Department of Physiology, KLE Academy of Higher Education and Research J N Medical
College Nehru Nagar Belgaum Principal Investigator Womens and Childrens Health Research Unit Wing Belgaum
Department of Physiology, KLE Academy of Higher Education and Research J N Medical
College Nehru Nagar Belgaum Principal Investigator Womens and Childrens Health Research Unit Wing Belgaum
KLES Dr Prabhakar Kore Charitable Hospital and Medical Research Centre, Belagavi
Department: Womens
and Childrens Health
Research Unit Wing
Institution: KLE
Academy of Higher
Education and
Researchs J N Medical
College Nehru Nagar Belgaum
9448124893 8312472891 mbbellad@hotmail.com
Dr Radha Sangavi
Raichur Institute of Medical Sciences, Raichur, Karnataka
Department of OBGYN, Survey 307 and 308, Industrial area, Hyderabad Road, Raichur, Karnataka 584102 Raichur
9902059441
radhasangavi16@gmail.com
Dr Ashalata Mallapur
S Nijalingappa Medical College and HSK Hospital and Research Centre, Bagalkote
Department of OBGYN, Near APMC Navanagar, Bagalkote, Karnataka 587102 Bagalkot
9945699986
drashalatamallapur@gmail.com
Dr Sudhir Mehta
Sawai Man Singh Medical College, Jaipur
Department: Medicine
Section: Hematology
Institution: SMS Medical College,Jawahar Lal Nehru Marg, Gangawal Park,
Adarsh Nagar, Jaipur Jaipur
Institional Ethics Committee-Racihur Institute of Medical Sciences, Raichur
Approved
Institutional Ethics Committee of Sawai Man Singh Medical College, Jaipur
Approved
Institutional Ethics Committee, KLE Academy of Higher Education and Research, Belagavi
Approved
SNMC-INSTITUTIONAL ETHICS COMMITTEE ON HUMAN SUBJECTS RESEARCH
Approved
Regulatory Clearance Status from DCGI
Status
Not Applicable
Health Condition / Problems Studied
Health Type
Condition
Patients
Anemia complicating pregnancy, childbirth and the puerperium
Intervention / Comparator Agent
Type
Name
Details
Intervention
Ferric carboxymaltose arm
Dose-up to 1 g
Frequency-Single dose
Route of
administration-Intravenous Duration of
therapy-A single dose administered during 14-17 weeks of pregnancy
Intervention
Iron Isomaltoside arm
Dose-up to 1 g
Frequency-Single dose
Route of administration-Intravenous
Duration of therapy-A single dose administered during 14-17 weeks of pregnancy
Comparator Agent
Oral iron arm
Dose-60 mg of elemental iron tablets
Frequency-two tablets a day when Hb is less than 11 g% and one tablet a day if Hb increases to more than 11 g% Route of administration-Oral Duration of therapy-from 14-17 weeks of pregnancy until delivery
Inclusion Criteria
Age From
18.00 Year(s)
Age To
40.00 Year(s)
Gender
Female
Details
Inclusion Criteria for Study Consent for Initial Participation
1. Pregnant women between 18–40 years of age at time of consent that received education about the study and capable of giving informed consent
2. Hemoglobin concentration of 7 – 10.4 g/dL
3. Expressed intent and expectation of remaining in the designated research area during the pregnancy and delivering at a facility in or near the research area and remaining in the area to enable study participation and data collection consistent with the research protocol
4. Expressed willingness that specifically includes agreement to randomization to the standard care study arm (of oral iron) or to one of the two arms involving treatment with single-dose IV iron
Additional Inclusion Criteria for Randomization and Continued Study Participation:
1. Presence of a live singleton, intrauterine fetus and dating ultrasound that indicates a pregnancy that, at randomization, would be between the beginning of week 14 and prior to 17 weeks 0 days;
2. Iron deficiency anemia defined for this study as moderate anemia with hemoglobin concentration level between 7 - 9.9 g/dL and serum transferrin saturation (TSAT) is <20% and/or ferritin is <30 ng/mL
ExclusionCriteria
Details
1. Fetal anomaly if detectable when an initial ultrasound is done to date the pregnancy (subsequent discovery of a fetal anomaly is not viewed as an exclusion criterion)
2. History of cardiovascular disease, hemoglobinopathy, or other disease or condition con-sidered a contraindication for treatment, including conditions recommended for exclusion by the manufacturers of oral or IV iron to be used in this study
