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

NCT02377466 | Terminated Phase 3 Results DMC

• 2 other identifiers: 2007192014-003326-41
• Study Type: interventional
• Target: 25
• Locations: 5 countries
• Sites: 50

Brief Summary

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.

Conditions

Obstetric Labour, Premature

Keywords

Spontaneous Preterm Labor; GSK221149; Retosiban

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

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

Secondary Outcomes (53)

• Time to Delivery

  Up to 17 weeks

• 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 EDD of 40 0/7 weeks gestation

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

  Up to 11 weeks

Study Arms (2)

Retosiban

EXPERIMENTAL

Retosiban treatment will be administered as a 6 mg IV loading dose over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion over 48 hours. For subjects with an inadequate response after the first hour of treatment, another 6 mg loading dose will be administered and infusion rate will be increased to 12 mg/hour for the remainder of the 48 hour treatment period. The retosiban dosing regimen will require adjustment in subjects treated concomitantly with drugs that are strong Cytochrome 3A4 inhibitors or inducers.

Drug: Retosiban IV infusion

Placebo

PLACEBO COMPARATOR

The placebo control will be a normal saline (0.9% sodium chloride \[NaCl\]) infusion matched for the loading dose and continuous infusion rates, including a dose increase in subjects with an inadequate response after the first hour of treatment.

Drug: Placebo IV infusion

Interventions

Retosiban IV infusion DRUG

Retosiban for IV administration will be supplied as solution for infusion, consisting of a clear colorless solution of retosiban at a concentration of 15 milligram per milliliter (mg/mL).

Retosiban

Placebo IV infusion DRUG

0.9% NaCl matched for the retosiban loading dose and continuous infusion rates

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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• PPD Development, LP: collaborator

Study Sites (50)

GSK Investigational Site

Birmingham, Alabama, 35233, United States

Location

GSK Investigational Site

Mobile, Alabama, 36604, United States

Location

GSK Investigational Site

Tucson, Arizona, 85712, United States

Location

GSK Investigational Site

Colton, California, 92324, United States

Location

GSK Investigational Site

Orange, California, 92868, United States

Location

GSK Investigational Site

Washington D.C., District of Columbia, 20010, United States

Location

GSK Investigational Site

Jacksonville, Florida, 32209, United States

Location

GSK Investigational Site

Augusta, Georgia, 30912, United States

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GSK Investigational Site

Columbus, Georgia, 31904, United States

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GSK Investigational Site

Chicago, Illinois, 60611, United States

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GSK Investigational Site

Chicago, Illinois, 60637, United States

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GSK Investigational Site

Maywood, Illinois, 60153, United States

Location

GSK Investigational Site

Park Ridge, Illinois, 60068, United States

Location

GSK Investigational Site

Kansas City, Kansas, 66160, United States

Location

GSK Investigational Site

Louisville, Kentucky, 40202, United States

Location

GSK Investigational Site

New Orleans, Louisiana, 70115, United States

Location

GSK Investigational Site

Jackson, Mississippi, 39216-4505, United States

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GSK Investigational Site

Richmond Heights, Missouri, 63117, United States

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GSK Investigational Site

Neptune City, New Jersey, 07753, United States

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GSK Investigational Site

Newark, New Jersey, 07103, United States

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GSK Investigational Site

Brooklyn, New York, 11201, United States

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GSK Investigational Site

New York, New York, 10032, United States

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GSK Investigational Site

The Bronx, New York, 10461, United States

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GSK Investigational Site

Durham, North Carolina, 27710, United States

Location

GSK Investigational Site

Cleveland, Ohio, 44106, United States

Location

GSK Investigational Site

Dayton, Ohio, 45409, United States

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GSK Investigational Site

Portland, Oregon, 97239, United States

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GSK Investigational Site

Lancaster, Pennsylvania, 17601, United States

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GSK Investigational Site

Charleston, South Carolina, 29425, United States

Location

GSK Investigational Site

Chattanooga, Tennessee, 37403, United States

Location

GSK Investigational Site

Galveston, Texas, 77555-0587, United States

Location

GSK Investigational Site

Charlottesville, Virginia, 22908, United States

Location

GSK Investigational Site

Tacoma, Washington, 98431, United States

Location

GSK Investigational Site

London, Ontario, N6A 4G5, Canada

Location

GSK Investigational Site

Rome, Lazio, 00168, Italy

Location

GSK Investigational Site

Milan, Lombardy, 20132, Italy

Location

GSK Investigational Site

Hokkaido, 060-8543, Japan

Location

GSK Investigational Site

Hyōgo, 650-0047, Japan

Location

GSK Investigational Site

Kagoshima, 890-8760, Japan

Location

GSK Investigational Site

Miyagi, 989-3126, Japan

Location

GSK Investigational Site

Miyazaki, 889-1692, Japan

Location

GSK Investigational Site

Nagasaki, 856-8562, Japan

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GSK Investigational Site

Okinawa, 904-2293, Japan

Location

GSK Investigational Site

Saitama, 350-0495, Japan

Location

GSK Investigational Site

Tochigi, 321-0293, Japan

Location

GSK Investigational Site

Tokyo, 135-8577, Japan

Location

GSK Investigational Site

Tokyo, 142-8666, Japan

Location

GSK Investigational Site

Tokyo, 157-8535, Japan

Location

GSK Investigational Site

Tokyo, 206-8512, Japan

Location

GSK Investigational Site

London, SE1 7EH, United Kingdom

Location

MeSH Terms

Conditions

Premature Birth

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: February 26, 2015
• First Posted: March 3, 2015
• Study Start: February 29, 2016
• Primary Completion: July 24, 2017
• Study Completion: July 24, 2017
• Last Updated: July 28, 2020
• Results First Posted: July 19, 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

CA (1); US (33); JP (13); GB (1); IT (2)