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

• ClinicalTrials.gov Identifier: NCT05912517
• Recruitment Status: Not yet recruiting
• First Posted: June 22, 2023
• Last Update Posted: December 6, 2023
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hemolytic Disease of the Fetus and Newborn	Drug: Nipocalimab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The participants will be randomized in a 2:1 to receive nipocalimab and placebo treatment.
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Estimated Study Start Date: March 9, 2024
• Estimated Primary Completion Date: August 5, 2027
• Estimated Study Completion Date: July 29, 2029

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Pregnancies That did not Result in Fetal Loss, Intrauterine Transfusion (IUT), Hydrops Fetalis, or Neonatal Death [ Time Frame: From randomization in the study through 4 weeks of age or 41 weeks Postmenstrual Age (PMA) during neonatal period, whichever is later ]
   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).

Secondary Outcome Measures :

1. Number of Participants With Hemolytic Disease of the Fetus and Newborn (HDFN) by Severity [ Time Frame: 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 ]
   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.
2. Time to First Occurrence of IUT or Hydrops Fetalis [ Time Frame: From randomization to delivery of baby (Up to 38 weeks) ]
   Time to first occurrence of IUT or hydrops fetalis will be reported.
3. Neonatal Mortality and Morbidity Index (NMMI) in Liveborn Neonates [ Time Frame: Through 38 weeks PMA or at discharge if earlier than 38 weeks PMA ]
   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'
4. Number of IUT's Received During the Pregnancy [ Time Frame: From randomization to delivery of baby (Up to 38 weeks) ]
   Number of IUT's received during the pregnancy will be reported.
5. Percentage of Pregnancies With Fetal Loss [ Time Frame: Time to delivery of baby (Up to 38 weeks) ]
   Percentage of pregnancies with fetal loss will be reported.
6. Percentage of Pregnancies With Fetal or Neonatal Death [ Time Frame: Through Week 4 or 41 weeks PMA ]
   Percentage of pregnancies with fetal or neonatal death (through the neonatal period) as a result of HDFN will be reported.
7. Percentage of Pregnancies With Hydrops Fetalis [ Time Frame: Up to 41 weeks PMA ]
   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).
8. Percentage of Pregnancies Receiving IUT During Pregnancy [ Time Frame: Up to 35 weeks of GA period ]
   Percentage of pregnancies receiving IUT during pregnancy will be reported.
9. Gestational Age (GA) at First IUT [ Time Frame: Up to 35 weeks of GA period ]
   GA at first IUT will be reported.
10. Percentage of Pregnancies Receiving >1 IUT During Pregnancy [ Time Frame: Up to 35 weeks of GA period ]
    Percentage of pregnancies receiving >1 IUT during pregnancy will be reported.
11. Percentage of Pregnancies Receiving IUT or HDFN Resulting in Fetal Demise (Less Than) <GA Week 20 [ Time Frame: Up to 20 weeks ]
    Percentage of pregnancies receiving IUT or HDFN resulting in fetal demise <GA Week 20 will be reported.
12. Gestational Age at Delivery [ Time Frame: Up to 38 weeks ]
    Gestational age at delivery will be reported.
13. Percentage of Pregnancies With Neonatal Death Through the Neonatal Period [ Time Frame: From randomization in the study through 4 weeks of age or 41 weeks PMA during neonatal period, whichever is later ]
    Percentage of pregnancies with neonatal death through the neonatal period will be reported.
14. Percentage of Liveborn Neonates With HDFN-related Morbidities Other Than Anemia and Hyperbilirubinemia or Jaundice [ Time Frame: From day of birth up to 4 weeks ]
    Percentage of liveborn neonates with HDFN-related morbidities other than anemia and hyperbilirubinemia or jaundice will be reported.
15. Absolute Weight of Liveborn Neonates or Infants [ Time Frame: Up to 104 weeks ]
    Absolute weight of liveborn neonates or infants will be reported.
16. Change From Baseline in Weight of Liveborn Neonates or Infants [ Time Frame: Baseline to up to 104 weeks ]
    Change from baseline in weight of liveborn neonates or infants will be reported.
17. Liveborn Neonates Length of Stay in Neonatal Intensive Care Unit [ Time Frame: From day of birth up to 27 days ]
    Liveborn neonates length of stay in neonatal intensive care unit will be reported.
18. Percentage of Liveborn Neonates Receiving Exchange Transfusions for HDFN [ Time Frame: From day of birth up to 27 days ]
    Percentage of liveborn neonates receiving exchange transfusions for HDFN will be reported.
19. Number of Neonatal Exchange Transfusions per Liveborn Neonate [ Time Frame: From day of birth up to 27 days ]
    Number of neonatal exchange transfusions per liveborn neonate will be reported.
20. Percentage of Liveborn Neonates or Infants with Simple Transfusions for HDFN [ Time Frame: For first database lock: From birth up to 4 weeks; for second database lock: From birth up to 12 weeks ]
    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.
21. Number of Simple Transfusions for HDFN per Liveborn Neonate or Infant [ Time Frame: 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 through the neonatal period (for the first database lock) or 12 weeks (for the second database lock) after birth will be reported.