3. Any condition that in the opinion of the consenting physician warrants study exclusion.
Method of Generating Random Sequence
Permuted block randomization, variable
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
1. Percentage of participants who achieve Hb of more than or equal to 11 g/dL at either a 30-34 week antenatal visit or at a birthing facility (comparing each IV iron arm to the oral iron arm)
2. Rate of Low birthweight (less than 2500 gram birthweight) births (comparing each IV iron arm to the oral iron arm)
Up to delivery
Secondary Outcome
Outcome
TimePoints
Antepartum and severe postpartum hemorrhage
Up to 42 days postpartum
Birth weight and length of live born babies
Measured within 72 hours post-delivery
Changes in hemoglobin concentration by moderate anemia subgroups (7 - 7.9, 8 - 8.9, and 9 - 9.9 g/dL)
Up to delivery
Changes in other iron indices (Transferrin Saturation, Ferritin and Complete Blood Count parameters)
Up to 42 days postpartum
Costs associated with clinical outcomes of IDA in pregnancy such as low birth weight, small for gestational age (SGA) and preterm infants, need for maternal or neonatal transfusion and incremental days of maternal or neonatal hospitalization
Up to 42 days postpartum
Hb and other iron indices of cord blood
At the time of delivery
Hypertensive disorders (pre-eclampsia, eclampsia)
Up to 42 days postpartum
Maternal and neonatal mortality
Up to 42 days postpartum
Maternal or neonatal infection including documented COVID-19 infection
Up to 42 days postpartum
Maternal well-being (quality of life)
At 42 days postpartum
Mode of delivery and C-section
At the time of delivery
Need for neonatal resuscitation
within 72 hours of birth
Neonatal admissions to an intensive care unit
Birth to 28 days of Life
Participant need for “rescue therapy” due to a drop in Hb level to less than 7 g/dL at any time after randomization and treatment
Up to 42 days postpartum
Possible change in treatment due to less than 1 g/dL improvement in Hb based upon analysis of blood collected at 26-30 weeks of pregnancy
Up to 30 weeks of pregnancy
Pregnancy loss and stillbirths
Up to end of pregnancy
Preterm and small for gestational age births
At the time of delivery
Referral of a study participant to a First Referral Unit or District Hospital with specialized services for thorough assessment of the causes of anemia
Up to 42 days postpartum
Self-reported breastfeeding practices
Up to 42 days postpartum
Time from delivery to cord clamping
within 72 hours of birth
Unanticipated or extended hospitalizations
Up to 42 days postpartum
Weight gain of participants by trimester of pregnancy
Up to delivery
Target Sample Size
Total Sample Size="4320" Sample Size from India="4320"
Derman RJ, Goudar SS, Thind S, Bhandari S, Aghai Z, Auerbach M, Boelig R, Charantimath US, Frasso R, Ganachari MS, Gaur KL, Georgieff MK, Jaeger F, Yogeshkumar S, Lalakia P, Leiby B, Majumdar M, Mehta A, Mehta S, Mehta S, Mennemeyer ST, Revankar AP, Sharma DK, Short V, Somannavar MS, Wallace D, Shah H, Singh M, Askari S, Bellad MB; RAPIDIRON Trial Group. RAPIDIRON: Reducing Anaemia in Pregnancy in India-a 3-arm, randomized-controlled trial comparing the effectiveness of oral iron with single-dose intravenous iron in the treatment of iron deficiency anaemia in pregnant women and reducing low birth weight deliveries. Trials. 2021 Sep 23;22(1):649. doi: 10.1186/s13063-021-05549-2. PMID: 34556166; PMCID: PMC8459820.
