Trial Outcomes & Findings for A Phase III Efficacy and Safety Study of Intravenous Retosiban Versus Placebo for Women in Spontaneous Preterm Labor (NCT NCT02377466)

NEWBORN-1 was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to investigate efficacy and safety of retosiban in female participants aged 12 to 45 years with an uncomplicated singleton pregnancy in preterm labor with intact membranes between 24 0/7 and 33 6/7 weeks gestation. The study was conducted in 3 countries.

Twenty-five participants were randomly assigned to study treatments: 12 participants to retosiban intravenous (IV) infusion and 13 participants to matched placebo IV infusion. Two participants randomized to retosiban arm did not receive study treatment. The study was terminated early due to feasibility of recruiting the study in a timely manner.

A Phase III Efficacy and Safety Study of Intravenous Retosiban Versus Placebo for Women in Spontaneous Preterm Labor

Time to delivery or treatment failure is the number of days from the first dose of study treatment until delivery or treatment failure whichever occurs first. Treatment failure is defined as the administration of any putative tocolytic medication for treatment of preterm labor or as prophylaxis of preterm labor. Maternal intent-to-treat (ITT) Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment irrespective of their compliance to the planned course of treatment. The mean number of days to delivery or treatment failure along with standard deviation has been presented. Statistical analysis was not performed due to early termination of the study and resultant small sample size.

The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, respiratory distress syndrome (RDS), bronchopulmonary dysplasia, necrotizing enterocolitis or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, retinopathy of prematurity, intraventricular hemorrhage (IVH), white matter injury and cerebellar hemorrhage. Neonates with any of the composite component has been presented. Statistical analysis was not performed due to early termination of study and resultant small sample size. Neonatal ITT Population comprised of all neonates whose mothers were the randomized participants who have been exposed to study treatment, that is, mothers from the ITT Population.

The time to delivery was calculated as the days between the delivery and start time of the study treatment infusion using the formula: Time to delivery (days) = (date and time of delivery minus date and time of start of infusion) divided by (24 multiplied by 60). The mean number of days to delivery along with standard deviation has been presented.

Gestational age at birth (weeks) is defined as the gestational age when the baby is born. Participants were considered to have delivered prior to 37 0/7 weeks, that is preterm, if the gestational age at birth is less than 37 0/7 weeks. The number of participants who delivered prior to 37 0/7 weeks gestation has been presented.

Participants were considered to have delivered at term if the gestational age was \>=37 0/7. The number of participants who delivered at term, that is, 37 0/7 to 41 6/7 weeks gestation has been presented.

The length of stay was collected from medical records and was calculated as the days between the delivery date and time and discharge date and time.

The number of participants who delivered prior to 35 0/7 weeks gestation has been presented.

The number of participants who delivered prior to 32 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 32 0/7 week's gestation and delivered were included.

The number of participants who delivered prior to 28 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 28 0/7 week's gestation and delivered were included.

The number of participants who delivered in less than or equal to 7 days from first dose of study treatment has been presented.

The number of participants who delivered in less than or equal to 48 hours from first dose of study treatment has been presented.

The number of participants who delivered in less than or equal to 24 hours from first dose of study treatment has been presented.

The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, bronchopulmonary dysplasia, necrotizing enterocolitis or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, retinopathy of prematurity, IVH, white matter injury and cerebellar hemorrhage. The number of neonates with any co-primary composite neonatal morbidity and mortality component, excluding RDS has been presented.

The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, bronchopulmonary dysplasia, necrotizing enterocolitis or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, retinopathy of prematurity, IVH, white matter injury and cerebellar hemorrhage. The number of neonates with each individual component of the composite component has been presented.

Neonatal healthcare resource utilization was collected from review of medical records. The number of neonatal participants who were admitted to a particular hospital unit that is, level III (or higher) intensive neonatal care (NICU), Intensive care unit (ICU), general ward, Level I - Basic Neonatal care, Well born nursery (SCBU) and Level II-Special Care Newborn nursery high dependency (NHDU) has been summarized. Neonatal Safety Population consisted of neonates whose mothers received study treatment.

