Iron Infusion Into a Vein Compared to Iron Tablet Taken by Mouth for Treating Iron Deficiency Anemia in Pregnancy (IVON)
Condition: Iron Deficiency Anemia of Pregnancy
MeSH terms: Anemia; Anemia, Iron-Deficiency; Iron Deficiencies; Deficiency Diseases
Study type: Interventional
Phase: Phase 3

Summary: 
      Background: Anaemia in pregnancy is a public health burden with high incidence in Africa.
      Currently high dose oral iron is recommended for treatment of mild to moderate anaemia and
      blood transfusion for severe anaemia. The high dose oral iron is often poorly tolerated and
      associated with several side effects. Various parenteral iron preparations are now available
      for treatment of iron deficiency anaemia (IDA). The earliest of these, iron dextran is not
      commonly used because of its potential to cause anaphylactic reactions. Newer preparations
      have been found to be safer and their use for treatment of IDA is currently being evaluated.

      Objective: This study sought out to compare the effectiveness of intravenous ferric
      carboxymaltose (intervention) versus oral ferrous sulphate (control) for treating IDA in
      pregnancy and to compare the tolerability, safety and the cost-effectiveness of intravenous
      versus oral iron among pregnant Nigerian women with moderate and severe IDA at 20-32 weeks'
      gestation.

      Methodology: This study will be a hybrid Type 1 effectiveness-implementation design. 1056
      eligible and consenting pregnant women with anaemia at 20 - 32 weeks gestation will be
      recruited. They will be randomized into either of 2 groups. Group A will have intravenous
      ferric carboxymaltose 20mg/kg to a maximum of 1000mg in 200mls of normal saline infusion over
      15 - 20 minutes at enrolment. Group B will have oral ferrous sulphate 200mg (65mg elemental
      iron) thrice daily from enrolment till delivery. They will be followed up through delivery
      and until 6 weeks post partum. Their haemoglobin concentration, full blood count, serum
      ferritin and serum transferrin will be assayed at specific intervals using standard
      laboratory techniques. Depression will be assessed at each visit using Edinburg Postnatal
      Depression Scale. Cost effectiveness analysis will also be done at each visit. The primary
      outcome measure will be incidence of maternal anaemia and rise in haemoglobin level.
      Secondary outcome measures will include safety and tolerability of trial drugs, severe
      maternal events, incidence of infant low birth weight and incidence of depression.
      Statistical analysis will be done using STATA version 16.0 statistical software (STATACorp,
      Texas, USA).
    

Detailed description: 
      1.0 INTRODUCTION Anemia in pregnancy (AIP) remains a critical global health problem
      especially in low- and middle-income countries (LMICs), affecting 46% of pregnant women in
      Africa and 49% in Asia. AIP is defined as a venous blood hemoglobin concentration of <11 g/dl
      in a pregnant woman. Iron deficiency anemia (IDA) is the commonest cause of AIP, accounting
      for 50-75% of AIP. Antenatal maternal anemia has significant implications on both maternal
      and neonatal outcomes, including maternal mortality from hemorrhage and morbidity from
      infections, and neonatal low birth weight and prematurity. It has also been associated with
      an increased risk of depression.

      In most LMICs, including Nigeria, routine treatment of IDA in pregnancy is with oral iron
      preparations, due to fears of serious adverse reactions from parenteral iron, including
      anaphylaxis, and the belief that oral iron is equally effective. Parenteral, especially
      intravenous, iron is also more expensive, and it is not clear whether its benefits are worth
      the cost. In settings like Nigeria, where most people still pay out-of-pocket for healthcare,
      cost effectiveness is particularly important. However, apart from the side effects caused by
      oral iron, it also takes longer to correct the anemia, and in cases where patients are unable
      to absorb iron, oral intake is rendered ineffective. Reservations on use of parenteral iron
      have been due largely to experience with high molecular weight iron dextran preparations,
      which had a relatively high incidence of anaphylactic reactions. Fortunately, there are now
      several safe parenteral iron preparations, such as iron sucrose, iron polymaltose, ferric
      carboxymaltose (FCM) and iron isomaltoside.

      2.0 AIMS AND OBJECTIVES Aims: To determine the comparative effectiveness of intravenous FCM
      (intervention) versus oral ferrous sulphate (control) for treating iron deficiency anemia in
      pregnancy and to compare the tolerability, safety, and the cost-effectiveness of intravenous
      versus oral iron among pregnant Nigerian women with moderate and severe IDA at 20-32 weeks'
      gestation. It also aims to evaluate the acceptability, feasibility, and fidelity of use of
      intravenous FCM for treating IDA.

      Objectives

        1. To determine effect of intravenous FCM on the prevalence of maternal anemia at 36 weeks'
           gestation and on increase in hemoglobin concentration 4 weeks after administration,
           compared with oral ferrous sulphate (FS) in pregnant women with IDA.

