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    Summary
    EudraCT Number:2014-003326-41
    Sponsor's Protocol Code Number:200719
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-11-10
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2014-003326-41
    A.3Full title of the trial
    Randomized, Double-Blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase III study where the treatment groups are assigned by chance and neither the patient or the study doctor know which treatment the patient will receive that will take place in many sites and will compare the efficacy of Retosiban with placebo in stopping spontaneous preterm labor and prolonging labor
    A.3.2Name or abbreviated title of the trial where available
    NEWBORN-1
    A.4.1Sponsor's protocol code number200719
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/162/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGlaxoSmithKline Research & Development Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGlaxoSmithKline Research & Development Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Limited
    B.5.2Functional name of contact pointRobert Stocken
    B.5.3 Address:
    B.5.3.1Street AddressStockley Park West, 1-3 Ironbridge Road
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0208990 3879
    B.5.5Fax number0208990 3511
    B.5.6E-mailrobert.c.stocken@gsk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRetosiban
    D.3.2Product code GSK221149
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRetosiban
    D.3.9.1CAS number 820957-38-8
    D.3.9.2Current sponsor codeGSK221149A
    D.3.9.3Other descriptive nameGSK 221149A
    D.3.9.4EV Substance CodeSUB29510
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Preterm Labour
    E.1.1.1Medical 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.1.1.2Therapeutic 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.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10036600
    E.1.2Term Premature labour
    E.1.2System Organ Class 10036585 - Pregnancy, puerperium and perinatal conditions
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the superiority of retosiban to prolong pregnancy and improve neonatal outcomes compared with placebo
    E.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    48 hours after IP infusion, then every week till delivery
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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.8.7Trial 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.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 16
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 16
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 900
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 916
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The investigator is responsible for ensuring that consideration has been given to the poststudy care of the subject's medical condition whether or not GSK is providing specific poststudy treatment.
    Poststudy IP is not provided as part of this protocol.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-07-24
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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