A Study of Nipocalimab in Pregnancies at Risk for Severe Hemolytic Disease of the Fetus and Newborn (HDFN) (AZALEA)

A Phase 3 Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Nipocalimab in Pregnancies at Risk for Severe Hemolytic Disease of the Fetus and Newborn (HDFN)

The purpose of this study is to assess the effectiveness of nipocalimab when compared to placebo in decreasing the risk of fetal anemia (a condition in which a baby's red blood cell volume falls below normal levels while the baby is developing in the womb) with live neonates in pregnant participants at risk for severe hemolytic disease of the fetus and newborn.

Study Overview

• Status: Recruiting
• Conditions: Hemolytic Disease of the Fetus and Newborn
• Intervention / Treatment: Drug: Nipocalimab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Study Contact; Phone Number: 844-434-4210; Email: Participate-In-This-Study@its.jnj.com

Study Locations

• Australia
  • South Brisbane, Australia, 4101
    • Recruiting
    • Mater Hospital Brisbane
• Brazil
  • Goiania, Brazil, 74605-050
    • Recruiting
    • Empresa Brasileira de Servicos Hospitalares - EBSERH - Hospital das Clinicas da UFG
  • Recife, Brazil, 50070902
    • Recruiting
    • Instituto de Medicina Integral Professor Fernando Figueira
  • Sao Paulo, Brazil, 05403-000
    • Recruiting
    • Hospital Das Clinicas Da Faculdade De Medicina Da USP
• Israel
  • Petah Tikva, Israel, 49100
    • Recruiting
    • Rabin Medical Center
  • Ramat Gan, Israel, 5265601
    • Recruiting
    • The Chaim Sheba Medical Center
• United Kingdom
  • Birmingham, United Kingdom, B15 2TG
    • Recruiting
    • Birmingham Women's Hospital
  • Manchester, United Kingdom, M13 9WL
    • Recruiting
    • St.Mary's Hospital
• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7516
      • Recruiting
      • University of North Carolina (UNC) - School of Medicine
  • Texas
    • Austin, Texas, United States, 78723
      • Recruiting
      • University of Texas Dell Medical School Department of Women's Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pregnant and an estimated gestational age (GA) (based on ultrasound dating) from Week 13^0/7 to Week 16^6/7 at randomization

• History of severe Hemolytic Disease of the Fetus and Newborn (HDFN) in a prior pregnancy defined as:

  1. documented fetal anemia, or received greater than or equal to (>=)1 IUT as a result of HDFN or
  2. fetal loss or neonatal death as a result of HDFN, with maternal alloantibody titers for Rhesus antigen D protein (RhD), Kell, Kell Rhesus antigen C protein (Rhc), Rhesus antigen E protein (RhE), or RhC antigen above the critical levels (anti-Kell >=4; other >=16) and evidence of an antigen-positive fetus
• During the current pregnancy, presence of maternal alloantibody to RhD, Rhc, RhE, or RhC antigen with titers above the critical level (anti-Kell >= 4; other >=16) based on the designated central lab results at screening
• Evidence of antigen-positivity corresponding to the current maternal alloantibody (RhD, Kell, Rhc, RhE, or RhC) confirmed by non-invasive antigen cell-free fetal DNA (cffDNA) performed at the central laboratory.
• Have screening laboratory values within the study protocol-specified parameters: a) albumin, >=2.6 grams (g) per deciliter (g/dL), international system (SI): >=26 gram per liter (g/L); b) alanine transaminase (AST) less than or equal to (<=) 2 × upper limit of normal (ULN); c) alanine transaminase (ALT) <=2 × ULN d) creatinine <=0.8 milligrams per deciliter (mg/dL), SI: <=70.7 micromole per liter (μmol/L), and Serum total immunoglobulins G (IgG) ≥ 600 mg/dL SI: >=6 g/L
• Otherwise healthy on the basis of physical examination, medical history, vital signs, 12-lead ECG, and clinical laboratory tests performed at screening.

