ANZCTR - Registration

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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

28/10/2021

Date data sharing statement initially provided

26/11/2018

Date results information initially provided

28/10/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women

Scientific title

Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1217-3954

Trial acronym

REVAMP

Linked study record

Health condition

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

Anaemia

Low birth weight

Prematurity

Small for Gestational Age

Maternal haemorrhage

Fatigue

Iron Deficiency

Maternal mortality

Infant anaemia

Infant iron deficiency

Condition category

Condition code

Blood

Anaemia

Reproductive Health and Childbirth

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]

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. Oral iron is provided in a manner consistent with standard health care practices. Adherence will be monitored by pill counting at the 34 week home visit where possible.

Control group

Active

Outcomes

Primary outcome [1]

Prevalence of maternal anaemia (Hb <11.0g/dl) at 36 weeks gestation, measured on venous blood on an automated analyser.

Timepoint [1]

Venous haemoglobin collected at 36 weeks gestation during the clinic visit, measured using an automated haematology analyser.

Secondary outcome [1]

Maternal fatigue measured by the Piper Fatigue Scale-12

Timepoint [1]

4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks gestation, 4 weeks post partum

Secondary outcome [2]

Maternal haemoglobin as measured on venous blood via automated analyser.

Timepoint [2]

4 weeks post intervention (for both IV iron and commencement of oral iron), week 36, at delivery, 4 weeks post partum

Secondary outcome [3]

Maternal anaemia (Hb<11g/dL) as measured on venous blood via automated analyser.

Timepoint [3]

4 weeks post intervention (for both IV iron and commencement of oral iron), at delivery, 4 weeks post partum

Secondary outcome [4]

Maternal cognitive function using digit span forward and backward test, and mental rotation tests.

Timepoint [4]

4 weeks post intervention (for both IV iron and commencement of oral iron), 4 weeks post partum

Secondary outcome [5]

Maternal iron deficiency (defined by i) ferritin<15mg/L, and ii) sTfR/Ferritin index – assay dependent cut-off)

Timepoint [5]

4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks, at delivery, 4 weeks post partum

Secondary outcome [6]

Severe anaemia requiring blood transfusion as defined by clinical notes

Timepoint [6]

From randomisation (receipt of oral or intravenous iron depending on allocation) to 4 weeks post partum

Secondary outcome [7]

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]

From randomisation to 4 weeks post partum

Secondary outcome [8]

Birth weight (as a continuous variable) using infant scales

Timepoint [8]

Within 24 hours of birth

Secondary outcome [9]

Low birth weight (birth weight <2500g) as a dichotomous variable

Timepoint [9]

Within 24 hours of birth

Secondary outcome [10]

Gestational-age (based on baseline ultrasound dating of pregnancy) adjusted birth weight

Timepoint [10]

<24 hours following birth

Secondary outcome [11]

Small for gestational age as a dichotomous variable (<10th centile)

Timepoint [11]

<24 hours following birth

Secondary outcome [12]

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]

<28 weeks gestation

Secondary outcome [13]

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]

>28 weeks gestation

Secondary outcome [14]

Gestation duration based on calculated duration of gestation, using dating at baseline ultrasound examination to date of actual delivery.

Timepoint [14]

Delivery visit

Secondary outcome [15]

Premature birth – neonate born prior to 37 completed weeks of gestation (including 36weeks and 6 days), based on gestation duration.

Timepoint [15]

Delivery visit

Secondary outcome [16]

Cord venous blood haemoglobin by automated analyser

Timepoint [16]

Delivery

Secondary outcome [17]

Infant haemoglobin (measurement of haemoglobin on venous blood by automated analyser)

Timepoint [17]

1 month post partum

Secondary outcome [18]

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]

Time of administration of intervention

Secondary outcome [19]

Incidence of all-cause sick visits to the clinic based on visits recorded by study staff at the study clinic

Timepoint [19]

Randomisation to 1 month post-partum.

Secondary outcome [20]

The incidence of diarrhoea sick visits to the clinic based on visits recorded by study staff at the study clinic

Timepoint [20]

Randomisation to 1 month post-partum.

Secondary outcome [21]

The incidence of clinical malaria-specific sick visits to the clinic based on visits recorded by study staff at the study clinic

Timepoint [21]

Randomisation to 1 month post-partum.

Secondary outcome [22]

Incidence of placental malaria at delivery based on placental histologic examination

Timepoint [22]

Delivery

Secondary outcome [23]

Incidence of peripheral parasitaemia by 36 weeks of gestation based on blood film microscopy

Timepoint [23]

Randomisation to 36 weeks gestation

Secondary outcome [24]

Incidence of cord blood parasitaemia at delivery based on blood film microscopy

Timepoint [24]

Delivery

Secondary outcome [25]

Prevalence of malaria parasitaemia based on blood film microscopy at each scheduled visit

Timepoint [25]

4 weeks post intervention (for both IV iron and commencement of oral iron), 36 weeks, at delivery, 4 weeks post partum

Secondary outcome [26]

Hypophosphatemia based on biochemical measurement of serum Phosphate.

