Clinical trial NCT02377466: A Phase III Efficacy and Safety Study of Intravenous Retosiban Versus Placebo for Women in Spontaneous Preterm Labor
Official title: Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Obstetric Labour, Premature
Keywords: Spontaneous Preterm Labor
GSK221149
Retosiban
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2015-03-03
Enrollment: 25
Sex: FEMALE
Minimum age (years): 12
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.
* 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.

Primary outcomes:
measure: Time to Delivery or Treatment Failure, Whichever Occurs First
timeFrame: Up to 17 weeks
measure: Number of Neonates With Any Diagnosis From the Neonatal Morbidity and Mortality Composite Component
timeFrame: Up to 28 days after the estimated date of delivery (EDD) of 40 0/7 weeks
Secondary outcomes:
measure: Time to Delivery
timeFrame: Up to 17 weeks
measure: Number of Participants With Births Prior to 37 0/7 Weeks Gestation
timeFrame: Up to 13 weeks
measure: Number of Participants With Births at Term
timeFrame: Up to 17 weeks
measure: Length of Neonatal Hospital Stay
timeFrame: Up to 28 days post EDD of 40 0/7 weeks gestation
measure: Number of Participants With Births Prior to 35 0/7 Weeks Gestation
timeFrame: Up to 11 weeks
measure: Number of Participants With Births Prior to 32 0/7 Weeks Gestation
timeFrame: Up to 8 weeks
measure: Number of Participants With Births Prior to 28 0/7 Weeks Gestation
timeFrame: Up to 4 weeks
measure: Number of Participants With Births <=7 Days From the First Study Treatment
timeFrame: Up to 7 days
measure: Number of Participants With Births at <=48 Hours From the First Study Treatment
timeFrame: Up to 48 hours
measure: Number of Participants With Births at <=24 Hours From the First Study Treatment
timeFrame: Up to 24 hours
measure: Number of Neonates With Any of the Co-primary Composite Neonatal Morbidity and Mortality, Excluding RDS
timeFrame: Up to 28 weeks after EDD (40 weeks gestation)
measure: Number of Neonates With Each Individual Component of the Composite Neonatal Morbidity and Mortality
timeFrame: Up to 28 days after the EDD of 40 0/7 weeks
measure: Number of Neonatal Participants With Admission to a Particular Hospital Unit
timeFrame: Up to 28 days post EDD (40 0/7 weeks gestation)
measure: Length of Stay in Specialized Care Unit
timeFrame: Up to 28 days post EDD (40 0/7 weeks gestation)
measure: Number of Newborn Participants With Hospital Readmission
timeFrame: Up to 28 days of EDD (40 0/7 weeks gestation)
measure: Length of Stay Following Readmission to Hospital
timeFrame: Up to 28 days after EDD (40 0/7 weeks gestation)
measure: Number of Participants With Ambulatory Surgery
timeFrame: Up to 28 days post EDD (40 0/7 weeks gestation)
measure: Time to Treatment Failure
timeFrame: Up to 17 weeks
measure: Number of Participants Who Received Any Putative Tocolytic
timeFrame: Up to 17 weeks
measure: Number of Participants With Subsequent Preterm Labor
timeFrame: Up to 11 weeks
measure: Number of Maternal Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 6 weeks after delivery
measure: Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline and up to 9 days
measure: Change From Baseline in Heart Rate
timeFrame: Baseline and up to 9 days
measure: Change From Baseline in Temperature
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Respiratory Rate
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Hematocrit Levels
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Hemoglobin and Erythrocyte Mean Corpuscular Hemoglobin Concentration (MCHC)
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes Count
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Erythrocyte Mean Corpuscular Volume (MCV) and Mean Platelet Volume (MPV)
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Erythrocyte Level
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) Levels
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Albumin and Protein Levels
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Anion Gap, Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Magnesium, Phosphate and Sodium Level
timeFrame: Baseline and up to 1 week
measure: Change From Baseline in Direct Bilirubin, Bilirubin, Indirect Bilirubin, Creatinine and Urate Levels
timeFrame: Baseline and up to 1 week
measure: Number of Participants Who Discontinued Study Treatment Due to Clinical and Laboratory Toxicities
timeFrame: Up to 48 hours post-infusion
measure: Number of Maternal Participants With a Score of 12 or Higher on the Edinburgh Postnatal Depression Scale (EPDS)
timeFrame: Up to 6 weeks post delivery
measure: Number of Maternal Participants With AEs of Special Interest (AESI).
