The use of iron administered as an infusion into a vein compared to the use of iron tablets taken by mouth for treating Nigerian women with iron deficiency anaemia during pregnancy

Plain English Summary

Background and study aims
Iron deficiency anaemia is a condition where a lack of iron in the body leads to fewer red blood cells. Anaemia in pregnancy is a public health burden with a high incidence in Africa. Currently pregnant women who are anaemic are treated with high-dose iron tablets taken by mouth if it is mild or moderate in severity. Those who have severe anaemia are given blood. Some women do not tolerate the tablets well as they may develop side effects like constipation, stomach pain, nausea or vomiting. There are iron preparations in existence that can be given in infusion (drip) form and have been found to be safe, and their use for the treatment of iron deficiency anaemia in pregnancy is currently being evaluated. The aim of this study is to compare the effectiveness of ferric carboxymaltose given as an infusion through a vein versus oral ferrous sulphate taken by mouth for treating iron-deficiency anaemia in pregnancy, and to compare the acceptability, safety and the cost-effectiveness of these two forms of iron preparation in pregnant Nigerian women with moderate and severe iron deficiency anaemia at 20 – 32 weeks (5 - 7 months) of pregnancy.

Who can participate?
Pregnant women aged between 15 and 49 who are anaemic at the time they are registering for antenatal care in the hospital.

What does the study involve?
Information is collected about the participants' health and pregnancy and a blood sample is taken. Participants are randomly allocated to one of two drug treatments. The drug may be a preparation that will be added to an infusion (drip) for administration only once and over 30 minutes, or it may be in tablet form which will be taken by mouth three times a day until delivery. During pregnancy, their blood will be checked regularly and they will be asked questions at each visit and assessed for depression using a questionnaire on three occasions in the course of the study. Participants will be monitored all through pregnancy, through delivery and until 6 weeks after they have delivered. Their babies will also be examined after delivery to get some information such as the birth weight and will also be followed up to collect information on their immunization status.

What are the possible benefits and risks of participating?
Though the drugs to be used in this study have been found to be relatively safe in pregnancy, it is still possible to suffer some side effects from any of the medications. Participants will be monitored closely to identify any side effect early and treat at no cost. All the trial drugs will be given free of charge and all the tests relating to this research will also be done for free. Participants will be given contacts of their caregivers and will be sent regular reminders about their appointments. The findings of this study will improve the knowledge about treatment of anaemia in pregnancy and enable existing treatments to be changed if need be in order to improve the well being of pregnant women and the outcome of their pregnancy.

Where is the study run from?
University of Lagos/Lagos University Teaching Hospital (LUTH) (Nigeria)

When is the study starting and how long is it expected to run for?
November 2020 to June 2023

Who is funding the study?
Bill and Melinda Gates Foundation (USA)

Who is the main contact?
Prof. Bosede B. Afolabi
bbafolabi@unilag.edu.ng

Study website

https://ivontrial.com

Type

Scientific

Contact name

Prof Bosede Afolabi

ORCID ID

http://orcid.org/0000-0002-7511-7567

Contact details

Department of Obstetrics and Gynecology
Faculty of Clinical Sciences
College of Medicine
University of Lagos/Lagos University Teaching Hospital (LUTH)
P. M. B. 12003
Surulere
Lagos
100254
Nigeria
+234 (0)8023154064
bbafolabi@unilag.edu.ng

Type

Public

Contact name

Dr Ochuwa Babah

ORCID ID

http://orcid.org/0000-0001-6680-3242

Contact details

Department of Obstetrics and Gynecology
Faculty of Clinical Sciences
College of Medicine
University of Lagos/Lagos University Teaching Hospital (LUTH)
P. M. B. 12003
Surulere
Lagos
100254
Nigeria
+234 (0)7038090032
obabah@unilag.edu.ng