Timepoint [26]

4 weeks post intervention (for both Iv iron and commencement of oral iron), 36 weeks

Secondary outcome [27]

Maternal inflammation (elevated C-reactive protein by serum assay)

Timepoint [27]

4 weeks post intervention (for both Iv iron and commencement of oral iron), 36 weeks gestation

Secondary outcome [28]

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]

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]

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]

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]

Infant ferritin (serum ferritin)

Timepoint [30]

1 month of age

Secondary outcome [31]

Cord ferritin by serum ferritin

Timepoint [31]

Delivery

Secondary outcome [32]

Maternal haemorrhage - antepartum or post partum haemorrhage diagnosed by study clinical staff

Timepoint [32]

Randomisation to 4 weeks post partum

Secondary outcome [33]

Maternal mortality

Timepoint [33]

Maternal death from randomisation to 1 month post partum

Secondary outcome [34]

Neonatal mortality, as observed by study staff/ clinical notes

Timepoint [34]

Death of child in the first month of life

Secondary outcome [35]

Maternal shock defined by systolic blood pressure <90mmHg, as observed by study staff

Timepoint [35]

Randomisation to 1 month post partum

Secondary outcome [36]

Maternal intensive care admission as observed by study staff

Timepoint [36]

Recruitment to 1 month post partum

Secondary outcome [37]

Neonatal intensive care admission as observed by study staff

Timepoint [37]

Birth to 1 month post partum

Secondary outcome [38]

Need for maternal blood transfusion, as observed by study staff

Timepoint [38]

Recruitment to 1 month post partum

Secondary outcome [39]

Maternal hospitalisation- any unplanned admission to hospital beyond usual post partum discharge procedures, as observed by study staff.

Timepoint [39]

Following delivery

Secondary outcome [40]

Delayed Adverse Events as detected by open questioning by study staff

Timepoint [40]

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

Sex

Females

Can healthy volunteers participate?

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 36 weeks gestation 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 at 36 weeks gestation. 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 analysis to investigate the robustness of the findings to missing data.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

1/10/2018

Actual

9/11/2018

Date of last participant enrolment

Anticipated

7/08/2020

Actual

2/03/2021

Date of last data collection

Anticipated

6/09/2022

Actual

Sample size

Target

862

Accrual to date

Final

862

Recruitment outside Australia

Country [1]

Malawi

State/province [1]

Zomba

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Bill and Melinda Gates Foundation

Address [1]

PO Box 23350
Seattle, WA 98102

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

University

Name [1]

University of Bergen

Address [1]

Postboks 7804
5020 Bergen

Country [1]

Norway

Other collaborator category [2]

University

Name [2]

University of Melbourne

Address [2]

792 Elizabeth St, Melbourne VIC 3000

Country [2]

Australia

Other collaborator category [3]

University

Name [3]

Walter and Eliza Hall Institute of Medical Research

Address [3]

1G Royal Parade
Parkville VIC 3052

Country [3]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

College of Medicine Research and Ethics Committee COMREC

Ethics committee address [1]

COMREC
College of Medicine
3rd Floor, John Chiphangwi Learning Resource Centre
Private Bag 360
Chichiri
Blantyre 3
Malawi

Ethics committee country [1]

Malawi

Date submitted for ethics approval [1]

Approval date [1]

28/02/2018

Ethics approval number [1]

P.02/18/2357

Ethics committee name [2]

The Walter and Eliza Hall Institute of Medical Research Human Research Ethics Committee

Ethics committee address [2]

1G Royal Pde
Parkville VIC 3052
Australia

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

Approval date [2]

23/02/2018

Ethics approval number [2]

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

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Sant-Rayn Pasricha

Address

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

Australia

Phone

+61393452618

Fax

[email protected]

Contact person for public queries

Name

Dr Sant-Rayn Pasricha

Address

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

Australia

Phone

+61393452618

Fax

[email protected]

Contact person for scientific queries

Name

Dr Sant-Rayn Pasricha

Address

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

Australia

Phone

+61393452618

Fax

[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?

Trial outcome data will be shared upon reasonable request.

When will data be available (start and end dates)?

Up to two years following completion of the trial.

Available to whom?

Members of the scientific community upon reasonable request.

Available for what types of analyses?

IPD meta analysis.

How or where can data be obtained?

Please contact Dr S Pasricha on [email protected].

What supporting documents are/will be available?

Current supporting documents:

Updated to:

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
23776	Data dictionary	2023	https://doi.org/10.26188/22344973

Results publications and other study-related documents

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Current Study Results

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Update to Study Results

Doc. No.	Type	Is Peer Reviewed?	Citations or Other Details	Attachment
4091	Plain language summary	No	Summary Background Anaemia affects 46% of preg... [More Details]
4720	Study results article	Yes	Published: April 20, 2023 Pasricha SR, Mwangi M... [More Details]	Pasricha et al. 2023-2.pdf
4721 [Marked for deletion]	Other files	No	Data sharing Underlying deidentified individual p... [More Details]
4822	Statistical analysis plan	Yes	Published April 14, 2022 Harding R, Ataide R, M... [More Details]	REVAMP_SAP_v2_GatesOpenResearch.pdf
4823	Basic results	No		REVAMP ANZCTR basic results template.docx
4824	Protocol	Yes	Published Nov 23, 2021 Mwangi MN, Mzembe G, Moy... [More Details]	Mwangi et al REVAMP.pdf

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Trial Review

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