| 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 premature births and extends pregnancy in women that are at risk of premature birth of an infant |
|
| 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 | 10036600 |
| E.1.2 | Term | Premature labour |
| 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 and improve neonatal outcomes compared with placebo |
|
| E.2.2 | Secondary objectives of the trial |
To describe the maternal, fetal, and neonatal safety profile during and after intravenous (IV) retosiban treatment compared with placebo
To determine the effect of retosiban treatment compared with placebo on health care resource use for the maternal and neonatal hospitalizations
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 |
subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. 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.
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 Labour (NOTE: Since local laws, customs, and institutional practice vary globally, investigator discretion in the enrollment of pediatric subjects is permitted, expect in Italy)
Italian Subjects: In Italy, the age restriction for study enrollment is 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 the earliest ultrasound performed before 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 criteria (a and 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
b. 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) consistent 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.
OR
-A 1-cm increase in cervical dilation by digital cervical examination
5. 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 |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria
apply:
1. Fever with a temperature >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 or 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. 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)
NOTES:
Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis
Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen (or positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria
11. History of sensitivity to any of the IPs or components thereof or a history of drug or other allergy that, in the opinion of the investigator or PPD medical monitor, contraindicates the subject’s participation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to delivery or treatment failure, whichever occurs first. Time to delivery will be calculated from the start of study treatment administration until delivery. Time to treatment failure will be calculated from the start of study treatment administration to the administration of any putative tocolytic medication
•Proportion of neonates with any diagnosis from the neonatal morbidity and mortality composite determined up to 28 days after the estimated date of delivery (EDD) of 400/7weeks:
•Fetal or neonatal death
•Respiratory distress syndrome (RDS)
o Requiring continuous positive airway pressure or mechanical ventilation. Diagnosis requires a chest radiograph consistent with RDS (reticulogranular
appearance to the lung fields or air bronchograms) within the first 24 hours of life, OR o Received surfactant for a clinical picture of RDS within the first 24 hours of life
•Broncho pulmonary dysplasia at ≥36 weeks postmenstrual age (determined by adding chronological age to GA at delivery), defined asf ollows:
o >21% supplemental oxygen requirement, OR o Use of high-flow nasal cannula at ≥1 L (21% oxygen)
•Necrotizing enterocolitis or isolated perforation
o Diagnosed by radiographic evidence of Stage II or higher according to Bell’s staging criteria (fixed/unchanging bowel loops, pneumatosis intestinalis, portal venous gas, pneumoperitoneum), OR
o Pneumatosis intestinalis, bowel necrosis, or perforation noted at surgery
•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
o Confirmed by an ophthalmologist based on international committee
Stage 4 or 5, OR
o Requiring surgical treatment with laser or other surgical intervention
including cryotherapy or treatment with antivascular endothelial growth factor
•Intraventricular hemorrhage (IVH)
o Grade 3 or 4 (severe IVH), OR
o Any grade of IVH with posthemorrhagic hydrocephalus requiring a shunt
•White matter injury, documented on cranial ultrasound or magnetic resonance imaging, as indicated by the following:
o Multiple cystic lucencies in periventricular white matter (may be bilateral or unilateral, may vary in size, and be diffuse or focal in distribution), OR
o Porencephalic cyst (not including subependymal or choroid plexus cysts), OR
o Persistent ventriculomegaly, moderate to severe
•Cerebellar hemorrhage (unilateral or bilateral)
|
|
| 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) |
Supportive Key Secondary
•Time to delivery
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
Supportive Other Secondary
•Proportion of births prior to 320/7 weeks’gestation
•Proportion of births prior to 280/7 weeks’gestation
•Proportion of births ≤7 days
•Proportion of births ≤48 hours
Proportion of births ≤24 hours
•Proportion of neonates with any of the co-primary 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
•Time to treatment failure
•Proportion of women receiving any putative tocolytic
•Proportion of women experiencing subsequent episodes of preterm labor
Maternal:
•Incidence of reported AEs and serious AEs (SAEs)
•Significant changes in vital signs and clinical laboratory tests
•Incidence of clinical and laboratory toxicities causing subject to discontinue study treatment
•Incidence of women scoring 12 or higher on the Edinburgh Postnatal Depression Scale (EPDS)
•Maternal AEs of special interest
•Maternal death
•Chorioamnionitis and its complications
o Clinical chorioamnionitis, preterm premature rupture of membranes, endomyometritis, wound infection, pelvic abscess, bacteremia, septic shock,
disseminated intravascular coagulation, and adult RDS
•Placental abruption
•Postpartum hemorrhage – postpartum hemorrhage and/or retained placenta
•Pulmonary edema
Fetal:
•Incidence of reported AEs and SAEs
•Fetal acidosis
•Fetal AEs of special interest
•Intrauterine fetal demise
•Category II or III fetal heart rate tracing
•Fetal inflammatory response syndrome characterized by cord blood interleukin-6 >11 pg/mL, funisitis, or chorionic vasculitis
Neonatal:
•Neonatal Apgar scores (at 1 and 5 minutes after birth),
•Growth parameters (weight, length, and head circumference) at birth and at discharge
•Incidence of reported AEs and SAEs
•Neonatal AEs of special interest will include the following:
•Neonatal death
•Asphyxia
•Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis)
•RDS
•Hypotension
•IVH/periventricular leukomalacia
•Bronchopulmonary dysplasia
•Neonatal acidosis
•Hyperbilirubinemia
•Necrotizing enterocolitis
•Hypoxic ischemic encephalopathy
Assess maternal and neonatal health care resource use associated with preterm labor and preterm delivery. Health care resource use of interest include:
•Maternal hospital admission (e.g., length of stay by hospital unit and type) and resource use (e.g., use of transport services and admission to extended stay facility)
•Neonatal interventions of interest (e.g., parenteral nutrition, surfactants, blood products), procedures (e.g., imaging, such as ultrasound and computed tomography), and surgical procedures
Neonatal hospital admission (e.g., length of stay by hospital unit and type) and resource use (e.g., use associated with neonatal comorbidities of interest).
|
|
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Australia |
| Canada |
| Ireland |
| Italy |
| Japan |
| United Kingdom |
| United States |
|
| 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 the study is defined as the neonatal record review at 28 days post EDD for the last subject randomly assigned to and treated with IP. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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