Exclusion Criteria:

• Currently pregnant with a multiple gestation (twins or more)
• Evidence of fetal anemia prior to randomization in the current pregnancy
• Current uncontrolled hypertension
• History of myocardial infarction, unstable ischemic heart disease, or stroke
• Has any confirmed or suspected clinical immunodeficiency syndrome or has a family history of congenital or hereditary immunodeficiency unless confirmed absent in the participant
• Has inflammatory or autoimmune diseases requiring immunosuppressive therapies that may jeopardize the safety of the participant
• Currently has a malignancy or has a history of malignancy within 3 years before screening (with the exception of localized basal cell carcinoma and/or squamous cell carcinoma skin cancer that has been adequately treated with no evidence of recurrence for at least 3 months
• Is currently receiving systemic corticosteroids or other immunosuppressants for disorders unrelated to the pregnancy
• Has received or planning to receive plasmapheresis, immunoadsorption therapy, intravenous immunoglobulin (IVIg), or any immunoglobulin (Ig)G fragment crystallizable (Fc)-related protein therapeutics during the current pregnancy
• Has a severe infection including opportunistic infections
• Presence of abnormal (protocol-specified) hematologic laboratory values during screening
• History of severe preeclampsia prior to GA Week 34 or severe fetal growth restriction (estimated fetal weight <3rd percentile, based on local fetal growth normative standards) in a previous pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nipocalimab; Participants will receive nipocalimab intravenously (IV) once weekly (qw) from randomization through gestational age (GA) Week 35.	Drug: Nipocalimab; Nipocalimab will be administered as an intravenous infusion.; Other Names: - JNJ-80202135; - M281
Placebo Comparator: Placebo; Participants will receive matching placebo IV qw from randomization through GA Week 35.	Drug: Placebo; Placebo will be administered as an intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Pregnancies That did not Result in Fetal Loss, Intrauterine Transfusion (IUT), Hydrops Fetalis, or Neonatal Death	Percentage of pregnancies that did not result in fetal loss, IUT, hydrops fetalis, or neonatal death (during the neonatal period) will be reported. Hydrops fetalis is defined as the presence of greater than or equal to(>=)2 abnormal fluid collections in the fetus or neonate, such as ascites, pleural effusions, pericardial effusion, and generalized skin edema (skin thickness greater (>)5 millimeter (mm). PMA is the time elapsed between the first day of the last menstrual period and birth (gestational age) plus the time elapsed after birth (chronological age).	From randomization in the study through 4 weeks of age or 41 weeks Postmenstrual Age (PMA) during neonatal period, whichever is later

