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Trial registered on ANZCTR


Registration number
ACTRN12618001268235
Ethics application status
Approved
Date submitted
17/07/2018
Date registered
27/07/2018
Date last updated
26/11/2018
Date data sharing statement initially provided
26/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women
Scientific title
Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women
Secondary ID [1] 295538 0
Nil
Universal Trial Number (UTN)
U1111-1217-3954
Trial acronym
REVAMP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia 308801 0
Low birth weight 308802 0
Prematurity 308803 0
Small for Gestational Age 308805 0
Maternal haemorrhage 308806 0
Fatigue 308868 0
Iron Deficiency 308870 0
Maternal mortality 308875 0
Infant anaemia 308880 0
Infant iron deficiency 308881 0
Condition category
Condition code
Blood 307736 307736 0 0
Anaemia
Reproductive Health and Childbirth 307737 307737 0 0
Normal pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be assigned to receive the following:
Intravenous iron treatment: intravenous ferric carboxymaltose 1000mg (weight >50kg) or 20mg/kg (weight <50kg) given over 15min once at recruitment (Day 0);
Intervention code [1] 301880 0
Treatment: Drugs
Comparator / control treatment
Oral iron treatment course: oral iron- 200mg ferrous sulphate (approx. 65mg elemental iron) given as tablets twice daily for 90 days (reaching a total dose of approx. 11.7g), for the remaining duration of pregnancy, whichever is shorter. Adherence will be monitored by pill counting at the 34 week home visit.
Control group
Active

