A Randomized Study Comparing the Efficacy and Safety of Retosiban Versus Atosiban for Women in Spontaneous Preterm Labour

NCT ID: NCT02292771

Last Updated: 2020-07-29

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 97 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-16
• Study Completion Date: 2017-08-25

Brief 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.

Conditions

Obstetric Labour, Premature

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Retosiban + Atosiban Placebo

Participants will receive retosiban 6 milligrams (mg) intravenous (IV) loading dose over 5 minutes, followed by a 6mg/hour continuous infusion over 48 hours. For subjects with an inadequate response after the first hour of treatment, investigators will administer another 6mg IV loading dose and increase the infusion rate to 12 mg/hour for the remainder of the 48-hour treatment period. Participants will also receive placebo infusion matched for the atosiban loading (bolus) dose and continuous infusion to ensure blinding.

Group Type: EXPERIMENTAL

Retosiban

Intervention Type: DRUG

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.

Placebo matching atosiban

Intervention Type: DRUG

A placebo infusion containing 0.9% NaCl matched for the atosiban loading (bolus) dose and continuous infusion.

Atosiban + Retosiban Placebo

Participants will receive atosiban in 3 successive stages: an initial bolus dose (6.75 mg) over 1 minute, immediately followed by a continuous infusion at 18 mg/hour for 3 hours, followed by a 6 mg/hour infusion for the remainder of the 48-hour treatment period. Participants will also receive placebo infusion matched for retosiban loading (bolus) dose and continuous infusion to ensure blinding.

Group Type: ACTIVE_COMPARATOR

Atosiban

Intervention Type: DRUG

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.

Placebo matching retosiban

Intervention Type: DRUG

A placebo infusion containing 0.9% sodium chloride (NaCl) matched for retosiban loading (bolus) dose and continuous infusion.

Interventions

Retosiban

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.

Intervention Type: DRUG

Atosiban

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.

Intervention Type: DRUG

Placebo matching retosiban

A placebo infusion containing 0.9% sodium chloride (NaCl) matched for retosiban loading (bolus) dose and continuous infusion.

Intervention Type: DRUG

Placebo matching atosiban

A placebo infusion containing 0.9% NaCl matched for the atosiban loading (bolus) dose and continuous infusion.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

PPD Development, LP

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

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

GSK Investigational Site

Tel Aviv, , Israel

GSK Investigational Site

Siena, Tuscany, Italy

GSK Investigational Site

Monza, , Italy

GSK Investigational Site

Monterrey, Nuevo León, Mexico

GSK Investigational Site

Ciudad Obregón, Sonora, Mexico

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Sungnam, , South Korea

GSK Investigational Site

Zaragoza, , Spain

GSK Investigational Site

Uppsala, , Sweden

GSK Investigational Site

Sheffield, , United Kingdom

Countries

Belgium; Germany; Israel; Italy; Mexico; South Korea; Spain; Sweden; United Kingdom

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

2014-001826-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

200721

Identifier Type: -

Identifier Source: org_study_id