EudraCT/CTIS number

2021-002867-23

IRAS number

ClinicalTrials.gov number

NCT04976179

Protocol/serial number

PACTR202012843695208

Scientific title

Intravenous versus oral iron for iron deficiency anaemia in pregnant Nigerian women (IVON): an open label, randomized controlled trial

Acronym

IVON

Study hypothesis

Current hypothesis as of 27/06/2022:

Hypothesis 1: The researchers expect a lower prevalence of anaemia at 36 weeks' gestation, a reduction in incidence of preterm delivery, and improvement in other maternal and perinatal outcomes among the intravenous iron, compared with the oral iron group.
Hypothesis 2: The researchers expect intravenous ferric carboxymaltose to be more acceptable, feasible and cost-effective than oral ferrous sulphate in the treatment of moderate to severe IDA in pregnancy

_____

Previous hypothesis as of 15/12/2020:

Hypothesis 1: The researchers expect a lower prevalence of anaemia at 36 weeks' gestation, a higher increase in maternal haemoglobin concentration levels at 4 weeks post treatment initiation, and improvement in other maternal and perinatal outcomes among the intravenous iron, compared with the oral iron group
Hypothesis 2: The researchers expect intravenous ferric carboxymaltose to be more acceptable, feasible and cost-effective than oral ferrous sulphate in the treatment of moderate to severe IDA in pregnancy

_____

Previous hypothesis:

Hypothesis 1: The researchers expect a 14% lower prevalence of anaemia at 36 weeks' gestation and a 1g/dl increase in maternal haemoglobin concentration levels at 4 weeks post treatment initiation among the intervention group, compared with the control group.
Hypothesis 2: The researchers expect intravenous isomaltoside to be more cost-effective than oral ferrous sulphate in the treatment of moderate to severe IDA in pregnancy.

Ethics approval(s)

1. Approved 02/12/2020, Lagos University Teaching Hospital Health Research and Ethics Committee (P.M.B. 12003, Surulere, Lagos, Nigeria; +234 (0)15850737, +234 (0)15852187, +234 (0)15852209; luthethics@yahoo.com), ref: ADM/DCST/HREC/APP/3971
2. Approved 17/01/2021, National Health Research and Ethics Committee (chairman@nhrec.net, +234-09-523-8367), ref: NHREC/01/01/2007
3. Approved 23/04/2021, National Agency for Food Drug Administration and Control (NAFDAC) (der.headquarters@nafdac.gov.ng, +234-09-523-8367), ref: NAFDAC/DER/VCTD/IVON/VOL.2

Study design

Multicenter interventional parallel open-label individually randomized controlled trial with a cost-effectiveness analysis

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

See study output table

Condition

Iron deficiency anaemia in pregnant women

Intervention

Current interventions as of 27/06/2022:

Eligible women will be admitted on a day case basis into the dedicated ward or day room for treatment initiation. They will be individually randomized in a 1:1 ratio to receive either intravenous ferric carboxymaltose or oral iron. "Sealed envelope" will generate the randomisation code list, shared ONLY with the unblinded pharmacist by email, who will then label each drug kit with a code according to the randomisation list and send to the appropriate study site. As each new patient is recruited in a particular site, her details will be entered into an electronic tablet and a code is generated that corresponds to the codes on a particular drug kit. She is then given a labelled drug kit that corresponds to her assigned code. The intervention group will receive intravenous ferric carboxymaltose will be 20 mg/kg body weight (but not exceeding 1000mg) given in 200 ml of normal saline as a single-dose infusion administered over 15 – 20minutes. The control group will receive oral ferrous sulphate 200 mg (65 mg elemental iron) three times daily from enrolment till delivery.

