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Trial registered on ANZCTR


Registration number
ACTRN12621000968875
Ethics application status
Approved
Date submitted
18/06/2021
Date registered
23/07/2021
Date last updated
23/07/2021
Date data sharing statement initially provided
23/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and Demonstration of IntraVenous Iron for Anaemia in pregnancy (EDIVA)
Scientific title
Efficacy and Demonstration of IntraVenous Iron for Anaemia in pregnancy in Bangladesh (EDIVA)
Secondary ID [1] 304493 0
None
Universal Trial Number (UTN)
U1111-1266-6468
Trial acronym
EDIVA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia 322338 0
Iron deficiency 322362 0
Maternal depression 322363 0
Low birthweight 322364 0
Prematurity 322365 0
small for gestational age 322368 0
Condition category
Condition code
Blood 320007 320007 0 0
Anaemia
Reproductive Health and Childbirth 320008 320008 0 0
Fetal medicine and complications of pregnancy
Diet and Nutrition 320037 320037 0 0
Other diet and nutrition disorders
Mental Health 320346 320346 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a two-arm (1:1) Phase III open-label superiority individual-randomised controlled trial assessing the effectiveness of the intravenous iron ferric carboxymaltose in reducing maternal anaemia, compared to the standard of care of oral iron supplementation. Women in their second or third trimester of pregnancy will be screened for anaemia and those found to be moderately-severely anaemic (haemoglobin <10g/dL) will be randomized to receive the intervention or the control.

Intervention: intravenous iron treatment course administered once during pregnancy. Intravenous ferric carboxymaltose (FCM) 1000 mg total dose for body weight of 50 kg or more, or 20 mg/kg for body weight less than 50 kg, will be given over 15 minutes by a skilled study physician/ medical technologist.

For participants receiving the intravenous iron treatment course: the skin will be cleaned with ethanol following standard aseptic procedure, and a sterile cannula will be inserted into the forearm or hand by a skilled study physician/medical technologist, and the cannula will be fixed in place with a sterile Tegaderm or clinical tape. The participant will be monitored over the 15 minutes of the infusion for any adverse events and at 10 minutes into the infusion, she will be asked if she experiences any problems and everything will be recorded. If the participant develops any complications, these will be attended to promptly and treated according to standard clinical management guidelines. The participant will be observed for a further 45 minutes and similarly, any problems experienced will be recorded.
Intervention code [1] 320854 0
Treatment: Drugs
Comparator / control treatment
Oral iron treatment course: oral iron- 200 mg ferrous sulphate (60 mg elemental iron) twice daily for remainder of pregnancy, as standard of care.

For those allocated to the oral iron arm, iron tablets will be provided at a dose of 60mg elemental iron twice daily for 90 days (or the duration of pregnancy, whichever is shorter). They will be educated according to a standard script that replicates instructions provided in routine clinical practice in Bangladesh. Study staff will ask participants in the oral iron arm to complete a survey on oral iron adherence at 36 weeks gestation.
Control group
Active

