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

NCT02292771 | Terminated Phase 3 Results DMC

• 2 other identifiers: 2007212014-001826-13
• Study Type: interventional
• Target: 97
• Locations: 9 countries
• Sites: 21

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

Keywords

Spontaneous Preterm Labor; retosiban; GSK221149; atosiban

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 17 weeks

Secondary Outcomes (41)

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

  Up to 13 weeks

• Number of Participants With Births at Term

  Up to 17 weeks

• Length of Neonatal Hospital Stay

  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

  Up to 28 weeks after EDD (40 weeks gestation)

• Number of Neonates With Any Composite Neonatal Morbidity and Mortality, Excluding RDS

  Up to 28 weeks after EDD (40 weeks gestation)

Study Arms (2)

Retosiban + Atosiban Placebo

EXPERIMENTAL

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.

Drug: Retosiban; Drug: Placebo matching atosiban

Atosiban + Retosiban Placebo

ACTIVE COMPARATOR

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.

Drug: Atosiban; Drug: Placebo matching retosiban

Interventions

Retosiban 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.

Retosiban + Atosiban Placebo

Atosiban 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.

Atosiban + Retosiban Placebo

Placebo matching retosiban DRUG

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

Atosiban + Retosiban Placebo

Placebo matching atosiban DRUG

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

Retosiban + Atosiban Placebo

Eligibility Criteria

• Age: 12 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• PPD Development, LP: collaborator

Study Sites (21)

GSK Investigational Site

Bruges, 8000, Belgium

Location

GSK Investigational Site

Brussels, 1200, Belgium

Location

GSK Investigational Site

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

GSK Investigational Site

Jena, Thuringia, 07743, Germany

Location

GSK Investigational Site

Hamburg, 22087, Germany

Location

GSK Investigational Site

Haifa, 31048, Israel

Location

GSK Investigational Site

Holon, 58100, Israel

Location

GSK Investigational Site

Kfar Saba, 44281, Israel

Location

GSK Investigational Site

Petah Tikva, 49100, Israel

Location

GSK Investigational Site

Safed, 13100, Israel

Location

GSK Investigational Site

Tel Aviv, 64239, Israel

Location

GSK Investigational Site

Siena, Tuscany, 53100, Italy

Location

GSK Investigational Site

Monza, 20052, Italy

Location

GSK Investigational Site

Monterrey, Nuevo León, 64460, Mexico

Location

GSK Investigational Site

Ciudad Obregón, Sonora, 85000, Mexico

Location

GSK Investigational Site

Seoul, 120-752, South Korea

Location

GSK Investigational Site

Seoul, 135-081, South Korea

Location

GSK Investigational Site

Sungnam, 463712, South Korea

Location

GSK Investigational Site

Zaragoza, 50009, Spain

Location

GSK Investigational Site

Uppsala, SE-75185, Sweden

Location

GSK Investigational Site

Sheffield, S10 2JF, United Kingdom

Location

MeSH Terms

Conditions

Premature Birth

Interventions

GSK221149A; atosiban

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2014
• First Posted: November 17, 2014
• Study Start: March 16, 2015
• Primary Completion: August 25, 2017
• Study Completion: August 25, 2017
• Last Updated: July 29, 2020
• Results First Posted: September 10, 2018

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

IL (6); ES (1); KR (3); BE (2); SE (1); DE (3); ME (2); IT (2); GB (1)