_____

Previous interventions as of 12/04/2021:

Eligible women will be admitted on a day case basis into the dedicated ward or day room for treatment initiation. They will be individually randomized in a 1:1 ratio to receive either intravenous ferric carboxymaltose or oral iron. "Sealed envelope" will generate the randomisation code list, shared ONLY with the unblinded pharmacist by email, who will then label each drug kit with a code according to the randomisation list and send to the appropriate study site. As each new patient is recruited in a particular site, her details will be entered into an electronic tablet and a code is generated that corresponds to the codes on a particular drug kit. She is then given a labelled drug kit that corresponds to her assigned code. The intervention group will receive intravenous ferric carboxymaltose will be 20 mg/kg body weight (but not exceeding 1000mg) given in 250 ml of normal saline as a single-dose infusion administered over 15 minutes. The control group will receive oral ferrous sulphate 200 mg (65 mg elemental iron) three times daily from enrolment till delivery.

_____

Previous interventions:

Eligible women will be admitted on a day case basis into the dedicated ward or day room for treatment initiation. They will be individually randomized in a 1:1 ratio to receive either intravenous iron isomaltoside or oral iron. "Sealed envelope" will generate the randomisation code list, shared ONLY with the unblinded pharmacist by email, who will then label each drug kit with a code according to the randomisation list and send to the appropriate study site. As each new patient is recruited in a particular site, her details will be entered into an electronic tablet and a code is generated that corresponds to the codes on a particular drug kit. She is then given a labelled drug kit that corresponds to her assigned code. The intervention group will receive iron isomaltoside 20 mg/kg single dose, maximum 1500 mg diluted in 100 ml 0.9% Normal Saline infusion and given over 30 minutes. The control group will receive oral ferrous sulphate 200 mg (65 mg elemental iron) three times daily from enrolment till delivery.

Intervention type

Drug

Pharmaceutical study type(s)

Phase

Phase III

Drug/device/biological/vaccine name(s)

Intravenous ferric carboxymaltose, oral ferrous sulphate

Primary outcome measure

Current primary outcome measure as of 14/03/2022:
1. Prevalence of maternal anaemia (diagnosed as haemoglobin less than 11g/dl), at 36 weeks' gestation, measured with a haematological auto-analyser.
2. Incidence of preterm birth, measured at delivery.

Previous primary outcome measure:
1. Prevalence of maternal anaemia (diagnosed as haemoglobin less than 11g/dl), at 36 weeks' gestation, measured with a haematological auto-analyser
2. Maternal haemoglobin levels measured using HemoCue at 4 weeks post-initiation of treatment and at delivery measured with a haematological auto-analyser

Secondary outcome measures

Current secondary outcome measures as of 20/07/2023:
1. Safety and tolerability, including the incidence of hypophosphatemia and severity of maternal adverse effects measured using medical records at Day 1 and 4 weeks post enrolment, at 36 weeks gestational age and at 6 weeks post delivery; added 12/04/2021: serum phosphate concentration measured with laboratory assays using maternal blood and cord blood taken at delivery
2. Severe maternal events, specifically, haemorrhage, sepsis, shock and the need for blood transfusion measured using medical records at delivery
3. The incidence of low infant birth weight (<2.5 kg), prematurity (<37 weeks’ gestation as dated from the last menstrual period or a first-trimester ultrasound scan), stillbirth and neonatal mortality (birth till 28 days of life), the proportion of infants being breastfed at 1, 2 and 4 weeks of life, and receiving BCG, oral polio and hepatitis vaccination in the same time period, measured using medical records
4. Depression linked to the emotional well-being of mothers measured using the validated Edinburgh Postnatal Depression Scale at enrolment, 36 weeks gestational age and 7 days post delivery
5. Maternal haemoglobin levels measured using HemoCue at 4 weeks post-initiation of treatment and at delivery measured with a haematological auto-analyser
6. Prevalence of maternal iron deficiency (diagnosed by serum ferritin level less than 30 ng/ml) at 36 weeks' gestation measured using laboratory assay

