The primary objective of this study is to demonstrate the superiority of retosiban to prolong pregnancy in females with spontaneous preterm labor compared with atosiban. This objective is based on the hypothesis that prolonging the time to delivery in the absence of harm may benefit the newborn, particularly in women who experience spontaneous preterm labor at early gestational ages (GA). This study is designed to test this hypothesis through a direct comparison with atosiban, a mixed oxytocin vasopressin antagonist indicated for short-term use to delay imminent preterm birth in women between 24\^0/7 and 33\^6/7 weeks' gestation in preterm labor. This is a randomized, double-blind, double-dummy study, which consists of 6 phases: Screening, Inpatient Randomized Treatment, Post Infusion Assessment, Delivery, Maternal Post Delivery Assessment, and Neonatal Medical Review. Approximately 330 females will be randomly assigned to retosiban or atosiban treatment in a 1:1 ratio. The duration of any one subject's (maternal or neonatal) participation in the study will be variable and dependent on GA at study entry and the date of delivery.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
97
Solution for infusion, consisting of a clear colorless solution of retosiban at a concentration of 15 milligram/milliliter (mg/mL) in 56% volume/volume ethanol/acetate buffer concentrate supplied in 5 mL vial containing 75mg retosiban.
Clear, colorless solution for injection in a 0.9-mL vial containing 6.75 mg of atosiban. Clear, colorless concentrate for solution for infusion in a 5-mL vial containing 37.5 mg atosiban.
A placebo infusion containing 0.9% sodium chloride (NaCl) matched for retosiban loading (bolus) dose and continuous infusion.
A placebo infusion containing 0.9% NaCl matched for the atosiban loading (bolus) dose and continuous infusion.
GSK Investigational Site
Bruges, Belgium
GSK Investigational Site
Brussels, Belgium
GSK Investigational Site
Freiburg im Breisgau, Baden-Wurttemberg, Germany
GSK Investigational Site
Jena, Thuringia, Germany
GSK Investigational Site
Hamburg, Germany
GSK Investigational Site
Haifa, Israel
GSK Investigational Site
Holon, Israel
GSK Investigational Site
Kfar Saba, Israel
GSK Investigational Site
Petah Tikva, Israel
GSK Investigational Site
Safed, Israel
...and 11 more locations
Time to Delivery From the Start of Investigational Product (IP) Administration
Time to delivery is the number of days from the first dose of study treatment until delivery. 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 adjusted mean number of days to delivery along with standard error has been presented. 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.
Time frame: Up to 17 weeks
Number of Participants With Births Prior to 37 0/7 Weeks Gestation
Gestational age (GA) at birth (weeks) is defined as the GA when the baby is born. Participants were considered to have delivered prior to 37 0/7 weeks, that is preterm , if the GA 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. Logistic regression model was used to calculate p-values.
Time frame: Up to 13 weeks
Number of Participants With Births at Term
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. Logistic regression model was used to calculate p-values.
Time frame: Up to 17 weeks
Length of Neonatal Hospital Stay
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. Log of length of stay was calculated as treatment plus GA at randomization plus established progesterone use based on Analysis of covariance (ANCOVA) model. The p-value was calculated using t-test method. 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.
Time frame: Up to 28 days post estimated date of delivery (EDD) of 40 0/7 weeks gestation
Number of Neonates With Composite Neonatal Morbidity and Mortality
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 (BPD), necrotizing enterocolitis (NEC) 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 (ROP), Intraventricular Hemorrhage (IVH), white matter injury and cerebellar hemorrhage.
Time frame: Up to 28 weeks after EDD (40 weeks gestation)
Number of Neonates With Any Composite Neonatal Morbidity and Mortality, Excluding RDS
The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, BPD, NEC 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, ROP, IVH, white matter injury and cerebellar hemorrhage. Number of neonates with any composite neonatal morbidity and mortality component, excluding RDS has been presented.
Time frame: Up to 28 weeks after EDD (40 weeks gestation)
Number of Neonates With Each Individual Component of Composite Neonatal Morbidity and Mortality
The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, BPD, NEC 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, ROP, IVH, cerebellar hemorrhage and white matter injury included Periventricular Leukomalacia PVL), porencephalic cyst, and persistent ventriculomegaly. Number of neonates with with each individual component of the composite neonatal morbidity and mortality has been presented.
Time frame: Up to 28 weeks after EDD (40 weeks gestation)
Length of Stay in Specialized Care Unit
Length of neonatal stay in specialized care unit like Intensive Care Unit (ICU) or Neonatal Intensive Care Unit (NICU) are reported.