        2. To determine effect of intravenous FCM on incidence of postpartum hemorrhage, sepsis,
           shock, need for blood transfusion, prevalence of depression and other maternal clinical
           outcomes, compared with oral FS in pregnant women with IDA.

        3. To determine effect of intravenous FCM on the incidence of low infant birthweight,
           prematurity, stillbirth, and neonatal mortality, and on breastfeeding and immunization,
           compared with use of oral FS in pregnant women with IDA.

        4. To measure implementation outcomes of intravenous FCM including its acceptability,
           feasibility, and fidelity in the context in which the trial is being carried out.

        5. To determine cost-effectiveness of intravenous FCM compared with oral FS in treatment of
           IDA in pregnancy.

      3.0 STUDY DESIGN: This study is a multicenter, parallel, open label, individually randomized
      controlled trial, with women allocated in a 1:1 ratio in conjunction with a
      cost-effectiveness analysis.

      3.1 Study setting and site selection: The study will be implemented in two most populated
      states in Nigeria; Kano State in North-West and Lagos State in South-West zone. One tertiary,
      two secondary and two primary healthcare facilities have been purposively selected from each
      state, making 10 targeted facilities based on antenatal patient flow, number of deliveries
      and proximity of all three levels of care to facilitate an effective two-way referral system.

      3.2 Sample size calculations: At 5% significance and precision level, 1,056 pregnant women
      (528 in each study arm) are required to detect a difference in improvement in prevalence of
      AIP at term by 14%, between control group (70% corrected) and intervention group (84%
      corrected), as seen in a multi-country international study in Europe, Asia, and Australia
      (30) at 90% power, adjusting for 15% attrition and protocol violations (31).

      3.3 Randomization: At enrolment, eligible participants will be randomized to one of the two
      treatment groups using a web-based randomization software known as 'Sealed envelope' in a 1:1
      ratio in blocks stratified according to center.

      3.4 Study intervention: Eligible pregnant women randomized to intervention arm (FCM) will be
      admitted on a day care basis for treatment initiation and will be given intravenous FCM in a
      single dose of 20mg/kg up to a maximum of 1000mg in 200 ml 0.9% sodium chloride infusion over
      a minimum of 15 - 20 minutes. Thereafter, they will be observed for a minimum of 30 minutes
      before being allowed to go home.

      The pregnant women randomized to the control arm (FS) will be given one 200mg tablet of
      ferrous sulphate containing 65mg of elemental iron, three times daily till 6 weeks
      post-delivery. The women will be sent daily reminders by text messages, questioned on
      compliance at each visit and asked to bring in their empty sachets for sighting and pill
      count.

      After delivery, all study participants will be tested for anemia with Hemocue before
      discharge. Those with hemoglobin concentration less than 11g/dl will be treated as per
      standard practice i.e., with FS 200mg tds, vitamin C 100mg tds and folic acid 5mg daily.

      All study participants in both arms will receive 5mg folic acid daily, vitamin C 100mg tds,
      and followed from enrollment till delivery and for 6 weeks post-partum. They will be seen
      4-weekly till 28 weeks, 2 weekly till 36 weeks and weekly till delivery and then at 2, 4 and
      6 weeks postpartum.

      3.5 Malaria Treatment and Prevention: Participants will be screened at enrolment for malaria
      parasitemia with SD BIOLINE Malaria Ag P.f and treated with Artemisinin based combination
      therapy if positive for malaria parasite. Thereafter, intermittent preventive treatment for
      malaria will be administered with three doses of three tablets of Sulphadoxine pyrimethamine
      (500/25) monthly except if patient is allergic to sulphonamides, in which case, patient will
      be placed on monthly artemisinin-lumefantrine (treatment dose). All pregnant women will also
      be given long lasting insecticide treated bed nets and counseled on usage.

      3.6 Physical examination: Full physical examinations will be performed at baseline, and at
      each visit. The initial evaluation will also include measurement of patient's weight and
      blood pressure.

      3.7 Laboratory evaluations: These will include:

        -  Full blood count at enrollment, 4 weeks post enrollment, 36 weeks' gestation, day of
           delivery and 6 weeks' postpartum.

        -  Malaria rapid diagnostic test (RDT) with SD BIOLINE Malaria Ag P.f at enrolment and if
           symptomatic for malaria at any time.

        -  Hemoglobin concentration with the Hemocue haemoglobinometer at enrolment and every study
           visit. The first will be used for enrollment.

        -  Iron profile: This will comprise serum ferritin, serum iron, total iron binding capacity
           and transferrin saturation at 4 weeks post enrollment, 36 weeks' gestation, day of
           delivery and 6 weeks postpartum. Only serum ferritin will be done at enrolment.