Previous secondary outcome measures from 14/03/2022 to 20/07/2023:
1. Safety and tolerability, including the incidence of hypophosphatemia and severity of maternal adverse effects measured using medical records at Day 1 and 4 weeks post enrolment, at 36 weeks gestational age and at 6 weeks post delivery; added 12/04/2021: serum phosphate concentration measured with laboratory assays using maternal blood and cord blood taken at delivery
2. Severe maternal events, specifically, haemorrhage, sepsis, shock and the need for blood transfusion measured using medical records at delivery
3. The incidence of low infant birth weight (<2.5 kg), prematurity (<37 weeks’ gestation as dated from the last menstrual period or a first-trimester ultrasound scan), stillbirth and neonatal mortality (birth till 28 days of life), the proportion of infants being breastfed at 1, 2 and 4 weeks of life, and receiving BCG, oral polio and hepatitis vaccination in the same time period, measured using medical records
4. Depression linked to the emotional well-being of mothers measured using the validated Edinburgh Postnatal Depression Scale at enrolment, 36 weeks gestational age and 7 days post delivery
5. Maternal haemoglobin levels measured using HemoCue at 4 weeks post-initiation of treatment and at delivery measured with a haematological auto-analyser

Previous secondary outcome measures:
1. Safety and tolerability, including the incidence of hypophosphatemia and severity of maternal adverse effects measured using medical records at Day 1 and 4 weeks post enrolment, at 36 weeks gestational age and at 6 weeks post delivery; added 12/04/2021: serum phosphate concentration measured with laboratory assays using maternal blood and cord blood taken at delivery
2. Severe maternal events, specifically, haemorrhage, sepsis, shock and the need for blood transfusion measured using medical records at delivery
3. The incidence of low infant birth weight (<2.5 kg), prematurity (<37 weeks’ gestation as dated from the last menstrual period or a first-trimester ultrasound scan), stillbirth and neonatal mortality (birth till 28 days of life), the proportion of infants being breastfed at 1, 2 and 4 weeks of life, and receiving BCG, oral polio and hepatitis vaccination in the same time period, measured using medical records
4. Depression linked to the emotional well-being of mothers measured using the validated Edinburgh Postnatal Depression Scale at enrolment, 36 weeks gestational age and 7 days post delivery

Overall study start date

01/11/2020

Overall study end date

15/06/2023

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Pregnant women aged 15 to 49 years old between 20- and 32-weeks’ gestational age
2. Baseline (enrolment) laboratory-confirmed moderate or severe anemia (Hb <10 g/dl)

Participant type(s)

Patient

Age group

Mixed

Lower age limit

15 Years

Upper age limit

49 Years

Sex

Female

Target number of participants

1,056

Total final enrolment

1056

Participant exclusion criteria

Current exclusion criteria as of 27/06/2022:

1. Medically confirmed significant bleeding, major surgery or received blood transfusion within the last 3 months.
2. Severe symptomatic anemia needing urgent correction with blood transfusion.
3. Anemia of other cause besides IDA e.g., Sickle cell anemia.
4. Clinically confirmed malabsorption syndrome.
5. Hypersensitivity to any form of iron treatment.
6. History of any immune related illness e.g., SLE, Rheumatoid arthritis.
7. Preexisting maternal depression or other psychiatric illness.
8. Severe allergic reactions such as severe asthma.
9. History of severe drug allergy.

_____

Previous exclusion criteria:

1. Medically confirmed significant bleeding, major surgery or received a blood transfusion within the last 3 months
2. Symptomatic anaemia with dyspnea or fatigue and a need for urgent correction
3. Concurrent anaemia of another cause besides IDA
4. Clinically-confirmed malabsorption syndrome or hypersensitivity to any form of iron treatment
5. Preexisting maternal depression or other psychiatric illness

Recruitment start date

09/08/2021

Recruitment end date

15/12/2022

Countries of recruitment

Nigeria

Study participating centre

Lagos University Teaching Hospital
Idi-Araba
Lagos
100254
Nigeria

Study participating centre

Lagos Island Maternity Hospital
Campbell Street
Lagos Island
Lagos
101231
Nigeria