Outcomes
Primary outcome [1] 327878 0
Maternal anaemia (haemoglobin <11g/dL), assessed by a finger prick test using a HemoCue301 portable haemolgobin analyzer
Timepoint [1] 327878 0
36 weeks gestation (this timepoint is after delivery of the intervention)
Secondary outcome [1] 396913 0
Maternal anaemia (haemoglobin <11g/dL), assessed by a finger prick test using a HemoCue301 portable haemolgobin analyzer
Timepoint [1] 396913 0
4 weeks post intervention, 42 days postpartum, 3 months postpartum and 6 months postpartum
Secondary outcome [2] 396920 0
Maternal haemoglobin levels (as a continuous variable), assessed by a finger prick test using a HemoCue301 portable haemolgobin analyzer
Timepoint [2] 396920 0
4 weeks post intervention, 36 weeks gestation, 42 days postpartum, 3 months and 6 months postpartum
Secondary outcome [3] 396921 0
Maternal iron deficiency (ferritin <15 mg/L), assessed by enzyme-linked immunosorbent assays (ELISAs) for serum ferritin.
Timepoint [3] 396921 0
4 weeks post intervention, 36 weeks gestation, 42 days postpartum, 3 months postpartum, 6 months postpartum
Secondary outcome [4] 396922 0
Maternal ferritin levels (as a continuous variable), assessed by enzyme-linked immunosorbent assays (ELISAs) for serum ferritin.
Timepoint [4] 396922 0
4 weeks post intervention, 36 weeks gestation, 42 days postpartum, 3 months postpartum and 6 months postpartum
Secondary outcome [5] 396923 0
Maternal depression measured by the Edinburgh postnatal depression scale
Timepoint [5] 396923 0
4 weeks post intervention, 36 weeks gestation, and 3 months postpartum
Secondary outcome [6] 396924 0
Mother to infant bonding measured by the mother to infant bonding scale
Timepoint [6] 396924 0
3 months postpartum
Secondary outcome [7] 396927 0
Adverse perinatal events including postpartum haemorrhage, need for blood transfusion, intensive care admission or mortality, as reported by patient or based on clinical records, or as observed by study staff.
Timepoint [7] 396927 0
From recruitment to 28 days postpartum
Secondary outcome [8] 396932 0
Maternal hypophosphatemia based on biochemical measurement of serum phosphate
Timepoint [8] 396932 0
4 weeks post intervention, 36 weeks gestation
Secondary outcome [9] 396933 0
Maternal inflammation, measured by enzyme-linked immunosorbent assays (ELISAs) for C-reactive protein
Timepoint [9] 396933 0
4 weeks post intervention, 36 weeks gestation, 42 days postpartum, 3 months postpartum and 6 months postpartum
Secondary outcome [10] 396934 0
Birthweight (as a continuous variable measured in grams) using infant scales
Timepoint [10] 396934 0
At delivery visit
Secondary outcome [11] 396935 0
Low birth weight (as a categorical variable, birth weight <2500g) using infant scales
Timepoint [11] 396935 0
At delivery visit
Secondary outcome [12] 396937 0
Gestational age at birth (weeks), based on calculated duration of gestation, using dating at baseline ultrasound examination to date of actual delivery.
Timepoint [12] 396937 0
At delivery visit
Secondary outcome [13] 396938 0
Premature birth (<37 weeks) Gestational age at birth (weeks), based on calculated duration of gestation, using dating at baseline ultrasound examination to date of actual delivery.
Timepoint [13] 396938 0
At delivery visit
Secondary outcome [14] 396939 0
Small for gestation age as a dichotomous variable (<10th centile), based on baseline ultrasound dating of pregnancy adjusted birth weight
Timepoint [14] 396939 0
At delivery visit
Secondary outcome [15] 396941 0
Child physical growth (length and weight) as a composite outcome, measured using infant scales and measuring tape
Timepoint [15] 396941 0
42 days postnatal, 3 months postnatal and 6 months postnatal
Secondary outcome [16] 396942 0
Infant haemoglobin levels (as a continuous variable) assessed by a finger prick test using a HemoCue301 portable haemolgobin analyzer
Timepoint [16] 396942 0
42 days postnatal, 3 months postnatal and 6 months postnatal
Secondary outcome [17] 396943 0
Infant ferritin levels (continuous), assessed by enzyme-linked immunosorbent assays (ELISAs) for serum ferritin.
Timepoint [17] 396943 0
42 days postnatal, 3 months postnatal and 6 months postnatal
Secondary outcome [18] 396944 0
Abortion (pregnancy loss before 28 weeks of gestation) as reported by participant, study staff or based on clinical records
Timepoint [18] 396944 0
<28 weeks gestation
Secondary outcome [19] 396945 0
Stillbirth (birth of a baby showing no signs of life after 28 weeks gestation) as reported by participant, study staff or based on clinical records
Timepoint [19] 396945 0
> 28 weeks gestation
Secondary outcome [20] 396946 0
Neonatal mortality as reported by participant, study staff or based on clinical records
Timepoint [20] 396946 0
Death of child within the first month of life
Secondary outcome [21] 396947 0
Infant adverse events including hospitalisation and clinic visits as reported by mother, study staff or based on clinical records
Timepoint [21] 396947 0
Throughout study from delivery through to 6 months old
Secondary outcome [22] 396988 0
Infusion related adverse events including allergic reactions as reported by study staff or based on clinical records
Timepoint [22] 396988 0
Time of administration of intervention, and any severe adverse events reported by study staff or based on clinical records up to two weeks post intervention
Secondary outcome [23] 397993 0
Child neurodevelopment, assessed by neonatal behavioral assessment scale
Timepoint [23] 397993 0
At delivery and 42 days postnatal
Secondary outcome [24] 397994 0
Child neurodevelopment, assessed by the auditory brainstem response tool
Timepoint [24] 397994 0
42 days postnatal and 6 months postnatal
Secondary outcome [25] 397995 0
Child neurodevelopment, assessed by the Bayleys scales of infant development
Timepoint [25] 397995 0
6 months postnatal
Secondary outcome [26] 397996 0
Child physical growth (length, cm) measured with measuring tape
Timepoint [26] 397996 0
42 days postnatal, 3 months postnatal and 6 months postnatal