Neonatal healthcare resource utilization was collected from review of medical records. The length of stay in a specialized care unit (NICU or ICU) has been presented for neonatal participants with admission to ICU or NICU.

Newborn hospital readmission following hospitalization for birth was collected from the newborn's medical records. The number of newborn participants who had readmission to hospital is presented.

Newborn hospital readmission following hospitalization for birth was collected from the newborn's medical records. Length of stay in hospital following readmission is presented for neonates.

Information regarding participants who had ambulatory surgery was collected from the newborn medical records. The number of neonatal participants with ambulatory surgery is presented.

Treatment failure is defined as the administration of any putative tocolytic medication for treatment of preterm labor or as prophylaxis of preterm labor. Time to treatment failure is the number of days from the first dose of study treatment until treatment failure. The mean number of days to delivery or treatment failure along with standard deviation has been presented. Only those maternal participants with treatment failure were included in the analysis. NA indicates standard deviation could not be calculated as only one participant was analyzed.

A putative tocolytic medication was the medication administered for active preterm labor or as prevention of preterm labor and included calcium channel blockers, nonsteroidal anti-inflammatory drugs, or beta agonists, or magnesium sulfate doses that exceeded prespecified IV loading doses, infusion rates, or total duration of administration.

The participants who had not delivered after 48 hours post-infusion were contacted to determine if they had delivered or experienced any subsequent episodes of preterm labor. A subsequent episode of preterm labor was only recorded if the participant reported it to the Principal Investigator during one of the telephone follow-up calls but did not then go on to immediately deliver. However, if labor started and led to immediate delivery, then the only data collected would be the pre-specified delivery data and thus would not be counted as a subsequent episode of preterm labor. The number of participants who had a subsequent episode of preterm labor after administration of the study treatment has been presented. Maternal Safety Population comprised of all maternal participants randomly assigned to treatment who have been exposed to study treatment.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that mey require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. Maternal Safety Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment. The number of maternal participants who experienced at least one AE and one SAE has been presented.

SBP and DBP were measured with participants in a semirecumbent or seated position. SBP and DBP were measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Heart rate was measured with the participants in a semirecumbent or seated position. Heart rate was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Temperature was measured with the participants in a semirecumbent or seated position. Temperature was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Respiratory rate was measured with the participants in a semirecumbent or seated position. Respiratory rate was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change in hematocrit levels from Baseline. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change in hemoglobin levels and MCHC from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change in MCV and MPV from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change in erythrocyte level from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change in ALP, ALT, AST, GGT and LDH from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change in albumin and protein levels from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change from Baseline in levels of anion gap, calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate, and sodium. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Blood samples were collected for the evaluation of change from Baseline in levels of direct bilirubin, bilirubin, indirect bilirubin, creatinine and urate. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

Number of maternal participants who discontinued study treatment due to clinical and laboratory toxicities is presented.

The effect of preterm birth on maternal health status was assessed using the EPDS. The EPDS is a 10-item self-reported assessment of depression, validated for administration during both the antenatal and the post-natal periods. Items are rated on a 4-point variable Likert scale, ranging from 0 to 3. The total score was calculated by adding individual scores for each item and ranged from 0 to 30. A score of less than 8 indicates depression not likely; score of 9 to 11 indicates possible depression and a score of more than 12 indicates an increased probability of depression. Maternal participants were required to complete the EPDS at the maternal follow-up assessment 6 weeks post-delivery.

Maternal AESI included: maternal death; chorioamnionitis and its complications (clinical chorioamnionitis, preterm premature rupture of membranes, endomyometritis, wound infection, pelvic abscess, bacteremia, septic shock, disseminated intravascular coagulation, and adult RDS); placental abruption; postpartum hemorrhage - postpartum hemorrhage and/or retained placenta and pulmonary edema. The number of participants with at least one AESI has been presented.

