| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Retosiban stops preterm labor and prolongs pregnancy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036595 |
| E.1.2 | Term | Premature delivery |
| E.1.2 | System Organ Class | 10036585 - Pregnancy, puerperium and perinatal conditions |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the superiority of retosiban to prolong pregnancy compared with atosiban |
|
| E.2.2 | Secondary objectives of the trial |
To describe the outcomes of newborns during the neonatal period (through 28 days post estimated date of delivery [EDD]) for retosiban compared with atosiban
To describe the maternal, fetal, and neonatal safety profile during and after IV retosiban treatment compared with atosiban treatment
To determine the effect of retosiban treatment compared with atosiban on health care resource use and patient-reported outcomes associated with the maternal and neonatal hospitalization
To obtain further data on the pharmacokinetics of retosiban in pregnant women, including the effect of covariates such as age, weight, race/ethnicity, and GA on retosiban clearance and volume of distribution
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Signed and dated written informed consent is required prior to a subject’s participation in the study 200721 (ZINN) and the performance of any protocol specific procedures. At sites where enrollment of adolescents is allowed, 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
Note: Prescreening alone does not necessarily require consent as this activity may be accomplished in the absence of study specific procedures or assessments. In many cases, standard care and standard medical triage will provide sufficient information or evidence as to whether or not the subject is eligible for the study
2.Females aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact membranes in spontaneous preterm labor (Note: This protocol includes pregnant adolescents, aged 12 to 17 years, as appropriate, unless national or local regulations restrict the age for study enrollment to subjects aged 18 to 45 years).
3.Gestational age between 240/7 and 336/7 weeks as determined by
(1) known fertilization date, either in vitro fertilization or intrauterine
insemination, or (2) a best estimated due date confirmed or established
by by the earliest ultrasound prior to 240/7 weeks' gestation. In
situations where prenatal ultrasound records are not available at the
time the subject presents, the investigator may enroll the subject using
the GA based on a verbal history from the subject with the intent of
getting confirmation from the medical records or from the subject's
primary care obstetrician as soon as possible
4.Females must be diagnosed with preterm labor according to both of
the following (a or b):
a.Regular uterine contractions , confirmed by tocodynamometry, at a
rate of ≥4 contractions of at least 30 seconds duration during a 30-
minute interval. Where tocodynamometry is not technically feasible,
assessment by manual palpation will be permitted and must be
documented
AND at least 1 of the following:
i.Cervical dilation ≥2 cm and ≤4 cm by digital cervical examination OR
ii.If <2 cm dilation by the required initial digital cervical examination, a
cervical change (2 examinations must be documented) consisting with 1
of the following:
• An absolute increase of at least 25% effacement (e.g., a change in
effacement from 50% to 75%) by digital examination or a 10 mm
decrease in cervical length by transvaginal ultrasound
• A 1-cm increase in cervical dilation by digital cervical examination
5.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
|
|
| E.4 | Principal exclusion criteria |
1.Fever with a temperature greater than 100.4°F (38°C) for more than 1 hour or ≥101°F (38.3°C) in the 24 hours prior to the start of study treatment
2.Women with maternal-fetal conditions that potentially necessitate the need for delivery, such as pre-eclampsia or fetal compromise
3.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)
4.Preterm premature rupture of membranes
5.Women with any confirmed or suspected contraindication to prolongation of pregnancy, such as placental abruption, chorioamnionitis, or placenta previa
6.Evidence of polyhydramnios (amniotic fluid index [AFI] >25 cm) or oligohydramnios (AFI <5 cm)
7.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), known or suspected maternal Zika
infection during gestation (see SPM for details), 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)
8.Women with a history of substance abuse during the pregnancy or dependency that may have the potential to complicate the pregnancy outcome
9.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
10.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)
11.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 GSK/PPD medical monitor, |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is time to delivery from the start of IP administration until delivery, |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
48 hours after IP infusion, then every week till delivery.
|
|
| E.5.2 | Secondary end point(s) |
The following are the key secondary efficacy endpoints:
Proportion of births prior to 370/7 weeks’ gestation
Proportion of births at term (370/7 to 416/7 weeks’ gestation)
Length of neonatal hospital stay
Proportion of neonates with any diagnosis from the neonatal morbidity and mortality composite determined up to 28 days after EDD (of 400/7 weeks) (details for each composite are provided in Section 6.2.2)
Fetal or neonatal death
Respiratory distress syndrome (RDS)
Bronchopulmonary dysplasia
Necrotizing enterocolitis or isolated perforation
Sepsis
Meningitis
Retinopathy of prematurity
Intraventricular hemorrhage (IVH)
White matter injury,
Cerebellar hemorrhage
Clearance and volume of distribution and the effect of covariates on
these parameters
The following are other secondary efficacy endpoints:
Proportion of neonates with any of the composite neonatal morbidity and mortality excluding RDS
Proportion of neonates with each individual component of the composite neonatal morbidity and mortality endpoints
Neonatal admission to a specialized care unit and length of stay
Newborn hospital readmission and length of stay
Ambulatory surgery
Proportion of births prior to 280/7 weeks’ gestation
Proportion of births prior to 320/7 weeks’ gestation
Proportion of births ≤7 days
Proportion of births ≤48 hours
Proportion of births ≤24 hours
The following are the safety endpoints (maternal, fetal, and neonatal, as appropriate):
Incidence of reported AEs and serious AEs
Significant changes in vital signs and clinical laboratory tests
Incidence of treatment-limiting toxicities including both clinical and laboratory etiology causing subject to discontinue study treatment
Edinburgh Postnatal Depression Scale
Follow-up amniotic fluid index determined by abdominal ultrasound
Fetal acidosis
Neonatal Apgar scores (at 1 and 5 minutes after birth), growth parameters (weight, length, and head circumference) at birth and at discharge, and documentation of any complications
AEs of special interest
Maternal
Death
Chorioamnionitis and its complications
Placental abruption
Postpartum hemorrhage and/or retained placenta
Pulmonary edema
Fetal
Intrauterine fetal demise
Category II or III fetal heart rate tracing (defined according to American College of Obstetricians and Gynecologists Practice Bulletin 106 [ACOG, 2009])
Fetal inflammatory response syndrome
Neonatal
Neonatal death
Asphyxia
Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis)
RDS
Hypotension
Intraventricular hemorrhage/periventricular leukomalacia with cysts or
porencephaly
Bronchopulmonary dysplasia
Neonatal acidosis
Hyperbilirubinemia
Necrotizing enterocolitis (any modified Bell's staging criteria)
Hypoxic ischemic encephalopathy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
48 hours after IP infusion, then every week till delivery.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Brazil |
| Bulgaria |
| Czech Republic |
| Germany |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Philippines |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial will be when all the subjects have been contacted via telephone for the Maternal Post-Delivery Assessment Phase have been conducted within 6 weeks (±2 weeks) following delivery |
| The end of trial will be when all the subjects have been contacted via telephone for the Maternal Post-Delivery Assessment Phase have been conducted within 6 weeks (±2 weeks) following delivery. The neonatologist subinvestigator will then conduct a review of the newborn birth hospitalization records, following discharge from an acute care setting through 28 days EDD, where EDD is defined as 40 0/7 weeks’ gestation for all subjects. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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