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Hemolytic Disease of the Fetus and Newborn (HDFN) by Severity	Number of participants with HDFN by severity will be reported. The severity of HDFN is defined as: 5 (fatal): fetal or neonatal death due to any reason; 4 (severe): hydrops fetalis (in fetus or newborn) or receiving IUT during pregnancy as a result of HDFN but not 5 (fatal); 3 (moderate): neonatal exchange transfusions received as a result of HDFN related hemolysis and jaundice but not 4 (severe) or 5 (fatal); 2 (mild): neonatal simple transfusions received due to HDFN after birth, with or without phototherapy, but not 3 (moderate), 4 (severe), or 5 (fatal); and 1 (minimal or none): not in 2 (mild), 3 (moderate), 4 (severe), or 5 (fatal) as described above. Here database lock implies the last participant has given birth or terminated their pregnancy, completed the Week 4 visit after delivery, and whose neonate has also completed the Week 4 visit (or 41 weeks PMA, whichever is later) or died prior to this timepoint.	For first database lock: from randomization in the study through 4 weeks of age or 41 weeks PMA during neonatal period, whichever is later for the first database lock; for second database lock: through 12 weeks after birth
Time to First Occurrence of IUT or Hydrops Fetalis	Time to first occurrence of IUT or hydrops fetalis will be reported.	From randomization to delivery of baby (Up to 38 weeks)
Neonatal Mortality and Morbidity Index (NMMI) in Liveborn Neonates	The NMMI will be assessed with the following categories: fatal: fetal/neonatal death; major morbidity: any of intraventricular hemorrhage grade 3/4, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage 2/3, respiratory distress syndrome requiring mechanical ventilation, bronchopulmonary dysplasia requiring oxygen support, or persistent pulmonary hypertension; Minor morbidity: anemia requiring simple transfusion, hyperbilirubinemia requiring an exchange transfusion, hypotension requiring treatment, intraventricular hemorrhage grade 1/2, necrotizing enterocolitis stage 1, or respiratory distress syndrome not requiring mechanical ventilation; None: no major or minor morbidities described above. Hyperbilirubinemia requiring phototherapy will be classified in this category'	Through 38 weeks PMA or at discharge if earlier than 38 weeks PMA
Number of IUT's Received During the Pregnancy	Number of IUT's received during the pregnancy will be reported.	From randomization to delivery of baby (Up to 38 weeks)
Percentage of Pregnancies With Fetal Loss	Percentage of pregnancies with fetal loss will be reported.	Time to delivery of baby (Up to 38 weeks)
Percentage of Pregnancies With Fetal or Neonatal Death	Percentage of pregnancies with fetal or neonatal death (through the neonatal period) as a result of HDFN will be reported.	Through Week 4 or 41 weeks PMA
Percentage of Pregnancies With Hydrops Fetalis	Percentage of pregnancies with hydrops fetalis will be reported. Hydrops fetalis is defined as the presence of >=2 abnormal fluid collections in the fetus or neonate, such as ascites, pleural effusions, pericardial effusion, and generalized skin edema (skin thickness >5 mm).	Up to 41 weeks PMA
Percentage of Pregnancies Receiving IUT During Pregnancy	Percentage of pregnancies receiving IUT during pregnancy will be reported.	Up to 35 weeks of GA period
Gestational Age (GA) at First IUT	GA at first IUT will be reported.	Up to 35 weeks of GA period
Percentage of Pregnancies Receiving >1 IUT During Pregnancy	Percentage of pregnancies receiving >1 IUT during pregnancy will be reported.	Up to 35 weeks of GA period
Percentage of Pregnancies Receiving IUT or HDFN Resulting in Fetal Demise (Less Than) <GA Week 20	Percentage of pregnancies receiving IUT or HDFN resulting in fetal demise <GA Week 20 will be reported.	Up to 20 weeks
Gestational Age at Delivery	Gestational age at delivery will be reported.	Up to 38 weeks
Percentage of Pregnancies With Neonatal Death Through the Neonatal Period	Percentage of pregnancies with neonatal death through the neonatal period will be reported.	From randomization in the study through 4 weeks of age or 41 weeks PMA during neonatal period, whichever is later
Percentage of Liveborn Neonates With HDFN-related Morbidities Other Than Anemia and Hyperbilirubinemia or Jaundice	Percentage of liveborn neonates with HDFN-related morbidities other than anemia and hyperbilirubinemia or jaundice will be reported.	From day of birth up to 4 weeks
Absolute Weight of Liveborn Neonates or Infants	Absolute weight of liveborn neonates or infants will be reported.	Up to 104 weeks