Maternal DREs included: signs and symptoms of labor discomfort (example, cramping, backache, muscle aches, nausea); subsequent episodes of preterm labor and hospitalization for delivery. The number of participants with at least one DRE has been presented.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. Fetal AEs and SAEs included the adverse events that were experienced by the fetus prior to delivery. The number of fetal participants who experienced at least one AE and one SAE has been presented.

The number of participants with fetal acidosis is presented.

Fetal AESI included: intrauterine fetal demise; category II or III fetal heart rate tracing; and fetal inflammatory response syndrome characterized by cord blood interleukin-6 \>11 picogram per milliliter (pg/mL), funisitis, or chorionic vasculitis. The number of participants who experienced at least one AESI has been presented.

APGAR is a quick test to assess the health of new born children. The test is performed at 1 and 5 minutes after birth. APGAR scale is determined by evaluating the new born on five categories (appearance, pulse, grimace, activity and respiration) on a scale from zero to two, then summing up the five values obtained. APGAR score ranges from 0 to 10 where a score of 7 and above is normal. The mean and standard deviation of APGAR scores at one minute and at five minutes of birth has been presented.

The weight of neonates was obtained from the neonate birth record. The mean weight of neonates and standard deviation has been presented.

The head circumference was determined from the neonate birth record.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. The number of participants who experienced at least one AE and one SAE has been presented. Neonatal Safety Population consisted of neonates whose mothers received randomized treatment.

Neonatal AESI included: Neonatal death; Asphyxia; Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis); RDS; Hypotension; IVH/periventricular leukomalacia; Bronchopulmonary dysplasia; Neonatal acidosis; Hyperbilirubinemia; Necrotizing enterocolitis; and Hypoxic ischemic encephalopathy. The number of neonatal participants who experienced at least one AESI has been presented.

The disease related neonatal events occurring in Infants born prior to 37 completed weeks included: apnea (severe), respiratory failure due to fatigue, hypoxia, or air leak from alveolar injury, patent ductus arteriosus, bradycardia, ventriculomegaly, cerebellar hemorrhage, hydrocephalus other than congenital, gastroesophageal reflux, aspiration pneumonia, anemia, retinopathy of prematurity (all stages), hearing disorder, temperature instability and hypoglycemia. The number of participants with at least one DRE has been presented.

Details on maternal health care resource use (both for hospitalizations related to preterm labor not resulting in a delivery and hospitalizations related to preterm labor/normal labor resulting in a delivery) associated with an episode of preterm labor, preterm delivery and normal term delivery (\>= 37 weeks gestation) were collected from review of medical records. Length of hospital stay associated with hospital admission for preterm labor and normal term labor/term delivery is presented. One participant in the retosiban arm did not have hospitalization data; hence, was excluded from the analysis at delivery. Only participants with data available at the specified time points were analyzed (indicated by n=X) in category titles. NA indicates standard deviation could not be calculated as only one participant was analyzed.

Maternal healthcare resource utilization associated with an episode of preterm labor and preterm delivery were collected from the review of medical records. One participant in the retosiban arm did not have hospitalization data; hence, was excluded from the analysis at delivery. The number of participants who had hospital admission for preterm labor and preterm delivery has been presented. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

Maternal healthcare resource utilization associated with an episode of preterm labor, preterm delivery and normal term delivery were collected from the review of medical records. The number of participants who were admitted to a particular hospital unit has been presented.

The means by which the maternal participants were transported to the hospital i.e. ground ambulance/emergency vehicle (gr. amb/emer. veh), air ambulance, family member or other means were obtained from the review of medical records. The number of maternal participants with the corresponding mode of transportation is presented for preterm labor visit and delivery visit. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).

Maternal blood samples were collected at the indicated time points for pharmacokinetic analysis. Data is a combined data set. Data is presented for 10 participants from retosiban arm of study 200719 (NCT02377466) and 43 participants from retosiban arm of study 200721 (NCT02292771).

Maternal blood samples were collected at the indicated time points for pharmacokinetic analysis. Data is a combined data set. Data is presented for 10 participants from retosiban arm of study 200719 (NCT02377466) and 43 participants from retosiban arm of study 200721 (NCT02292771).