Study participating centre

Mother and Child Centre
1st Avenue
1st Gate
Festac Town
Amuwo-Odofin
Lagos
102312
Nigeria

Study participating centre

Simpson Primary Health Centre
Simpson Street
Ebute-Metta
Lagos
101212
Nigeria

Study participating centre

Iwaya Primary Health Centre
Omotola street
Iwaya
Lagos
100213
Nigeria

Study participating centre

Aminu Kano Teaching Hospital
Zaria Road
Kano
7002333
Nigeria

Study participating centre

Sheikh Jeddah General Hospital
Bello Road 700224 Sabon Gari West
Kano
700271
Nigeria

Study participating centre

Bammali General Hospital
Emir Palace Road 700224 Kan Karofi
Kano
713261
Nigeria

Study participating centre

Kumbotsu Comprehensive Primary Health Centre
Kumbotsu
Kano
700104
Nigeria

Study participating centre

Sharada Primary Health Centre
Sharada
Kano
700234
Nigeria

Study participating centre

Kabuga Comprehensive Primary Health Centre
Gwarzo Rd, Kofar Dukayuwa
Nigeria
Kano
700282
Nigeria

Organisation

University of Lagos

Sponsor details

College of Medicine
Lagos
12003
Nigeria
+234 (0)8023002960
provost@cmul.edu.ng

Sponsor type

University/education

Website

http://www.unilag.edu.ng/

ROR

https://ror.org/05rk03822

Funder type

Charity

Funder name

Bill and Melinda Gates Foundation

Alternative name(s)

Bill & Melinda Gates Foundation, Gates Foundation, BMGF, B&MGF, GF

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both public and private)

Location

United States of America

Publication and dissemination plan

The researchers plan to publish the protocol in a peer-reviewed journal. The researchers plan to publish the study findings in high-impact peer-reviewed journals. The findings of the study will be presented at conferences (both international and local) so as to disseminate the findings to a large body of professionals in the field of Obstetrics and Gynaecology. The findings will be used in developing standard operating care manual/ protocol for the management of iron deficiency anaemia in pregnancy. The researchers will issue press releases about the findings of the study.

Intention to publish date

30/06/2024

Individual participant data (IPD) sharing plan

The datasets generated during and/or analysed during the current study will be stored in a publicly available repository. The researchers will store the data and deposit it in ‘Open Science Framework’ after approval is obtained from the ethics committee. The researchers will also provide metadata along with the data to describe it. No patient identifier will be included in the data shared. Potential new users may access our data including the metadata on the ‘Open Science Framework’. The researchers will share the data at the time of publication of our first paper. The assigned DOI number, the OSF website details and the approach to data sharing will be included as an appendix to all publications emanating from this research to facilitate accessibility to our data and metadata. The researchers will also share these at any conference presentation both international and local, and also on the study website to facilitate access by other researchers.
The individual participant data (IPD) sharing will commence at the time of the first publication or within 6 months of completing the study. The duration of IPD sharing will be 2 years. The tentative start date for IPD sharing is 01/01/2024 and the tentative end date is 31/12/2025.
Key access criteria include:
1. The principal investigator will bear overall responsibility for this data and will be responsible for deciding whether to supply research data to a potential new user. The CMUL HREC will provide an independent oversight function.
2. Data will be made available at the time of publication, at the latest. Depending on the nature of the data itself, data may be made available earlier, either on an individual basis to interested researchers and/or potential new collaborators.
3. The researchers will ensure that the informed consent forms clearly spell out and seek consent for future data sharing. However, only de-identified data will be shared.
4. All external users will sign and be bound by our data sharing agreements and will not be allowed to use the data for reasons other than stated in their application.
5. IPD sharing will be by open access on Open Science Framework during the period of IPD sharing.

IPD sharing plan summary

Stored in publicly available repository

Study outputs

• ISRCTN63484804_PIS.doc Uploaded 11/12/2020