Change From Baseline in Weight of Liveborn Neonates or Infants	Change from baseline in weight of liveborn neonates or infants will be reported.	Baseline to up to 104 weeks
Liveborn Neonates Length of Stay in Neonatal Intensive Care Unit	Liveborn neonates length of stay in neonatal intensive care unit will be reported.	From day of birth up to 27 days
Percentage of Liveborn Neonates Receiving Exchange Transfusions for HDFN	Percentage of liveborn neonates receiving exchange transfusions for HDFN will be reported.	From day of birth up to 27 days
Number of Neonatal Exchange Transfusions per Liveborn Neonate	Number of neonatal exchange transfusions per liveborn neonate will be reported.	From day of birth up to 27 days
Percentage of Liveborn Neonates or Infants with Simple Transfusions for HDFN	Percentage of liveborn neonates or infants with simple transfusions for HDFN through the neonatal period (for the first database lock) or 12 weeks (for the second database lock) after birth will be reported.	For first database lock: From birth up to 4 weeks; for second database lock: From birth up to 12 weeks
Number of Simple Transfusions for HDFN per Liveborn Neonate or Infant	Number of simple transfusions for HDFN per liveborn neonate or infant through the neonatal period (for the first database lock) or 12 weeks (for the second database lock) after birth will be reported.	For first database lock: From birth up to 4 weeks; for second database lock: From birth up to 12 weeks
Percentage of Liveborn Neonates With Hyperbilirubinemia Treated With Phototherapy	Percentage of liveborn neonates with hyperbilirubinemia treated with phototherapy will be reported.	From day of birth up to 27 days
Number of Days of Phototherapy Received for Hyperbilirubinemia per Liveborn Neonate	Number of days of phototherapy received for hyperbilirubinemia per liveborn neonate will be reported.	From day of birth up to 27 days
Percentage of Liveborn Neonates or Infants Receiving Intravenous Immunoglobulin (IVIg) for HDFN Treatment	Percentage of liveborn neonates or infants receiving IVIg for HDFN treatment will be reported.	For first database lock: From birth up to 4 weeks; for second database lock: From birth up to 12 weeks
Number of Maternal Deaths	Number of maternal deaths will be reported.	Form randomization up to 24 weeks postpartum
Number of Participants with Adverse Events (AEs)	Number of participants with AEs, serious adverse events, and AEs of special interest (AESIs), AE's leading to discontinuations, infections, serious infections, infusion reactions, and hypersensitivity reactions will be reported. Treatment-emergent adverse events associated with the following situations are considered as AESIs: hypoalbuminemia, clinically significant bleeding with a corresponding placental finding on ultrasound, maternal infections that led to clinically significant morbidities or mortalities in fetus or neonates, Infections that are severe or require intravenous (IV) anti-infective or operative or invasive intervention in maternal participants or neonates or infants, and infants with hypogammaglobulinemia.	From randomization up to 24 weeks postpartum
Number of Maternal Pregnancy Complications	Number of maternal pregnancy complications will be reported.	Up to 38 weeks
Number of IUT Related complications	Number of participants with IUT related complications will be reported.	Up to 35 weeks of GA period
Percentage of Pregnancies With Cesarean Delivery, Preterm Birth, Fetal Growth, and Preeclampsia	Percentage of pregnancies with cesarean delivery, cesarean delivery due to IUT complications, preterm birth <GA week 28, preterm birth <GA week 32, preterm birth <GA week 34, preterm birth <GA week 37, fetal growth restriction, and preeclampsia will be reported.	Up to 38 weeks of GA period
Percentage of Liveborn Neonates or Infants Who Died	Percentage of liveborn neonates or infants who died will be reported.	Up to 104 weeks
Percentage of Liveborn Neonates or Infants With AEs	Percentage of liveborn neonates or infants with AEs, SAEs, AESIs, infections, serious infections will be reported. An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. Any event requiring hospitalization (or prolongation of hospitalization) that occurs during participation in the study must be reported as an SAE.	Up to 104 weeks
Percentage of Liveborn Neonates or Infants Receiving IVIg for Non-HDFN Indications	Percentage of liveborn neonates or infants receiving IVIg for non-HDFN indications will be reported.	Up to 104 weeks
Percentage of Liveborn Neonates or Infants With Abnormal Hearing	Percentage of liveborn neonates or infants with abnormal hearing will be reported.	Up to 104 weeks