timeFrame: Up to 6 weeks post-delivery
measure: Number of Maternal Participants With Disease Related AEs (DRE)
timeFrame: Up to 6 weeks post-delivery
measure: Number of Fetal Participants With AEs and SAEs Prior to Delivery
timeFrame: Up to 17 weeks post-infusion
measure: Number of Participants With Fetal Acidosis
timeFrame: Up to 16 weeks
measure: Number of Participants With Fetal AESI
timeFrame: Up to 17 weeks
measure: Neonatal APGAR Scores
timeFrame: Up to 5 minutes after birth
measure: Weight of Neonates
timeFrame: Up to 17 weeks
measure: Head Circumference of Neonates
timeFrame: Up to 17 weeks
measure: Number of Neonatal Participants With AEs and SAEs
timeFrame: Up to 28 days after the EDD of 40 weeks gestation
measure: Number of Neonatal Participants With AESI
timeFrame: Up to 28 days after EDD of 40 weeks gestation
measure: Number of Neonatal Participants With DRE
timeFrame: Up to 28 days after EDD of 40 weeks gestation
measure: Maternal Length of Stay in Hospital
timeFrame: Up to 28 days post EDD (40 0/7 weeks gestation)
measure: Number of Participants With Hospital Admissions Related to Preterm Labor and Preterm Delivery
timeFrame: Up to 28 days after EDD (40 0/7 weeks of gestation)
measure: Number of Participants Admitted to Particular Hospital Unit
timeFrame: Up to 28 days post EDD (40 0/7 weeks gestation)
measure: Number of Participants With Different Modes of Transportation to Hospital
timeFrame: Up to 28 days post EDD (40 0/7 weeks gestation)
measure: Retosiban Clearance
timeFrame: Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion
measure: Volume of Distribution of Retosiban
timeFrame: Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Mobile
country: United States
facility: GSK Investigational Site
state: Alabama
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Colton
country: United States
facility: GSK Investigational Site
state: California
city: Orange
country: United States
facility: GSK Investigational Site
state: California
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Columbus
country: United States
facility: GSK Investigational Site
state: Georgia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Maywood
country: United States
facility: GSK Investigational Site
state: Illinois
city: Park Ridge
country: United States
facility: GSK Investigational Site
state: Illinois
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Kansas
city: Louisville
country: United States
facility: GSK Investigational Site
state: Kentucky
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Richmond Heights
country: United States
facility: GSK Investigational Site
state: Missouri
city: Neptune
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Newark
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Brooklyn
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Dayton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Lancaster
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Charleston
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Chattanooga
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Galveston
country: United States
facility: GSK Investigational Site
state: Texas
city: Charlottesville
country: United States
facility: GSK Investigational Site
state: Virginia
city: Tacoma
country: United States
facility: GSK Investigational Site
state: Washington
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hyogo
country: Japan
facility: GSK Investigational Site
city: Kagoshima
country: Japan
facility: GSK Investigational Site
city: Miyagi
country: Japan
facility: GSK Investigational Site
city: Miyazaki
country: Japan
facility: GSK Investigational Site
city: Nagasaki
country: Japan
facility: GSK Investigational Site
city: Okinawa
country: Japan
facility: GSK Investigational Site
city: Saitama
country: Japan
facility: GSK Investigational Site
city: Tochigi
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: