] 398135 0
36 weeks’ gestation
Secondary outcome [2] 398137 0
Mean levels of maternal iron biomarkers (Ferritin and sTfR). Iron biomarkers will be measured in an accredited laboratory using serum samples in automated platforms (e.g. Modular P800 and Modular Analytics E170 systems (Roche))
Timepoint [2] 398137 0
36 weeks’ gestation
Secondary outcome [3] 398138 0
Proportion of women with maternal inflammation (using C-reactive protein). This will be measured using laboratory analysis of patient samples.
Timepoint [3] 398138 0
36 weeks’ gestation
Secondary outcome [4] 398139 0
Proportion of women with maternal postpartum haemorrhage, assessed through the participant's patient medical record. When the participant delivers outside the health facility this will be self-reported and noted as such.
Timepoint [4] 398139 0
Following delivery
Secondary outcome [5] 398140 0
Mean change from baseline in maternal Hb. This will be determined by a Sysmex haematology analyser.
Timepoint [5] 398140 0
1, 3, 6, 9 and 12 months postpartum
Secondary outcome [6] 398141 0
Proportion of women with maternal anaemia. This will be determined by a Sysmex haematology analyser.
Timepoint [6] 398141 0
1, 3, 6, 9 and 12 months postpartum
Secondary outcome [7] 398142 0
Mean levels of iron biomarkers (Ferritin, Transferrin saturation). These will be measured in an accredited laboratory using serum samples in automated platforms (e.g. Modular P800 and Modular Analytics E170 systems (Roche)). Maternal postpartum outcome.
Timepoint [7] 398142 0
1, 3, 6, 9 and 12 months postpartum
Secondary outcome [8] 398143 0
Proportion of women with iron deficiency (defined by ferritin<15mg/L), as measured in an accredited laboratory using serum samples in automated platforms (e.g. Modular P800 and Modular Analytics E170 systems (Roche))
Timepoint [8] 398143 0
1, 3, 6, 9 and 12 months postpartum
Secondary outcome [9] 398144 0
Proportion of women with postpartum depression (defined by EDPS > 13)
Timepoint [9] 398144 0
3 months postpartum
Secondary outcome [10] 398145 0
The proportion of women with maternal inflammation (defined by C-reactive protein). Determined by laboratory testing of the participant's serum sample.
Timepoint [10] 398145 0
3 months postpartum
Secondary outcome [11] 398146 0
Mean gestation duration (in weeks), assessed by reviewing the LNMP and reviewing the participants medical and trial records.
Timepoint [11] 398146 0
delivery
Secondary outcome [12] 398147 0
Proportion of sub-optimal pregnancy outcomes (defined as a composite outcome: low birthweight (<2500g); prematurity (birth <37 weeks); small for gestational age (centile score) as defined by International reference standards for gestational age-specific birthweight; stillbirth). Individual outcomes will be assessed via LNMP, fundal height, SECA scale weighting, revision of medical and trial records.
Timepoint [12] 398147 0
Delivery
Secondary outcome [13] 398148 0
Proportion of neonates born prematurely (defined as birth before 37 week’s gestation), assessed by reviewing the LNMP and reviewing the participants medical and trial records.
Timepoint [13] 398148 0
Delivery
Secondary outcome [14] 398149 0
Proportion of infants with low birth weight (defined as a birth weight <2500g). This will be assessed by reviewing the participant's medical records.
Timepoint [14] 398149 0
Delivery
Secondary outcome [15] 398150 0
Proportion of stillbirth. Assessed after reviewing the participants medical and trial records.
Timepoint [15] 398150 0
Delivery
Secondary outcome [16] 398151 0
Proportion of neonatal mortality. Assessed after reviewing the participants medical and trial records.
Timepoint [16] 398151 0
Delivery
Secondary outcome [17] 398152 0
Mean cord blood Hb. This will be determined by a Sysmex haematology analyser.
Timepoint [17] 398152 0
Delivery
Secondary outcome [18] 398153 0
Proportion of neonates with anaemia (with correction for gestational age). This will be determined by a Sysmex haematology analyser and after reviewing the participant's medical and trial records for gestational age determination.
Timepoint [18] 398153 0
Delivery
Secondary outcome [19] 398154 0
Child development scores measured by Evoked Response Potentials (ERP)
Timepoint [19] 398154 0
6 months and 12 months
Secondary outcome [20] 398155 0
Child development scores measured by Bayley Scales of Infant and Toddler development and the Malawi Development Assessment Tool
