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

Phase 3TerminatedNCT02377466

GlaxoSmithKline25 enrolled

Overview

The study's primary objective is to demonstrate the superiority of retosiban to prolong pregnancy and improve neonatal outcomes compared with placebo. It is a Phase III, randomized, double-blind, parallel-group, multicenter study and will be conducted in approximately 900 females, aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact membranes in preterm labor between 24\^0/7 and 33\^6/7 weeks of gestation. Eligible maternal subjects will be randomly assigned in a 1:1 ratio to receive either retosiban IV infusion or placebo IV infusion over 48 hours. If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of betamethasone administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the antecedent treatment was at least 7 days prior to study enrolment. Investigators have discretion to use a standardized regimen of magnesium sulphate, as well as intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection. Prior to randomization, each subject will be stratified by progesterone treatment and gestational age. The progesterone strata will consist of subjects on established progesterone therapy or subjects not on established progesterone therapy at Screening. The study will comprise 6 phases: Screening, Inpatient Randomized Treatment, Post Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal Medical Review. The duration of any subject's (maternal or neonatal) participation in the study will be variable and dependent on gestational ages (GA) at study entry and the date of delivery.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Eligibility

Sex: FEMALEMin age: 12 YearsMax age: 45 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Signed and dated written informed consent is required prior to a subject's participation in the study and the performance of any protocol specific procedures. Adolescents aged 12 to 17 years must provide written agreement to participate in the study in accordance with applicable regulatory and country or state requirements. Subjects will also be asked to sign a release for medical records at the time of consenting to allow access to both the maternal and neonatal records including information about delivery and infant care as well as information collected prior to the consent having been signed. * Females aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact membranes in preterm. * Gestational age between 24 and 33 weeks as determined by (1) known fertilization date, either in vitro fertilization or intrauterine insemination, (2) last menstrual period confirmed by the earliest ultrasound prior to 24 weeks gestation, or (3) the earliest ultrasound alone prior to 24 weeks gestation, whichever is the most accurate method available for each subject. In situations where prenatal ultrasound records are not available at the time the subject presents, the investigator will make every effort to obtain these records (either via computer records, directly from the subject's primary care obstetrician, or via telephone). However, in cases in which these records are not readily available (e.g., off hours, holiday), it is within the investigator's discretion to use GA based on a verbal history from the subject with the intent of getting confirmation from the medical records as soon as possible. * Females must be diagnosed with preterm labor according to both of the following criteria: a) Regular uterine contractions at a rate of \>=4 contractions of at least 30 seconds' duration during a 30-minute interval confirmed by tocodynamometry and at least 1 of the following, b) Cervical dilation \>=2 centimeter (cm) and \<=4 cm by digital cervical examination or c) If \<2 cm dilation by digital cervical examination, a cervical change consisting of an increase of at least 25% effacement or 1-cm dilation. * Current or past tocolytic treatment as follows: a) Subjects in whom tocolytic treatment has not been initiated prior to consent are eligible for the study, b) Transferred or referred subjects for whom parenteral magnesium sulfate treatment has been started before Screening are eligible provided they meet all eligibility criteria, c) Subjects receiving a prohibited tocolytic in this study are eligible only if the treatment is stopped before randomization and provided they meet all eligibility criteria, d) Subjects with a historical failure of a tocolytic treatment in a previous episode of preterm labor during the current pregnancy are eligible provided they meet all eligibility criteria. Exclusion Criteria: * Fever with a temperature \>100.4 degree Fahrenheit (38 degree centigrade) for more than 1 hour or \>=101 degree Fahrenheit (38.3 degree centigrade) in the 24 hours prior to the start of study treatment. * Women with maternal-fetal conditions that potentially necessitate the need for delivery, such as pre-eclampsia or fetal compromise. * A fetus with any diagnosis, condition, treatment, or other factor that in the opinion of the investigator has the potential to affect or confound assessments of efficacy or safety (for example: nonreassuring fetal status, intrauterine growth restriction, major congenital anomaly). * Preterm premature rupture of membranes. * Women with any confirmed or suspected contraindication to prolongation of pregnancy, such as placental abruption, chorioamnionitis, or placenta previa. * Evidence of polyhydramnios (AFI \>25 cm) or oligohydramnios (AFI \<5 cm). * Women with co-morbid medical or obstetric conditions that in the opinion of the investigator have the potential to complicate the pregnancy course and outcomes, such as uncontrolled hypertension or uncontrolled diabetes (if known, history of glycosylated hemoglobin \>8% at any time during pregnancy), or compromise the safety of the subject, such as underlying cardiovascular disorder (specifically ischemic cardiac disease, congenital heart disease, pulmonary hypertension, valvular heart disease, arrhythmias, and cardiomyopathy). * Women with a history of substance abuse during the pregnancy or urine drug screen positive for cocaine, phencyclidine (PCP), methamphetamine, or amphetamine. * Women in whom the combination of history and screening test results is suggestive of abuse or dependency that may have the potential to complicate the pregnancy outcome. * Women with any diagnosis, condition, treatment, or other factor that, in the opinion of the investigator, has the potential to affect or confound assessments of efficacy or safety. * Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). * History of sensitivity to any of the investigational products (IPs) or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline/ Pharmaceutical Product Development (GSK/PPD) medical monitor, contraindicates the subject's participation.