Brief Summary
Anemia is a
worldwide problem with iron deficiency being the most common cause. When occurring
in pregnancy, anemia increases the risk of adverse maternal, fetal and neonatal
outcomes, including maternal mortality,
preterm and low birth weight (LBW) deliveries, perinatal and neonatal deaths, and
long-term developmental sequelae in the surviving offspring. Anemia rates are among the highest in south
Asia, and India’s latest National Family Health Survey (NFHS-4) for 2015-16 indicates
that anemia with hemoglobin (Hb) <11.0 g/dL affects over
50% of pregnant women. For close to 40 years, India’s first-level
treatment for anemia in pregnancy has been oral iron; however, side effects, poor
adherence to tablet ingestion and low therapeutic impact are among reasons for consideration
of a new paradigm for treatment of pregnant women with iron deficiency anemia. The
Government of India has given high priority to reducing the prevalence of
anemia in India, and several initiatives have been directed at this objective. The
latest anemia strategy, built on prior strategies and supported by the Ministry of Health and Family
Welfare, was presented in a 2018 publication, Anemia Mukt Bharat-Intensified
National Iron Plus Initiative.The same overall strategy remains in effect, but a few changes have been made
to specific intervention guidelines.Notably, this research focuses on pregnant
women, one of the population groups targeted by Anemia Mukt Bharat which
has the goal of reducing prevalence of anemia among children, adolescents and
women in the reproductive age group by 3% a year. The current anemia strategy,
supported by the RAPIDIRON Trial, can help facilitate India’s efforts to
achieve a 2025 Global World Health Assembly target of a 50% reduction of anemia
among women of reproductive age.
This
study, a 3-arm, randomized-controlled trial has two primary outcomes of
interest. The research is designed to
assess if a single dose of an intravenous (IV) iron formulation (ferric
carboxymaltose in intervention arm
1 or iron isomaltoside, also known by the international non-proprietary name of
ferric derisomaltose, in intervention arm 2), administered early in the
second trimester of pregnancy for treatment of moderate iron deficiency anemia
(IDA), will result in a greater percentage of pregnant participants in the IV
iron arms achieving a normal for pregnancy Hb concentration of >11
g/dL in the third trimester at either a 30-34 week antenatal visit or based on
blood collected prior to delivery when compared to the percentage of participants
randomized to an active, comparator arm (arm 3) provided oral iron.Low birth weight (< 2500 grams), one
ofseveral adverse pregnancy outcomes associated
with IDA, is the other primary outcome. The hypothesis for this clinical
outcome is that the LBW delivery rates for participants randomized to the IV
iron arms will be significantly lower when compared to the LBW delivery rate of
participants randomly assigned to the oral iron arm.
Comparison
of differences between arms are proposed for the following secondary outcomes
of interest: changes in hemoglobin concentration by moderate anemia subgroups
(i.e., 7 - 7.9,8- 8.9, and 9 - 9.9 g/dL), other
participantiron indices (serum
transferrin saturation and ferritin levels), Hb and other iron indices of cord
blood, weight gain of participants by trimester of pregnancy, mode of
delivery/C-section, antepartum and severe postpartum hemorrhage, hypertensive
disorders (pre-eclampsia and eclampsia), maternal or neonatal infection
including documented COVID-19 infection, maternal and neonatal mortality, preterm
and small for gestational age births, pregnancy loss and stillbirths, birth
weight and length of live born babies (measured within 72 hours post-delivery),
the need for neonatal resuscitation, neonatal admissions to an intensive care
unit, time from delivery to cord clamping, unanticipated or extended
hospitalizations, breastfeeding practices including self-reported exclusive
breastfeeding, and maternal well-being (quality of life). Due to consideration
of current Anemia Mukt Bharat interventional guidelines for anemia
treatment in pregnant women,3 two additional secondary outcomes will
be assessed: participant need for “rescue therapy” when Hb concentration drops
to <7 g/dL at any time after treatment; and referral to a higher level of
care for evaluation because hemoglobin improvement is <1 g/dL based upon
analysis ofblood collected at26-30 weeks of pregnancy.
Transferrin saturation (TSAT) and ferritin
level will be used in the study to establish that a pregnant woman has anemia
and iron deficiency, and these indices will be monitored during the study.At defined study visits when a complete blood
count is performed, reticulocyte hemoglobin (Ret-He) and immature reticulocyte
fraction (IRF) will also be calculated (to support exploratory analyses) since
reticulocyte indices are markers for iron deficiency and potential tools for
assessing response after iron therapy. Other tests to better understand the
problem of anemia among pregnant women in India will also be performed.Adverse reactions to oral or IV iron will be carefully
monitored, documented and assessed by independent adjudicators with expertise
in the use of IV iron. The research will additionally explore factors necessary
for India-wide scale-up and identify obstacles to change as well as approaches
for removing such obstacles.