Bayley Scales of Infant Development and Toddler Development	The Bayley Scales of infant development is considered the standard assessment of early child development and includes cognition, language, motor skills, social emotional, and adaptive behavior will be reported. The Bayley Scales (3rd edition) are reference standards that measure infant and toddler development in five areas: cognition, language, motor skills, social-emotional and adaptive behavior. The cognition, language and motor skills scales are directly administered to the infant, while social-emotional, and adaptive behavior scales are caregiver questionnaires. The scores are standardized using norm reference samples with representative demographics and age adjusted for prematurity. Higher scores in the Bayley Scales indicate better outcomes.	Week 52 and 104
Change From Baseline in Generalized Anxiety Disorder 7-Item (GAD7) Over time During Pregnancy and Postpartum	Change from baseline in GAD7 over time during pregnancy and postpartum will be reported. The GAD-7 scale is a self-administered questionnaire designed to measure anxiety. The recall period for all items is the past 2 weeks. Responses to all items are rated on a 4-point Likert scale ranging from 0 "not at all" to 3 "nearly every day". The total score ranges from 0 to 21, with higher scores indicating higher severity of anxiety symptoms.	Baseline (Day 1) and Week 30 during pregnancy and Week 4 postpartum
Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form Domain Score	Change from baseline in SF-36v2 acute form domain score will be reported. The SF-36 version 2 acute is a self-administered, 36-item questionnaire measuring health-related quality of life and includes 8 domains that measure physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality social functioning, role limitations due to emotional problems, and mental health. The 8 domains can be aggregated into 2 summary scales that reflect physical and mental health: a physical component summary and a mental component summary. Responses to all items are rated on a 3, 5, or 6-point Likert scale, with higher scores indicating better health status.	Baseline (Day 1) and Week 30 during pregnancy and Week 4 postpartum
Change From Baseline in EuroQol Five-dimension Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Score	Change from baseline in EQ-5D-5L visual analogue score will be reported. The EQ-5D descriptive system is comprised of 5 items across the following 5 dimensions: mobility, self-care, usual activities, pain or discomfort and anxiety or depression. The EQ-5D-5L uses a 5-point Likert response scale ranging from "no problems" to "extreme problems", with higher scores indicating better quality of life. EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ-VAS). EQ-VAS score ranges from 0 to 100, where 0 = worst imaginable health state and 100 = best imaginable health state. Higher score indicates good health state.	Baseline (Day 1) and Week 30 during pregnancy and Week 4 postpartum
Change From Baseline in EuroQol 5-Dimension Descriptive (EQ-5D) Index Score	Change from baseline in EQ-5D index score will be reported. The EQ-5D descriptive system is comprised of 5 items across the following 5 dimensions: mobility, self-care, usual activities, pain or discomfort and anxiety or depression. The EQ-5D-5L descriptive system uses a 5-point Likert response scale ranging from "no problems" to "extreme problems", with higher scores indicating better quality of life.	Baseline (Day 1) and Week 30 during pregnancy and Week 4 postpartum
Infant Health-Related Quality of Life Instrument (IQI) Score for Neonate or Infant Overtime	IQI score for neonate or infant will be reported. The IQI consists of 7 health attributes including sleeping, feeding, breathing, stooling or poo, mood, skin, and interaction. Responses to all items are rated on a 4-point Likert scale, with higher scores indicating better quality of life.	Weeks 4, 8 and 52

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Publications and helpful links

Helpful Links

• Azalea trial link
• Participant Recruitment Poster

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2023
• Primary Completion (Estimated): August 5, 2027
• Study Completion (Estimated): July 10, 2029

Study Registration Dates

• First Submitted: June 13, 2023
• First Submitted That Met QC Criteria: June 13, 2023
• First Posted (Actual): June 22, 2023

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Hemolysis
• Other Study ID Numbers: CR109199; 2021-002359-12 (EudraCT Number); 80202135EBF3001 (Other Identifier: Janssen Research & Development, LLC); 2022-502629-16-00 (Registry Identifier: EUCT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No