Outcomes

Primary Outcomes

Time to Delivery or Treatment Failure, Whichever Occurs First

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.

Time frame: Up to 17 weeks

Number of Neonates With Any Diagnosis From the Neonatal Morbidity and Mortality Composite Component

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.

Time frame: Up to 28 days after the estimated date of delivery (EDD) of 40 0/7 weeks

Secondary Outcomes

Time to 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 mean number of days to delivery along with standard deviation has been presented.

Time frame: Up to 17 weeks

Number of Participants With Births Prior to 37 0/7 Weeks Gestation

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.

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.

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.

Time frame: Up to 28 days post EDD of 40 0/7 weeks gestation

Number of Participants With Births Prior to 35 0/7 Weeks Gestation

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

Time frame: Up to 11 weeks

Number of Participants With Births Prior to 32 0/7 Weeks Gestation

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.

Time frame: Up to 8 weeks

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 <=7 Days From the First Study Treatment

The 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 at <=48 Hours From the First Study Treatment

The 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 at <=24 Hours From the First Study Treatment

The 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 Neonates With Any of the Co-primary 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, 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.

Time frame: Up to 28 weeks after EDD (40 weeks gestation)

Number of Neonates With Each Individual Component of the 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, 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.

Time frame: Up to 28 days after the EDD of 40 0/7 weeks

Number of Neonatal Participants With Admission to a Particular Hospital Unit

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.

Time frame: Up to 28 days post EDD (40 0/7 weeks gestation)

Length of Stay in Specialized Care Unit

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.

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 collected from the newborn's medical records. The number of newborn participants who had readmission to hospital is presented.

Time frame: Up to 28 days of EDD (40 0/7 weeks gestation)

Length of Stay Following Readmission to Hospital

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.

Time frame: Up to 28 days after EDD (40 0/7 weeks gestation)

Number of Participants With Ambulatory Surgery

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

Time frame: Up to 28 days post EDD (40 0/7 weeks gestation)

Time to Treatment Failure

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.

Time frame: Up to 17 weeks

Number of Participants Who Received Any Putative Tocolytic

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.

Time frame: Up to 17 weeks

Number of Participants With Subsequent Preterm Labor

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.

Time frame: Up to 11 weeks

Number of Maternal Participants With 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 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.

Time frame: Up to 6 weeks after delivery

Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

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).

Time frame: Baseline and up to 9 days

Change From Baseline in Heart Rate

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).

Time frame: Baseline and up to 9 days

Change From Baseline in Temperature

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).