Timepoint [20] 398155 0
6 months and 12 months of age
Secondary outcome [21] 398156 0
Mean child physical growth as defined by z-scores. Weight will be measured via SECA scales, an infantometer will be used for length and a tape measure will be used for MUAC and head circumference.
Timepoint [21] 398156 0
1, 6 and 12 months of age
Secondary outcome [22] 398157 0
Mean infant haemoglobin. This will be determined by a Sysmex haematology analyser.
Timepoint [22] 398157 0
6 and 12 months of age
Secondary outcome [23] 398158 0
Proportion of infants with anaemia. This will be determined by a Sysmex haematology analyser.
Timepoint [23] 398158 0
6 and 12 months postpartum
Secondary outcome [24] 398159 0
Mean levels of infant iron biomarkers (Ferritin, Transferrin saturation). This will be measured in an accredited laboratory using serum samples in automated platforms (e.g. Modular P800 and Modular Analytics E170 systems (Roche)).
Timepoint [24] 398159 0
6 and 12 months of age
Secondary outcome [25] 398160 0
Proportion of infants with iron deficiency, as measured in an accredited laboratory using serum samples in automated platforms (e.g. Modular P800 and Modular Analytics E170 systems (Roche))
Timepoint [25] 398160 0
6 and 12 months of age
Secondary outcome [26] 398161 0
Proportion of women with at least one treatment-related adverse effect. Examples include Headache, dizziness, Injection site reactions, Hypertension, Elevated liver enzymes, Hypophosphataemia. These will be assessed via direct observation, self-report and after reviewing medical records.
Timepoint [26] 398161 0
immediately post-infusion and within 7 days of commencement of treatment.
Secondary outcome [27] 398162 0
Incidence of treatment-related adverse effects on the mother, assessed by direct observation, and by self-report.
Timepoint [27] 398162 0
immediately post-infusion, and within 7 days of commencement of treatment
Secondary outcome [28] 398163 0
Number of unplanned visits to the clinic (cause-specific for diarrhoea and clinical malaria), as recorded by the trial clinician and by self-report and reviewing of medical records.
Timepoint [28] 398163 0
Duration of trial
Secondary outcome [29] 398164 0
Incidence of all-cause sick clinic visits assessed by reviewing a participant's medical records and by self-report at scheduled visits.
Timepoint [29] 398164 0
during the entire duration of a participant's trial participation, including antenatal, postpartum and overall follow-up period (up to 1 year after birth).
Secondary outcome [30] 398165 0
The proportion of women with placental malaria (past or active infection on histology, parasites on placental blood film). This will be assessed by evaluating haemotoxylin and Eosin stained FFPE placental slides from collected tissue.
Timepoint [30] 398165 0
Delivery
Secondary outcome [31] 398166 0
Proportion of women with malaria parasitaemia (asymptomatic) detected by a) microscopy, b) rapid diagnostic tests, and c) PCR.
Timepoint [31] 398166 0
36 weeks’ gestation,
Secondary outcome [32] 398167 0
Proportion of women with bacteraemia, assessed for those participants with clinical symptoms and confirmed positive blood culture.
Timepoint [32] 398167 0
36 weeks’ gestation
Secondary outcome [33] 398168 0
Proportion of women with hypophosphatemia (clinical and biochemical), assessed clinically and by laboratory serum analysis.
Timepoint [33] 398168 0
36 weeks’ gestation and 3 months postpartum.
Secondary outcome [34] 398171 0
Number of unplanned infant visits to the clinic (cause specific for diarrhea and clinical malaria), as recorded by the trial clinician and by self-report and reviewing of medical records.
Timepoint [34] 398171 0
From delivery to 12 months of age
Secondary outcome [35] 398172 0
Incidence of all-cause sick clinic visits in infant, as recorded by the trial clinician and by self-report and reviewing of medical records.
Timepoint [35] 398172 0
by 12 months of age.
Secondary outcome [36] 398174 0
Proportion of infants with malaria parasitaemia (asymptomatic) detected by a) microscopy, b) rapid diagnostic tests, and c) PCR.
Timepoint [36] 398174 0
1, 3, 6, 9 and 12 months of age
Secondary outcome [37] 400881 0
Mean cord blood ferritin, as measured in an accredited laboratory using cord serum samples in automated platforms (e.g. Modular P800 and Modular Analytics E170 systems (Roche))
Timepoint [37] 400881 0
At delivery.

