A Randomized Study Comparing the Efficacy and Safety of Retosiban Versus Atosiban for Women in Spontaneous Preterm Labour
Condition: Obstetric Labour, Premature
MeSH terms: Obstetric Labor, Premature
Intervention: Retosiban; Atosiban; Placebo matching retosiban; Placebo matching atosiban
Intervention description: 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.
Intervention MeSH terms: Vasotocin; Atosiban
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 97.0
Sex: Female
Minimum age: 12 Years
Maximum age: 45 Years
Healthy volunteers: No
Keywords: Spontaneous Preterm Labor; retosiban; GSK221149; atosiban

Summary:

      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.
    

Eligibility criteria:

        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 labor (Note: This protocol includes pregnant adolescents, aged 12
             to 17 years, as appropriate, based on national or local regulations.).

          -  Gestational age between 24^0/7 and 33^6/7 weeks as determined by known fertilization
             date, either in vitro fertilization or intrauterine insemination, last menstrual
             period confirmed by the earliest ultrasound prior to 24^0/7 weeks' gestation, or the
             earliest ultrasound alone prior to 24^0/7 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.

          -  Subjects must be diagnosed with preterm labor according to both of the following
             criteria:

        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:

        Cervical dilation >=2 centimeter (cm) and <=4 cm by digital cervical examination or If <2
        cm dilation by digital cervical examination, a cervical change consisting of an increase of
        at least 25% effacement or 1 cm dilation

          -  Treatment naïve subjects and subjects not adequately responding to tocolytics other
             than atosiban (e.g., transfers from other care units) during their current episode of
             preterm labor may be eligible for the study. Historical failure of a tocolytic
             treatment in a previous episode of preterm labor is not a required inclusion
             criterion. Tocolytic failure is defined by progressive cervical changes or continuing
             uterine contractions.

        Exclusion Criteria:

          -  Fever with a temperature greater than 100.4°fahrenheit (F) (38°Celcius [C]) for more
             than 1 hour or >=101°F (38.3°C) 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 (e.g., 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 (amniotic fluid index [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, 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 or urine drug screen findings suggestive of
             substance abuse that may either be implicated as the cause of preterm labor (e.g.,
             abuse of cocaine or methamphetamines) or have the potential to complicate the
             pregnancy outcome (e.g., alcohol abuse or opioid addiction).

          -  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.

          -  Women with documented active hepatitis B or hepatitis C viral infection, unstable
             liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy,
             hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis,
             known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic
             gallstones).

          -  History of sensitivity to the IPs or components thereof or a history of drug or other
             allergy that, in the opinion of the investigator or GlaxoSmithKline (GSK)/PPD medical
             monitor, contraindicates their participation.