Time frame: Up to 28 days post EDD (40 0/7 weeks gestation)
Number of Newborn Participants With Hospital Readmission
Newborn hospital readmission following hospitalization for birth was obtained from the newborn's medical records. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to 28 days of EDD (40 0/7 weeks gestation)
Number of Participants With Births Prior to 28 0/7 Weeks Gestation
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.
Time frame: Up to 4 weeks
Number of Participants With Births Prior to 32 0/7 Weeks Gestation
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.
Time frame: Up to 8 weeks
Number of Participants With Births Prior to 35 0/7 Weeks Gestation
Number of participants who delivered prior to 35 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 35 0/7 week's gestation and delivered were included.
Time frame: Up to 11 weeks
Number of Participants With Births <=7 Days From the First Study Treatment
Number of participants who delivered in less than or equal to 7 days from first dose of study treatment has been presented.
Time frame: Up to 7 days
Number of Participants With Births <=48 Hours From the First Study Treatment
Number of participants who delivered in less than or equal to 48 hours from first dose of study treatment has been presented.
Time frame: Up to 48 hours
Number of Participants With Births <=24 Hours From the First Study Treatment
Number of participants who delivered in less than or equal to 24 hours from first dose of study treatment has been presented.
Time frame: Up to 24 hours
Number of Maternal Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
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. 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 non-serious AE and one SAE has been presented.
Time frame: Up to 6 weeks after delivery
Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) in Maternal Participants
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).
Time frame: Baseline and up to 1 week
Change From Baseline in Heart Rate in Maternal Participants
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).
Time frame: Baseline and up to 1 week
Change From Baseline in Respiratory Rate in Maternal Participants
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).
Time frame: Baseline and up to 1 week
Change From Baseline in Temperature in Maternal Participants
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).
Time frame: Baseline and up to 1 week
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes Count in Maternal Participants
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). NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Change From Baseline in Erythrocytes in Maternal Participants
Blood samples were collected for the evaluation of change in erythrocytes 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). NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Change From Baseline in Hemoglobin and Erythrocyte Mean Corpuscular Hemoglobin Concentration (MCHC) in Maternal Participants
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. NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Change From Baseline in Erythrocyte Mean Corpuscular Volume (MCV) and Mean Platelet Volume (MPV) in Maternal Participants
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). NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) Levels in Maternal Participants
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). NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Change From Baseline in Albumin and Protein Levels in Maternal Participants
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). NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Magnesium, Phosphate and Sodium Level in Maternal Participants
Blood samples were collected for the evaluation of change from Baseline in levels of 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). NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Change From Baseline in Direct Bilirubin, Bilirubin, Indirect Bilirubin, Creatinine and Urate Levels in Maternal Participants
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). NA indicates standard deviation was not calculable for a single data point.
Time frame: Baseline and up to 1 week
Number of Maternal Participants With AEs of Special Interest (AESI)
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.
Time frame: Up to 6 weeks post-delivery
Number of Maternal Participants With Disease Related AEs (DRE)
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.
Time frame: Up to 6 weeks post-delivery
Number of Participants With Fetal Non-serious AEs and SAEs
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 non-serious AE and one SAE has been presented.
Time frame: Up to 17 weeks
Number of Participants With Fetal AESI
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.
Time frame: Up to 17 weeks
Neonatal APGAR Scores
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.Only those participants with data available at the specified data points were analyzed.
Time frame: Up to 5 minutes after birth
Weight of Neonates
The weight of neonates was obtained from the neonate birth record. The mean weight of neonates and standard deviation has been presented. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to 17 weeks
Head Circumference of Neonates
The head circumference was determined from the neonate birth record. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to 17 weeks
Number of Neonatal Participants With Non-serious AEs and SAEs
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 non-serious AE and one SAE has been presented. Neonatal Safety Population consisted of neonates whose mothers received randomized treatment.
Time frame: Up to 28 days after the EDD of 40 weeks gestation
Number of Neonatal Participants With AESI
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.
Time frame: Up to 28 days after EDD of 40 weeks gestation
Number of Neonatal Participants With DRE
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.
Time frame: Up to 28 days after EDD of 40 weeks gestation
Maternal Length of Stay in Hospital
The length of hospital stay associated with hospital admission for preterm labor and term labor/term delivery was collected from review of medical records. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
Time frame: Up to 28 days post EDD (40 0/7 weeks gestation)
Number of Participants Admitted to Particular Hospital Unit
Maternal healthcare resource utilization associated with an episode of preterm labor and normal term delivery were collected from the review of medical records. The number of participants who were admitted to a particular hospital unit like general ward, private/semi-private room, recovery, and other has been presented.
Time frame: Up to 28 days post EDD (40 0/7 weeks gestation)
Retosiban Clearance
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).
Time frame: Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion
Volume of Distribution of Retosiban
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).
Time frame: Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion
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