Eligibility
Key inclusion criteria
Confirmed singleton pregnancy in the third trimester (27-35 weeks of gestation, dated by Last Menstrual Period)

Moderate to severe anaemia not requiring an immediate blood transfusion (Hb <10 g/dl)

Negative malaria parasitaemia by mRDT

Currently afebrile with no evidence of septicaemia

Resident in the study catchment area of Zomba district (Malawi)

Able to deliver at health facilities within Zomba district (Malawi)

Written informed consent (including assent if <18 years old)
Minimum age
No limit
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Previous enrolment in REVAMP trial – ACTRN12618001268235.

Actively participating in another intervention trial.

Known hypersensitivity to any of the study drugs.

Clinical symptoms of malaria or other infection (no fever, no focal symptoms of internal infection i.e. LRTI/ diarrhoea).

Any condition requiring hospitalisation in the next seven days or serious concomitant illness.

Known history of sickle cell or sickle-haemoglobin C anaemia.

Clinically low haemoglobin level requiring a blood transfusion (usually Hb <5g/dl).

Preeclampsia

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)
Participants will be randomly allocated to one of the two treatments arms with 1:1 allocation via a computer-generated randomisation schedule of randomly permuted blocks stratified by site to achieve balance between the arms within each site.

Individual participant codes will be pre-packed in envelopes, sealed and held securely at research sites. The eligible participants who have met all inclusion/exclusion criteria will receive study medication assigned to the next available randomisation number during the randomisation study visit. The study medication shall be determined after the research staff open the specific participant envelope, which will prescribe the participant’s group allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation list will be generated by an independent statistician at the University of Melbourne (Australia) who will not reveal the block size until the database is ready for unblinding.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We plan to recruit 295 women per arm, or 590 women in total when accounting for 10% drop-out by week 36 (primary outcome timepoint).

For our primary outcome of maternal anaemia at 36 weeks gestation, we will be able to detect a reduction in the proportion of women with anaemia (Hb<11g/dL) at 36 weeks gestation from 63% in the oral iron arm to 49% in the IV iron arm with 90% power (two-sided 5%). We assumed that the mean Hb in oral iron treated women is 10.5g/dL and the standard deviation (SD) is 1.5g/dL, thus 63% of women are expected to be anaemic (Hb<11g/dL) at 36 weeks after oral iron. We assumed that the prevalence of anaemia in IV iron treated women would be 14% lower than that of women in the oral iron arm following the pivotal FCM vs oral iron trial.

Assessment of effectiveness: Descriptive statistics will be presented for all outcomes, by treatment group across the follow-up time points. Anaemia will be analysed using a log-binomial regression model with study participants included as a random intercept. The model will include the standard of care (oral iron) group as the reference group. The primary maternal hypothesis will be evaluated by obtaining the estimate of the risk ratio of IV iron versus standard of care (oral iron) and two-sided 95% confidence interval extracted at 36 weeks’ gestation. Birthweight will be analysed by fitting a linear regression model. The primary neonatal hypothesis will be evaluated by estimating the absolute difference in birthweight between IV iron and standard care (oral iron) and two-sided 95% confidence interval. Secondary repeated time point binary outcomes will be analysed similar to anaemia and secondary single time point continuous outcomes will be analysed similar to birthweight. Secondary, single time point binary outcomes (e.g., low birth weight) will be analysed using a log-binomial regression model and secondary, multiple time point continuous outcomes (e.g., haemoglobin) will be analysed using a likelihood-based longitudinal data analysis model91. Appropriate transformations may be applied to the variables before fitting the model if considered skewed (e.g. ferritin). In case of non-convergence of the log-binomial models, a Poisson model with robust standard errors will be fitted instead. Exploratory subgroup analyses (e.g., site, parity, iron deficiency) will be performed for maternal and neonatal outcomes, irrespective of their findings. The analyses models for all study outcomes will adjust for the randomisation stratification variables of site as a main effect.


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 outside Australia
Country [1] 23953 0
Malawi
State/province [1] 23953 0
Zomba

Funding & Sponsors
Funding source category [1] 309128 0
Charities/Societies/Foundations
Name [1] 309128 0
Bill and Melinda Gates Foundation
Address [1] 309128 0
PO Box 23350
Seattle, WA 98102
Country [1] 309128 0
United States of America
Primary sponsor type
Other
Name
Training and Research Unit of Excellence (TRUE), Malawi
Address
P.O Box 30538, Chichiri, Blantyre 3, Malawi
Country
Malawi
Secondary sponsor category [1] 310079 0
None
Name [1] 310079 0
Address [1] 310079 0
Country [1] 310079 0
Other collaborator category [1] 281911 0
University
Name [1] 281911 0
University of Melbourne
Address [1] 281911 0
792 Elizabeth St, Melbourne VIC 3000
Country [1] 281911 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308994 0
National Health Science Research Council - Malawi
Ethics committee address [1] 308994 0
1st Floor Lingadzi House, Robert Mugabe Crescent, Private Bag B303, Lilongwe 3,
Ethics committee country [1] 308994 0
Malawi
Date submitted for ethics approval [1] 308994 0
19/11/2020
Approval date [1] 308994 0
20/04/2021
Ethics approval number [1] 308994 0
20/11/2622
Ethics committee name [2] 309000 0
WEHI - HRC
Ethics committee address [2] 309000 0
WEHI - 1G Royal Parade
Parkville VIC 3052
Australia
Ethics committee country [2] 309000 0
Australia
Date submitted for ethics approval [2] 309000 0
09/07/2021
Approval date [2] 309000 0
Ethics approval number [2] 309000 0

Summary
Brief summary
Antenatal anaemia causes significant risks for both mother and child by amplifying the risks and consequences of serious complications for mothers and their babies. Across Africa, few women receive or take the full recommended course of antenatal oral iron and may present for their initial visit far into the second trimester.

We hypothesise that intravenous iron, given as a single rapid infusion of Ferric Carboxymaltose, can assist mothers recovering from anaemia and is superior to the standard of care oral iron tablets.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112590 0
A/Prof Sant-Rayn Pasricha
Address 112590 0
Population Health and Immunity/ Infection and Immunity Divisions
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Australia
Country 112590 0
Australia
Phone 112590 0
+61 393452618
Fax 112590 0
Email 112590 0
pasricha.s@wehi.edu.au
Contact person for public queries
Name 112591 0
A/Prof Sant-Rayn Pasricha
Address 112591 0
Population Health and Immunity/ Infection and Immunity Divisions
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Australia
Country 112591 0
Australia
Phone 112591 0
+61 393452618
Fax 112591 0
Email 112591 0
pasricha.s@wehi.edu.au
Contact person for scientific queries
Name 112592 0
A/Prof Sant-Rayn Pasricha
Address 112592 0
Population Health and Immunity/ Infection and Immunity Divisions
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Australia
Country 112592 0
Australia
Phone 112592 0
+61 393452618
Fax 112592 0
Email 112592 0
pasricha.s@wehi.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All data pertaining to trial outcomes and underlying any publication.
When will data be available (start and end dates)?
Up to two years after completion of the trial.
November 2024 - November 2026
Available to whom?
researchers who provide a methodologically sound proposal
Available for what types of analyses?
to achieve the aims in any approved proposal that we receive and for IPD meta-analyses
How or where can data be obtained?
Any requests can be directed to A/Prof Sant-Rayn Pasricha:
Dr Sant-Rayn Pasricha
Population Health and Immunity/ Infection and Immunity Divisions
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville VIC 3052
Australia
Australia
+61393452618
pasricha.s@wehi.edu.au
What supporting documents are/will be available?
No other documents available
Summary results
No Results