Outcomes
Primary outcome [1] 306776 0
Prevalence of maternal anaemia (Hb <11.0g/dl) at timepoint closest to delivery as measured by HemoCue measurement, by trial staff.
Timepoint [1] 306776 0
Capillary haemoglobin measured at the visit closest to delivery; home visits will occur every 2 weeks from week 34 gestation onwards.
Secondary outcome [1] 349556 0
Maternal fatigue measured by the Piper Fatigue Scale-12
Timepoint [1] 349556 0
4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks gestation, 4 weeks post partum
Secondary outcome [2] 349557 0
Maternal haemoglobin as measured on venous blood via automated analyser.
Timepoint [2] 349557 0
4 weeks post intervention (for both IV iron and commencement of oral iron), week 36, at delivery, 4 weeks post partum
Secondary outcome [3] 349559 0
Maternal anaemia (Hb<11g/dL) as measured on venous blood via automated analyser.
Timepoint [3] 349559 0
4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks, at delivery, 4 weeks post partum
Secondary outcome [4] 349560 0
Maternal cognitive function using digit span forward and backward test, and mental rotation tests.
Timepoint [4] 349560 0
4 weeks post intervention (for both IV iron and commencement of oral iron), 4 weeks post partum
Secondary outcome [5] 349561 0
Maternal iron deficiency (defined by i) ferritin<15mg/L, and ii) sTfR/Ferritin index – assay dependent cut-off)
Timepoint [5] 349561 0
4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks, at delivery, 4 weeks post partum
Secondary outcome [6] 349564 0
Severe anaemia requiring blood transfusion as defined by clinical notes
Timepoint [6] 349564 0
From randomisation (receipt of oral or intravenous iron depending on allocation) to 4 weeks post partum
Secondary outcome [7] 349565 0
Severe medical events: shock (systolic blood pressure <90mmHg), need for blood transfusion, ICU admission, or mortality: individually and as a composite outcome, based on direct clinical observation by study staff,
Timepoint [7] 349565 0
From randomisation to 4 weeks post partum
Secondary outcome [8] 349568 0
Birth weight (as a continuous variable) using infant scales
Timepoint [8] 349568 0
Within 24 hours of birth
Secondary outcome [9] 349570 0
Low birth weight (birth weight <2500g) as a dichotomous variable
Timepoint [9] 349570 0
Within 24 hours of birth
Secondary outcome [10] 349573 0
Gestational-age (based on baseline ultrasound dating of pregnancy) adjusted birth weight
Timepoint [10] 349573 0
<24 hours following birth
Secondary outcome [11] 349574 0
Small for gestational age as a dichotomous variable (<10th centile)
Timepoint [11] 349574 0
<24 hours following birth
Secondary outcome [12] 349575 0
Abortion - pregnancy loss before 28 completed weeks of gestation, as reported by patient or based on clinical records, or as observed by study staff.
Timepoint [12] 349575 0
<28 weeks gestation
Secondary outcome [13] 349576 0
Stillbirth – defined as the birth of a baby showing no signs of life after 28 weeks of gestation (>28 weeks), as reported by patient, based on clinical records, or as observed by study staff..
Timepoint [13] 349576 0
>28 weeks gestation
Secondary outcome [14] 349577 0
Gestation duration based on calculated duration of gestation, using dating at baseline ultrasound examination to date of actual delivery.
Timepoint [14] 349577 0
Delivery visit
Secondary outcome [15] 349578 0
Premature birth – neonate born prior to 37 completed weeks of gestation (including 36weeks and 6 days), based on gestation duration.
Timepoint [15] 349578 0
Delivery visit
Secondary outcome [16] 349579 0
Cord venous blood haemoglobin by automated analyser
Timepoint [16] 349579 0
Delivery
Secondary outcome [17] 349580 0
Infant haemoglobin (measurement of haemoglobin on venous blood by automated analyser)
Timepoint [17] 349580 0
1 month post partum
Secondary outcome [18] 349581 0
Adverse events, as recorded by direct questioning of participants during administration visit. Such adverse events may include flushing, rash, allergic reactions, headache etc.
Timepoint [18] 349581 0
Time of administration of intervention
Secondary outcome [19] 349582 0
Incidence of all-cause sick visits to the clinic based on visits recorded by study staff at the study clinic
Timepoint [19] 349582 0
Randomisation to delivery
Secondary outcome [20] 349583 0
The incidence of diarrhoea sick visits to the clinic based on visits recorded by study staff at the study clinic
Timepoint [20] 349583 0
Randomisation to delivery
Secondary outcome [21] 349584 0
The incidence of clinical malaria-specific sick visits to the clinic based on visits recorded by study staff at the study clinic
Timepoint [21] 349584 0
Randomisation to delivery
Secondary outcome [22] 349585 0
Incidence of placental malaria at delivery based on placental histologic examination
Timepoint [22] 349585 0
Delivery
Secondary outcome [23] 349586 0
Incidence of peripheral parasitaemia by 36 weeks of gestation based on blood film microscopy
Timepoint [23] 349586 0
Randomisation to 36 weeks gestation
Secondary outcome [24] 349587 0
Incidence of cord blood parasitaemia at delivery based on blood film microscopy
Timepoint [24] 349587 0
Delivery
Secondary outcome [25] 349588 0
Prevalence of malaria parasitaemia based on blood film microscopy at each scheduled visit
Timepoint [25] 349588 0
4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks, at delivery, 4 weeks post partum
Secondary outcome [26] 349589 0
Hypophosphatemia based on biochemical measurement of serum Phosphate.
Timepoint [26] 349589 0
4 weeks post intervention (for both Iv iron and commencement of oral iron), 36 weeks
Secondary outcome [27] 349590 0
Maternal inflammation (elevated C-reactive protein by serum assay)
Timepoint [27] 349590 0
4 weeks post intervention (for both Iv iron and commencement of oral iron), 36 weeks gestation
Secondary outcome [28] 349591 0
Health systems costs of providing the treatments and follow-up for the intervention and comparator based on measurement of resource use and costing of relevant resources, with direct measurement of health care resource utilisation.
Timepoint [28] 349591 0
Each planned visit that coincides with a pregnancy visit (baseline (second trimester), week 36, delivery), unplanned visits (e.g. during any episode of infection requiring management).
Secondary outcome [29] 349592 0
Direct and indirect patient costs including patient out-of-pocket costs for both health care and other costs e.g. transport/ food, and lost income for receiving the intervention and the comparator
Timepoint [29] 349592 0
Each planned visit that coincides with a pregnancy visit (baseline (second trimester), week 36, delivery), unplanned visits (e.g. during any episode of infection requiring management).
Secondary outcome [30] 350004 0
Infant ferritin (serum ferritin)
Timepoint [30] 350004 0
1 month of age
Secondary outcome [31] 350005 0
Cord ferritin by serum ferritin
Timepoint [31] 350005 0
Delivery
Secondary outcome [32] 350006 0
Maternal haemorrhage - antepartum or post partum haemorrhage diagnosed by study clinical staff
Timepoint [32] 350006 0
Randomisation to 4 weeks post partum
Secondary outcome [33] 350007 0
Maternal mortality
Timepoint [33] 350007 0
Maternal death from randomisation to 1 month post partum
Secondary outcome [34] 350008 0
Neonatal mortality, as observed by study staff/ clinical notes
Timepoint [34] 350008 0
Death of child in the first month of life
Secondary outcome [35] 350009 0
Maternal shock defined by systolic blood pressure <90mmHg, as observed by study staff
Timepoint [35] 350009 0
Randomisation to 1 month post partum
Secondary outcome [36] 350010 0
Maternal intensive care admission as observed by study staff
Timepoint [36] 350010 0
Recruitment to 1 month post partum
Secondary outcome [37] 350011 0
Neonatal intensive care admission as observed by study staff
Timepoint [37] 350011 0
Birth to 1 month post partum
Secondary outcome [38] 350012 0
Need for maternal blood transfusion, as observed by study staff
Timepoint [38] 350012 0
Recruitment to 1 month post partum
Secondary outcome [39] 350013 0
Maternal hospitalisation- any unplanned admission to hospital beyond usual post partum discharge procedures, as observed by study staff.
Timepoint [39] 350013 0
Following delivery
Secondary outcome [40] 350019 0
Delayed Adverse Events as detected by open questioning by study staff
Timepoint [40] 350019 0
Each scheduled visit (4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks, at delivery, 4 weeks post partum

