Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Time to Delivery or Treatment Failure, Whichever Occurs First
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 12 Years 至 45 Years（Child, Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Retosiban
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.
干预措施: Retosiban IV infusion (Drug)
Placebo
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.
干预措施: Placebo IV infusion (Drug)
结局指标
主要结局
Time to Delivery or Treatment Failure, Whichever Occurs First
时间窗: Up to 17 weeks
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.
Number of Neonates With Any Diagnosis From the Neonatal Morbidity and Mortality Composite Component
时间窗: Up to 28 days after the estimated date of delivery (EDD) of 40 0/7 weeks
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.
次要结局
- 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)
- Number of Participants With Births Prior to 32 0/7 Weeks Gestation(Up to 8 weeks)
- Number of Participants With Births at <=48 Hours From the First Study Treatment(Up to 48 hours)
- Number of Participants With Births at <=24 Hours From the First Study Treatment(Up to 24 hours)
- Number of Participants With Births Prior to 28 0/7 Weeks Gestation(Up to 4 weeks)
- Number of Participants With Births <=7 Days From the First Study Treatment(Up to 7 days)
- Number of Neonates With Any of the Co-primary Composite Neonatal Morbidity and Mortality, Excluding RDS(Up to 28 weeks after EDD (40 weeks gestation))
- Number of Neonates With Each Individual Component of the Composite Neonatal Morbidity and Mortality(Up to 28 days after the EDD of 40 0/7 weeks)
- Length of Stay Following Readmission to Hospital(Up to 28 days after EDD (40 0/7 weeks gestation))
- Number of Participants With Ambulatory Surgery(Up to 28 days post EDD (40 0/7 weeks gestation))
- Change From Baseline in Temperature(Baseline and up to 1 week)
- Number of Participants With Subsequent Preterm Labor(Up to 11 weeks)
- Number of Neonatal Participants With Admission to a Particular Hospital Unit(Up to 28 days post EDD (40 0/7 weeks gestation))
- Length of Stay in Specialized Care Unit(Up to 28 days post EDD (40 0/7 weeks gestation))
- Number of Newborn Participants With Hospital Readmission(Up to 28 days of EDD (40 0/7 weeks gestation))
- Change From Baseline in Respiratory Rate(Baseline and up to 1 week)
- Change From Baseline in Hematocrit Levels(Baseline and up to 1 week)
- Change From Baseline in Hemoglobin and Erythrocyte Mean Corpuscular Hemoglobin Concentration (MCHC)(Baseline and up to 1 week)
- Number of Maternal Participants With AEs of Special Interest (AESI).(Up to 6 weeks post-delivery)
- Time to Treatment Failure(Up to 17 weeks)
- Number of Participants Who Received Any Putative Tocolytic(Up to 17 weeks)
- Number of Maternal Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to 6 weeks after delivery)
- Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)(Baseline and up to 9 days)
- Change From Baseline in Heart Rate(Baseline and up to 9 days)
- Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes Count(Baseline and up to 1 week)
- Change From Baseline in Erythrocyte Mean Corpuscular Volume (MCV) and Mean Platelet Volume (MPV)(Baseline and up to 1 week)
- Change From Baseline in Erythrocyte Level(Baseline and up to 1 week)
- Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) Levels(Baseline and up to 1 week)
- Change From Baseline in Albumin and Protein Levels(Baseline and up to 1 week)
- Change From Baseline in Anion Gap, Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Magnesium, Phosphate and Sodium Level(Baseline and up to 1 week)
- Change From Baseline in Direct Bilirubin, Bilirubin, Indirect Bilirubin, Creatinine and Urate Levels(Baseline and up to 1 week)
- Number of Participants Who Discontinued Study Treatment Due to Clinical and Laboratory Toxicities(Up to 48 hours post-infusion)
- Number of Maternal Participants With a Score of 12 or Higher on the Edinburgh Postnatal Depression Scale (EPDS)(Up to 6 weeks post delivery)
- Number of Maternal Participants With Disease Related AEs (DRE)(Up to 6 weeks post-delivery)
- Number of Fetal Participants With AEs and SAEs Prior to Delivery(Up to 17 weeks post-infusion)
- Number of Participants With Fetal Acidosis(Up to 16 weeks)
- Number of Participants With Fetal AESI(Up to 17 weeks)
- Weight of Neonates(Up to 17 weeks)
- Neonatal APGAR Scores(Up to 5 minutes after birth)
- Head Circumference of Neonates(Up to 17 weeks)
- Number of Neonatal Participants With AEs and SAEs(Up to 28 days after the EDD of 40 weeks gestation)
- Maternal Length of Stay in Hospital(Up to 28 days post EDD (40 0/7 weeks gestation))
- Number of Neonatal Participants With AESI(Up to 28 days after EDD of 40 weeks gestation)
- Number of Neonatal Participants With DRE(Up to 28 days after EDD of 40 weeks gestation)
- Number of Participants With Hospital Admissions Related to Preterm Labor and Preterm Delivery(Up to 28 days after EDD (40 0/7 weeks of gestation))
- Number of Participants Admitted to Particular Hospital Unit(Up to 28 days post EDD (40 0/7 weeks gestation))
- Number of Participants With Different Modes of Transportation to Hospital(Up to 28 days post EDD (40 0/7 weeks gestation))
- Retosiban Clearance(Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion)
- Volume of Distribution of Retosiban(Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion)