Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Atosiban Therapy for Women in Spontaneous Preterm Labor
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 97
- 试验地点
- 1
- 主要终点
- Time to Delivery From the Start of Investigational Product (IP) Administration
研究概览
简要总结
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.
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 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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Retosiban (Drug)
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.
干预措施: Placebo matching atosiban (Drug)
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.
干预措施: Atosiban (Drug)
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.
干预措施: Placebo matching retosiban (Drug)
结局指标
主要结局
Time to Delivery From the Start of Investigational Product (IP) Administration
时间窗: Up to 17 weeks
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.
次要结局
- Length of Stay in Specialized Care Unit(Up to 28 days post EDD (40 0/7 weeks gestation))
- Number of Participants With Births Prior to 37 0/7 Weeks Gestation(Up to 13 weeks)
- Number of Newborn Participants With Hospital Readmission(Up to 28 days of EDD (40 0/7 weeks gestation))
- Number of Participants With Births <=48 Hours From the First Study Treatment(Up to 48 hours)
- Change From Baseline in Respiratory Rate in Maternal Participants(Baseline and up to 1 week)
- 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))
- Number of Neonatal Participants With AESI(Up to 28 days after EDD of 40 weeks gestation)
- Number of Participants With Births Prior to 28 0/7 Weeks Gestation(Up to 4 weeks)
- Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) in Maternal Participants(Baseline and up to 1 week)
- Change From Baseline in Temperature in Maternal Participants(Baseline and up to 1 week)
- Number of Participants With Fetal Non-serious AEs and SAEs(Up to 17 weeks)
- Number of Neonatal Participants With Non-serious AEs and SAEs(Up to 28 days after the EDD of 40 weeks gestation)
- Number of Participants With Births at Term(Up to 17 weeks)
- Number of Participants With Births <=7 Days From the First Study Treatment(Up to 7 days)
- Number of Participants With Births <=24 Hours From the First Study Treatment(Up to 24 hours)
- Change From Baseline in Erythrocytes in Maternal Participants(Baseline and up to 1 week)
- Number of Maternal Participants With AEs of Special Interest (AESI)(Up to 6 weeks post-delivery)
- Head Circumference of Neonates(Up to 17 weeks)
- Number of Neonates With Each Individual Component of Composite Neonatal Morbidity and Mortality(Up to 28 weeks after EDD (40 weeks gestation))
- Number of Participants With Births Prior to 32 0/7 Weeks Gestation(Up to 8 weeks)
- Number of Participants With Births Prior to 35 0/7 Weeks Gestation(Up to 11 weeks)
- Change From Baseline in Heart Rate in Maternal Participants(Baseline and up to 1 week)
- Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes Count in Maternal Participants(Baseline and up to 1 week)
- Change From Baseline in Hemoglobin and Erythrocyte Mean Corpuscular Hemoglobin Concentration (MCHC) in Maternal Participants(Baseline and up to 1 week)
- Change From Baseline in Erythrocyte Mean Corpuscular Volume (MCV) and Mean Platelet Volume (MPV) in Maternal Participants(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 in Maternal Participants(Baseline and up to 1 week)
- Change From Baseline in Albumin and Protein Levels in Maternal Participants(Baseline and up to 1 week)
- Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Magnesium, Phosphate and Sodium Level in Maternal Participants(Baseline and up to 1 week)
- Change From Baseline in Direct Bilirubin, Bilirubin, Indirect Bilirubin, Creatinine and Urate Levels in Maternal Participants(Baseline and up to 1 week)
- Number of Maternal Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to 6 weeks after delivery)
- Number of Maternal Participants With Disease Related AEs (DRE)(Up to 6 weeks post-delivery)
- Number of Participants With Fetal AESI(Up to 17 weeks)
- Number of Neonatal Participants With DRE(Up to 28 days after EDD of 40 weeks gestation)
- Number of Participants Admitted to Particular Hospital Unit(Up to 28 days post EDD (40 0/7 weeks gestation))
- Neonatal APGAR Scores(Up to 5 minutes after birth)
- Weight of Neonates(Up to 17 weeks)
- 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)
- Maternal Length of Stay in 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)