Eligibility
Key inclusion criteria
Participants meeting the following criteria will be included in the trial:
1. Confirmed singleton pregnancy at 13-26 weeks gestation
2. Moderate to severe anaemia not requiring an immediate blood transfusion (Hb <10g/dl)
3. Negative malaria parasitaemia
4. Resident in the study catchment area of Blantyre and Zomba district
5. Plan to deliver at a health facility
6. 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
1. Hypersensitivity to any of the study drugs
2. Clinical symptoms of malaria or bacterial infection
3. Any condition requiring hospitalization or serious concomitant illness
4. Chronic illness that may adversely affect foetal growth and viability
5. Low haemoglobin with symptomatic severe anaemia, requiring a blood transfusion (usually Hb <5g/dl)
6. Previous history of pre-eclampsia

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified randomisation by centre (Blantyre/ Zomba)
Sequence generated by computerised sequence generation
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
Sample size is calculated based on the maternal primary outcome of anaemia at delivery. Haider et al identified a 50% reduction in anaemia prevalence in women receiving oral iron. In the proposed study, all women in the trial will have moderate to severe anaemia (Hb<10g/dL) at baseline. In a cohort of pregnant women in the Gambia, we observed that 60% of pregnant women with Hb<10g/dL at 20 weeks’ gestation who then receive iron interventions continue to have Hb<10g/dL by 30 weeks. The Fer-ASAP trial demonstrated a 14% reduction in absolute anaemia prevalence compared with oral iron. We hypothesise that routine iron supplementation will reduce anaemia prevalence from 100% to 60% (as seen in the Gambia, and similar to data from Haider et al). We hypothesize that ferric carboxymaltose will result in a 10% absolute improvement in anaemia cure (to a prevalence of 50%), as discussed above. To show this with 80% power at a two-sided alpha level of 5%, and incorporating a 10% loss to follow-up, we expect to require a total sample size of 862 pregnant women or 431 per arm is needed (using Pearson’s chi-square test). This sample size allows 86.5% power to detect the clinically meaningful effect size (100g) for birth weight. Finally, 80% power for anaemia and 86.5% power for birthweight means our trial will have 69% power to demonstrate both outcomes (if they are independent).

A detailed statistical analysis plan describing the proposed analyses will be finalised before the trial database is locked for final analysis. Analyses will be undertaken on an intention-to-treat basis (maternal outcomes: all women randomized; neonatal outcomes: all live-borns with the exception of the stillbirth outcome). Descriptive statistics will be presented for all outcomes, by treatment groups across the follow-up time points. The primary maternal outcome anaemia at pre-delivery (based on the capillary Hb closest prior to delivery) will be analysed using a binomial log-linear regression, with the oral iron group as the reference, and incorporating clinic and treatment in the model. The primary maternal hypothesis will be evaluated by obtaining the estimate of the risk ratio of IV iron versus oral iron and a 95% confidence interval. The secondary neonatal outcome birthweight will be analysed by fitting a linear regression model with a model specification similar to that of the primary maternal outcome. This hypothesis will be evaluated by obtaining the estimate of the absolute difference in birth weight between IV iron and oral iron and a 95% confidence interval. Other secondary binary outcomes will be analysed similarly as the primary maternal outcome and other secondary continuous outcomes as the birthweight outcome, where applicable also taking into account in the model the repeated data collection of the outcome. Missing values in all outcomes will be reported across treatment groups and follow-up time points. Multiple imputations under the missing at random assumption will be performed as a secondary analysis for handling missing data in the primary maternal and neonate outcome; results will be compared with the primary complete case analysis to investigate the robustness of the findings to missing data.

Recruitment
Recruitment status
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] 10663 0
Malawi
State/province [1] 10663 0
Blantyre, Zomba

Funding & Sponsors
Funding source category [1] 300116 0
Charities/Societies/Foundations
Name [1] 300116 0
Bill and Melinda Gates Foundation
Address [1] 300116 0
PO Box 23350
Seattle, WA 98102
Country [1] 300116 0
United States of America
Primary sponsor type
University
Name
University of Malawi, College of Medicine
Address
College of Medicine,
Private Bag 360,
Chichiri,
Blantyre 3
Malawi
Country
Malawi
Secondary sponsor category [1] 299567 0
None
Name [1] 299567 0
Address [1] 299567 0
Country [1] 299567 0
Other collaborator category [1] 280248 0
University
Name [1] 280248 0
University of Bergen
Address [1] 280248 0
Postboks 7804
5020 Bergen
Country [1] 280248 0
Norway
Other collaborator category [2] 280249 0
University
Name [2] 280249 0
University of Melbourne
Address [2] 280249 0
792 Elizabeth St, Melbourne VIC 3000
Country [2] 280249 0
Australia
Other collaborator category [3] 280260 0
University
Name [3] 280260 0
Walter and Eliza Hall Institute of Medical Research
Address [3] 280260 0
1G Royal Parade
Parkville VIC 3052
Country [3] 280260 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300956 0
College of Medicine Research and Ethics Committee COMREC
Ethics committee address [1] 300956 0
COMREC
College of Medicine
3rd Floor, John Chiphangwi Learning Resource Centre
Private Bag 360
Chichiri
Blantyre 3
Malawi
Ethics committee country [1] 300956 0
Malawi
Date submitted for ethics approval [1] 300956 0
Approval date [1] 300956 0
28/02/2018
Ethics approval number [1] 300956 0
P.02/18/2357
Ethics committee name [2] 300991 0
The Walter and Eliza Hall Institute of Medical Research Human Research Ethics Committee
Ethics committee address [2] 300991 0
1G Royal Pde
Parkville VIC 3052
Australia
Ethics committee country [2] 300991 0
Australia
Date submitted for ethics approval [2] 300991 0
Approval date [2] 300991 0
23/02/2018
Ethics approval number [2] 300991 0
18/02

Summary
Brief summary
Anaemia in pregnancy remains a critical global health problem, affecting 46% of pregnant women in Africa and 49% in Asia. Antenatal anaemia is associated with critical risks for both mother and child. Control of maternal anaemia, an important contributor to maternal mortality, is a key WHO Nutrition target and component of the third Sustainable Development Goal. Treatment with oral iron is poorly tolerated and requires extended contact with a well-functioning health system; this is difficult to achieve and few women receive or consume full courses of iron. At high adherence, oral antenatal iron supplementation markedly increases birthweight and gestation duration, and appears safe in malaria endemic settings.
A new intravenous iron formulation, ferric carboxymaltose, now available in developed countries, provides the opportunity to give high doses of iron (up to 15mg/kg or 1000mg) in a single rapid infusion. Unlike previous drugs which required prolonged or multiple infusions and carried a risk of severe reactions, ferric carboxymaltose can be given in just 15 minutes, and severe reactions are rare. Ferric carboxymaltose is increasingly used for first line treatment of iron deficiency in developed medical settings, including in pregnancy (For example, see clinical pathway from a recently published expert review). Thus, in low and middle-income countries, intravenous iron could present a novel, innovative opportunity to rapidly cure moderate and severe antenatal anaemia, thereby improving crucial maternal and neonatal outcomes.

This open label randomized controlled effectiveness trial will assess whether, in Malawi, treatment of moderate and severe antenatal anaemia (Hb<10g/dL) with a single dose of intravenous ferric carboxymaltose up to 1000mg improves critical maternal (including anaemia, wellbeing) and neonatal (including birthweight, gestation duration) outcomes and is safe (infection, hypophosphataemia) compared to oral iron (delivered as ferrous sulfate via routine antenatal care mechanisms). Women will also receive intermittent preventive therapy against malaria (IPTp). The trial will be undertaken under full supervision of an ethical review committee and Data Safety Monitoring Board, whom will be able to assess the ongoing safety of participants in the trial.

The trial will recruit 862 women in two centres in Malawi. Women will be recruited during the second trimester and be followed up until delivery.. These data will define a clinical rationale for developing the infrastructure and economic case for implementing this complex intervention in a LMIC setting.
Trial website
NA
Trial related presentations / publications
NA
Public notes

Contacts
Principal investigator
Name 85406 0
Dr Sant-Rayn Pasricha
Address 85406 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 85406 0
Australia
Phone 85406 0
+61393452618
Fax 85406 0
Email 85406 0
pasricha.s@wehi.edu.au
Contact person for public queries
Name 85407 0
Dr Sant-Rayn Pasricha
Address 85407 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 85407 0
Australia
Phone 85407 0
+61393452618
Fax 85407 0
Email 85407 0
pasricha.s@wehi.edu.au
Contact person for scientific queries
Name 85408 0
Dr Sant-Rayn Pasricha
Address 85408 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 85408 0
Australia
Phone 85408 0
+61393452618
Fax 85408 0
Email 85408 0
pasricha.s@wehi.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
To be finalised.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
Summary results
No Results