        -  Serum phosphate: maternal phosphate level at enrollment, 4 weeks post enrollment, on day
           of delivery and 6 weeks postpartum; and cord blood phosphate on day of delivery.

      All samples aside point of care tests (POCT) will be analyzed at Synlab (an internationally
      accredited medical laboratory).

      3.9 Visit schedules and assessments

        -  The participants' subsequent clinic visits will be scheduled to hold every 4 weeks till
           28 weeks' gestation and every 2 weeks till 36 weeks, then weekly until delivery.
           Thereafter, they will be seen at 2, 4 and 6 weeks postpartum. Reminders on appointments
           will be sent by SMS to all participants 24 hours before scheduled visit.

        -  Women diagnosed as having depression using Edinburg Postnatal Depression Scale (EPDS)
           will be referred to a psychiatrist for further management.

      4.0 DATA ANALYSIS PLAN Data analysis will be by intention-to-treat. Categorical variables
      will be expressed as frequencies and percentages. For continuous variables, a Shapiro-Wilk
      test of normality will be performed, and normally distributed data will be presented as means
      ± SD, while non-normally distributed data will be presented as median and interquartile range
      (IQR). The risk of occurrence of IUGR, perinatal death and other key outcome variables will
      be computed and compared in both groups. A multivariate regression analysis will be performed
      to determine the odds of each of the key outcomes among women who received the intervention
      with respect to those who did not, after controlling for common confounders. This will be
      presented as regression coefficients and their 95% confidence intervals. Level of
      significance will be set at 5%. Post-regression analysis will be performed to determine the
      goodness-of-fit of the final model. STATA version15.0 (Stata Corp LP, College Station, TX,
      USA) will be used for statistical analysis.

      5.0 MONITORING PLAN - There will also be a Steering committee, Clinical Trial Monitors, and a
      Data and Safety Monitoring Committee (DSMC).

      6.0 ETHICS AND RESEARCH INTEGRITY: This trial has been registered in Pan African Clinical
      Trials Registry (PACTR202012843695208), International Standard Randomized Controlled Trial
      Number registry (ISRCTN63484804) and Nigeria Clinical Trial Registry (NCTR, 86233598).

      Ethical approvals have been obtained from the National Health Research and Ethics Committee
      of Nigeria (NHREC), and HREC of both teaching hospitals and health care boards in both
      states. All study investigators and site coordinators are GCP certified. The research nurses
      will also be GCP certified.

      All participants will sign informed consent form prior to enrolment. Personal data of each
      participant will be kept strictly confidential and will be stored securely in a central
      electronic database. Only authorized personnel will have access to the data of all
      participants collated centrally. The statistician will be granted access to the electronic
      database during statistical analysis or at any other time the PI might require her to review
      the data. All research drugs and investigations relating to the research will be offered
      free.

      This research poses minimal or no risk to both mother and baby. Blood specimen collection
      might cause minimal discomfort in form of pain and care will be taken to minimize this. The
      intervention drug FCM is known to be safe in pregnancy and is not expected to have
      significant adverse effects on participants.

      All research staff will be adequately trained to monitor, recognize, and manage any
      significant adverse drug event. In the rare instance of any moderate/severe adverse drug
      events such as hypophosphatemia and anaphylaxis, trained research staff will effectively
      resuscitate and transfer care to higher level health facility for adequate care at no cost to
      the participant.

      All participants will receive other routine medication (malaria prophylaxis, tetanus toxoid
      prophylaxis and folic acid supplementation) as normally prescribed. Malaria prophylaxis,
      insecticide treated net and folic acid will be provided to the participants all through
      pregnancy. The participants will enjoy equal rights and quality care all through the duration
      of the research.

      Environmental issues are not applicable to this study. 7.0 DISSEMINATION STRATEGIES The study
      findings will be presented at conferences (both international and local). Findings will be
      published in high impact peer reviewed journals. Charts will be created from findings, and
      these will be used in counselling pregnant women at the various antenatal clinics on
      complications associated with anemia and preventive measures that may be employed. The
      researchers will issue press release on study finding.
    

Intervention name(s): Ferric carboxymaltose; Ferrous sulfate
Intervention type(s): Drug; Drug
Intervention description(s): Ferric carboxymaltose to be given as an intravenous infusion; Ferrous sulphate tablet to be taken orally
Other intervention name(s): Ferinject; Fesulf
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomized using Sealed Envelope software and assigned into 2 parallel study arrms as they are recruited. Those in the FCM group will receive Intravenous Ferric Carboxymaltose (Interventional drug) and those in the FS group will receive Oral Ferrous Sulphate (Standard drug).
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: anaemia in pregnancy; iron deficiency; ferric carboxymaltose; ferrous sulphate; intravenous; oral; side effects; effectiveness