22. Percentage of Liveborn Neonates With Hyperbilirubinemia Treated With Phototherapy [ Time Frame: From day of birth up to 27 days ]
    Percentage of liveborn neonates with hyperbilirubinemia treated with phototherapy will be reported.
23. Number of Days of Phototherapy Received for Hyperbilirubinemia per Liveborn Neonate [ Time Frame: From day of birth up to 27 days ]
    Number of days of phototherapy received for hyperbilirubinemia per liveborn neonate will be reported.
24. Percentage of Liveborn Neonates or Infants Receiving Intravenous Immunoglobulin (IVIg) for HDFN Treatment [ Time Frame: For first database lock: From birth up to 4 weeks; for second database lock: From birth up to 12 weeks ]
    Percentage of liveborn neonates or infants receiving IVIg for HDFN treatment will be reported.
25. Number of Maternal Deaths [ Time Frame: Form randomization up to 24 weeks postpartum ]
    Number of maternal deaths will be reported.
26. Number of Participants with Adverse Events (AEs) [ Time Frame: From randomization up to 24 weeks postpartum ]
    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.
27. Number of Maternal Pregnancy Complications [ Time Frame: Up to 38 weeks ]
    Number of maternal pregnancy complications will be reported.
28. Number of IUT Related complications [ Time Frame: Up to 35 weeks of GA period ]
    Number of participants with IUT related complications will be reported.
29. Percentage of Pregnancies With Cesarean Delivery, Preterm Birth, Fetal Growth, and Preeclampsia [ Time Frame: Up to 38 weeks of GA period ]
    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.
30. Percentage of Liveborn Neonates or Infants Who Died [ Time Frame: Up to 104 weeks ]
    Percentage of liveborn neonates or infants who died will be reported.
31. Percentage of Liveborn Neonates or Infants With AEs [ Time Frame: Up to 104 weeks ]
    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.
32. Percentage of Liveborn Neonates or Infants Receiving IVIg for Non-HDFN Indications [ Time Frame: Up to 104 weeks ]
    Percentage of liveborn neonates or infants receiving IVIg for non-HDFN indications will be reported.
33. Percentage of Liveborn Neonates or Infants With Abnormal Hearing [ Time Frame: Up to 104 weeks ]
    Percentage of liveborn neonates or infants with abnormal hearing will be reported.
34. Bayley Scales of Infant Development and Toddler Development [ Time Frame: Week 52 and 104 ]
    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.
35. Change From Baseline in Generalized Anxiety Disorder 7-Item (GAD7) Over time During Pregnancy and Postpartum [ Time Frame: Baseline (Day 1) and Week 30 during pregnancy and Week 4 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.
36. Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form Domain Score [ Time Frame: Baseline (Day 1) and Week 30 during pregnancy and Week 4 postpartum ]
    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.
37. Change From Baseline in EuroQol Five-dimension Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Score [ Time Frame: Baseline (Day 1) and Week 30 during pregnancy and Week 4 postpartum ]
    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.
38. Change From Baseline in EuroQol 5-Dimension Descriptive (EQ-5D) Index Score [ Time Frame: Baseline (Day 1) and Week 30 during pregnancy and Week 4 postpartum ]
    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.
39. Infant Health-Related Quality of Life Instrument (IQI) Score for Neonate or Infant Overtime [ Time Frame: Weeks 4, 8 and 52 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Study Contact; 844-434-4210; Participate-In-This-Study@its.jnj.com

Locations

United States, Connecticut

Yale New Haven Hospital

New Haven, Connecticut, United States, 06511

Yale New Haven Hospital

New Haven, Connecticut, United States, 06520-8064

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

United States, North Carolina

University of North Carolina (UNC) - School of Medicine

Chapel Hill, North Carolina, United States, 27599-7516

University of North Carolina

Chapel Hill, North Carolina, United States, 27599-7516

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

University of Cincinnati

Cincinnati, Ohio, United States, 45267

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Texas

Dell Children's Medical Center of Central Texas

Austin, Texas, United States, 78723

Brazil

Instituto de Mastologia e Oncologia

Goiânia, Brazil, 74110060

Canada, Quebec

Centre Hospitalier Sainte Justine

Montreal, Quebec, Canada, H3T 1C5

Israel

The Chaim Sheba Medical Center

Ramat Gan, Israel, 5265601

United Kingdom

Birmingham Children's Hospital

Birmingham, United Kingdom, B15 2TG

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

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

More Information

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT05912517
• 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 )
• First Posted: June 22, 2023
• Last Update Posted: December 6, 2023
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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
• URL: https://www.janssen.com/clinical-trials/transparency

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hemolysis; Pathologic Processes