Eligibility
Key inclusion criteria
- In their second (13-25 completed weeks) or third trimester (26-32 completed weeks of gestation), dated by Last Menstrual Period.
- Moderate to severe anaemia (capillary Hb <10g/dL).
- Not known to have a multiple pregnancy.
- Expected to deliver the baby inside or within 30 minutes of road transport of the study catchment area.
- Have drinking water groundwater iron <1mg/L.
- Willing to provide written informed consent (if the pregnant woman is <18 years of age, consent will be collected from her guardian, while she will sign an assent form).
Minimum age
No limit
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Women visiting the region temporarily or expecting to travel out of the study site for more than one month over the subsequent 12 months.
- Women expecting to deliver their baby outside the study region.
- Known to have a diagnosis of thalassemia or other inherited red cell condition.
- Known to have a prior allergy to intravenous iron.
- Women with high drinking groundwater iron.
- Women with severe anaemia requiring an emergency blood transfusion (Hb <5g/dL), or with haemodynamic or acute clinical compromise as judged by a study physician.
- Known hypersensitivity to any of the study drugs.
- Clinical symptoms of current bacterial/viral infection (e.g.fever).
- Any condition requiring urgent hospitalization or serious concomitant illness.
- Women in the third trimester of pregnancy currently already enrolled in the second trimester of the EDIVA Activity 2.
- Women who have already received a dose of intravenous iron during the current pregnancy

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)
Sequence generated by computerised sequence generation.
The randomisation list will be generated by an independent statistician in Australia.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We expect the prevalence of moderate and severe anaemia to be 10% in this population, and that a further 25% of women will not be eligible or willing to participate in the trial. As such, we expect we will need to screen ~12,000 women for eligibility. We plan to recruit 450 women per arm, or 900 women in total when accounting for ~13% drop-out (similar to our previous trial site [BRISC] trial, ACTRN12617000660381) by week 36 (primary outcome timepoint). This will be a single randomised controlled trial, with non-competitive recruitment in each trimester such that a minimum of 40% of participants are recruited in each of the second and third trimesters.

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 60% in the oral iron arm to 50% in the intravenous (IV) iron arm with 80% power (two-sided 4.9% alpha accounting for one interim analysis). Assuming 50% of women enter the study in the second or third trimester of pregnancy, we will be able to detect a 15% absolute difference (60% oral iron vs 45% IV iron) with 84% power within the subset of women in that particular trimester (two-sided 4.9% alpha). 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. A recent systematic review of parenteral iron in pregnancy (in both high- and low-income countries) found that at 2-6 weeks post treatment, IV iron increases Hb compared with oral iron by 0.7g/dL. Thus, assuming a SD of 1.5g/dL, 45% of women are expected to be anaemic at delivery after IV iron.

For our key secondary outcome of birthweight, after accounting for a miscarriage and stillbirth rate of 1%, we will be able to detect a birthweight increase of 100g in the IV iron arm compared to the oral iron arm with 87% power (two-sided 5% alpha). Assuming 50% of women enter the study in each trimester of pregnancy, we will be able to detect an increase of 150g with 90% power per trimester (two-sided 5% alpha). We assume a SD of 450g (per trimester).

The above sample size estimate incorporates one pre-planned interim analysis for the primary outcome of anaemia at 36 weeks gestation to allow for early stopping using the Haybittle-Peto rule (p-value<0.001 IV vs oral iron).

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] 23787 0
Bangladesh
State/province [1] 23787 0
Narayanganj district

Funding & Sponsors
Funding source category [1] 308855 0
Charities/Societies/Foundations
Name [1] 308855 0
Bill and Melinda Gates Foundation
Address [1] 308855 0
500 5th Ave N, Seattle, WA 98109, United States
Country [1] 308855 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)
Address
68, Shaheed Tajuddin Ahmed Sarani Mohakhali, Dhaka 1212, Bangladesh
Country
Bangladesh
Secondary sponsor category [1] 309787 0
None
Name [1] 309787 0
Address [1] 309787 0
Country [1] 309787 0
Other collaborator category [1] 281854 0
Other Collaborative groups
Name [1] 281854 0
Walter and Eliza Hall Institute
Address [1] 281854 0
1G Royal Parade
Parkville VIC 3052
Country [1] 281854 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308763 0
International Centre for Diarrhoeal Disease Research, Bangladesh Ethical Review Committee
Ethics committee address [1] 308763 0
68, Shaheed Tajuddin Ahmed Sarani Mohakhali, Dhaka 1212, Bangladesh
Ethics committee country [1] 308763 0
Bangladesh
Date submitted for ethics approval [1] 308763 0
25/03/2021
Approval date [1] 308763 0
29/03/2021
Ethics approval number [1] 308763 0
PR-20125
Ethics committee name [2] 308764 0
Walter and Eliza Hall Institute Human Research Ethics Committee
Ethics committee address [2] 308764 0
1G Royal Parade, Parkville VIC 3052
Ethics committee country [2] 308764 0
Australia
Date submitted for ethics approval [2] 308764 0
04/03/2021
Approval date [2] 308764 0
02/06/2021
Ethics approval number [2] 308764 0
21/5

Summary
Brief summary
Anaemia in pregnancy is a major public health problem globally that has adverse effects on maternal and neonatal health outcomes. The primary cause of anaemia in pregnancy is iron deficiency. In most low- and middle-income countries (LMICs), oral iron supplementation is the primary anaemia treatment and prevention strategy and is provided in routine antenatal care. Despite being policy in many countries, major challenges exist with the consumption coverage of at least 90 iron tablets during pregnancy. Consequently, there has been limited progress in reducing the burden of anaemia among pregnant women in many LMICs, such as Bangladesh. In high-income settings, modern intravenous iron products such as ferric carboxymaltose (FCM) are widely available, providing an opportunity to deliver high doses of iron in a single, short infusion. We hypothesize that in LMICs, intravenous iron formulations like FCM will rapidly cure moderate to severe anaemia in pregnancy, thereby improving maternal and neonatal outcomes.

This open label randomized controlled effectiveness trial will assess whether, in Bangladesh, 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 (including adverse events, hypophosphataemia) compared to oral iron (delivered as ferrous sulfate via routine antenatal care mechanisms). The trial will recruit 900 women the Narayanganj District, Bangladesh. Women will be recruited during the second or third trimester and be followed up until 6 months postpartum. 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
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111802 0
Dr Sant-Rayn Pasricha
Address 111802 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 111802 0
Australia
Phone 111802 0
+61393452618
Fax 111802 0
Email 111802 0
pasricha.s@wehi.edu.au
Contact person for public queries
Name 111803 0
Dr Sant-Rayn Pasricha
Address 111803 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 111803 0
Australia
Phone 111803 0
+61393452618
Fax 111803 0
Email 111803 0
pasricha.s@wehi.edu.au
Contact person for scientific queries
Name 111804 0
Dr Sant-Rayn Pasricha
Address 111804 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 111804 0
Australia
Phone 111804 0
+61393452618
Fax 111804 0
Email 111804 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?
De-identified individual participant data underlying published results
When will data be available (start and end dates)?
At least one year following publication of the main trial outcomes.
There is no end date for when data will be available.
Available to whom?
Researchers who provide a methodologically sound proposal and completed a data request form
Available for what types of analyses?
To achieve aims in the approved proposal
How or where can data be obtained?
Access subject to approval by the Principal Investigator:
Dr Sant-Rayn Pasricha (pasricha.s@wehi.edu.au)
What supporting documents are/will be available?
No other documents available
Summary results
No Results