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

Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor

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.

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.