Hemolytic Disease of the Fetus and Newborn Clinical Trial
— AZALEAOfficial 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)
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.
| Status | Recruiting |
| Enrollment | 120 |
| Est. completion date | July 10, 2029 |
| Est. primary completion date | August 5, 2027 |
| Accepts healthy volunteers | No |
| Gender | Female |
| Age group | 18 Years to 45 Years |
| Eligibility | 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 |
| Country | Name | City | State |
|---|---|---|---|
| Australia | Mater Hospital Brisbane | South Brisbane | |
| Belgium | C.H.U. Brugmann | Bruxelles | |
| Brazil | Universidade Federal De Minas Gerais | Belo Horizonte | |
| Brazil | Empresa Brasileira de Servicos Hospitalares EBSERH Hospital das Clinicas da UFG | Goiania | |
| Brazil | Instituto de Medicina Integral Professor Fernando Figueira | Recife | |
| Brazil | Instituto D Or de Pesquisa e Ensino IDOR | Rio de Janeiro | |
| Brazil | Hospital Das Clinicas Da Faculdade De Medicina Da USP | Sao Paulo | |
| Germany | Universitatsklinikum Gießen und Marburg / Standort Gießen | Giessen | |
| Israel | Rabin Medical Center | Petah Tikva | |
| Israel | The Chaim Sheba Medical Center | Ramat Gan | |
| Japan | Gifu Prefectural General Medical Center | Gifu | |
| Netherlands | Leiden University Medical Center | Leiden | |
| United Kingdom | Birmingham Women's Hospital | Birmingham | |
| United Kingdom | St.Mary's Hospital | Manchester | |
| United States | University of Texas Dell Medical School Department of Women's Health | Austin | Texas |
| United States | University of North Carolina (UNC) - School of Medicine | Chapel Hill | North Carolina |
| United States | University Of Texas Medical Branch At Galveston | Galveston | Texas |
| United States | Advocate Children's Hospital | Park Ridge | Illinois |
| Lead Sponsor | Collaborator |
|---|---|
| Janssen Research & Development, LLC |
United States, Australia, Belgium, Brazil, Germany, Israel, Japan, Netherlands, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | 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 | |
| Secondary | 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) | |
| Secondary | 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 | |
| Secondary | 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) | |
| Secondary | Percentage of Pregnancies With Fetal Loss | Percentage of pregnancies with fetal loss will be reported. | Time to delivery of baby (Up to 38 weeks) | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | Percentage of Pregnancies Receiving IUT During Pregnancy | Percentage of pregnancies receiving IUT during pregnancy will be reported. | Up to 35 weeks of GA period | |
| Secondary | Gestational Age (GA) at First IUT | GA at first IUT will be reported. | Up to 35 weeks of GA period | |
| Secondary | 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 | |
| Secondary | 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 | Up to 20 weeks |
| |
| Secondary | Gestational Age at Delivery | Gestational age at delivery will be reported. | Up to 38 weeks | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | Absolute Weight of Liveborn Neonates or Infants | Absolute weight of liveborn neonates or infants will be reported. | Up to 104 weeks | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | Number of Maternal Deaths | Number of maternal deaths will be reported. | Form randomization up to 24 weeks postpartum | |
| Secondary | 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 | |
| Secondary | Number of Maternal Pregnancy Complications | Number of maternal pregnancy complications will be reported. | Up to 38 weeks | |
| Secondary | Number of IUT Related complications | Number of participants with IUT related complications will be reported. | Up to 35 weeks of GA period | |
| Secondary | 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 | Up to 38 weeks of GA period |
| |
| Secondary | Percentage of Liveborn Neonates or Infants Who Died | Percentage of liveborn neonates or infants who died will be reported. | Up to 104 weeks | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Active, not recruiting |
NCT03842189 -
A Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of M281 Administered to Pregnant Women at High Risk for Early Onset Severe Hemolytic Disease of the Fetus and Newborn (HDFN)
|
Phase 2 |