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CTRI Number  CTRI/2020/09/027730 [Registered on: 10/09/2020] Trial Registered Prospectively
Last Modified On: 07/07/2023
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   Reducing Anemia in Pregnancy in India 
Scientific Title of Study   Reducing Anemia in Pregnancy in India: the RAPIDIRON Trial 
Secondary IDs if Any  
Secondary ID  Registry 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)  
Name  Dr Mrutyunjaya B Bellad 
Address  1st Floor, Department of OBGYN, KLE Academy of Higher Education and Research, J N Medical College Nehru Nagar Belgaum

Belgaum
KARNATAKA
590010
India 
Phone  9448124893  
Fax  8312472891  
Email  mbbellad@hotmail.com  
 
Details Contact Person
Scientific Query

Modification(s)  
Name  Dr Shivaprasad S Goudar 
Address  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

Belgaum
KARNATAKA
590010
India 
Phone  9448126371  
Fax  8312472891  
Email  sgoudar@jnmc.edu  
 
Details Contact Person
Public Query

Modification(s)  
Name  Dr Shivaprasad S Goudar 
Address  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

Belgaum
KARNATAKA
590010
India 
Phone  9448126371  
Fax  8312472891  
Email  sgoudar@jnmc.edu  
 
Source of Monetary or Material Support
Modification(s)  
Childrens Investment Fund Foundation, 7 Clifford Street London, W1S 2FT United Kingdom 
 
Primary Sponsor  
Name  Childrens Investment Fund Foundation 
Address  7 Clifford Street London, W1S 2FT United Kingdom 
Type of Sponsor  Other [Independent philanthropic organisation] 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 4  
Contact Person  Name of Site  Site Address  Phone/Fax/Email 
Dr Mrutyunjaya B Bellad  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
 
9414042033

sudhirm02@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 4  
Name of Committee  Approval Status 
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" 
Phase of Trial   N/A 
Date of First Enrollment (India)   01/02/2021 
Date of First Enrollment (Global)  No Date Specified 
Estimated Duration of Trial   Years="3"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Not Applicable 
Recruitment Status of Trial (India)  Closed to Recruitment of Participants 
Publication Details
Modification(s)  
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 of  several 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 participant  iron 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 of  blood collected at  26-30 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.

The study will be carried out in India in primary and community health centers (PHCs, CHCs), hospitals and birthing facilities located in two research areas in the states of Karnataka and Rajasthan. Approximately 4,320 pregnant women who meet eligibility criteria and have hemoglobin (Hb) concentrations of 7 to 9.9 g/dL (the WHO definition of moderate anemia) and confirmed IDA will be randomized 1:1:1 to one of two IV iron intervention arms or to the arm that will be given oral iron. This study supports the overall goals of the Ministry of Health and Family Welfare (MOHFW) for pregnancy care; thus, all study participants will be followed according to the Ministry’s antenatal care guidelines, and data will be collected through 42 days post-delivery.

 

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