E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
preterm labour and improve neonatal health |
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E.1.1.1 | Medical condition in easily understood language |
preterm labor and the health and development of the child after the child’s mother participated in a retosiban study for preterm labor during mother’s pregnancy. |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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 |
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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 |
The study objective is to assess the safety and outcomes in infants and children who were exposed to retosiban or comparator in the Phase III treatment studiess.
Specific objectives include the following:
•To characterize the clinical safety in terms of infant and children morbidity and mortality in infants and children exposed to retosiban or comparator in utero
•To characterize the clinical safety in terms of neurodevelopment in infants and children exposed to retosiban or comparator in utero
•To characterize parental productivity loss related to a sick child and infant resource utilization in terms of hospital admissions, length of stay, emergency room/urgent care (ER/UC) visits, surgical procedures, and referral to specialty care or therapy visits for infants (up to age 2 years) exposed to retosiban or comparator in utero
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Infants eligible for enrollment in the study must meet all of the following criteria:
1.Mother is randomly assigned and dosed (retosiban or comparator) in 1 of the Phase III retosiban clinical studies.
2.Infant is alive at 28 days post EDD.
3.Written informed consent is obtained from the parent(s) or legal guardian(s) of the infant. The parent/legal guardian of participants aged 12 to 17 years must also provide written agreement for the infant to participate in the study where required by applicable regulatory and country or state requirements.
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E.4 | Principal exclusion criteria |
All infants who meet the inclusion criteria will be eligible to enroll in the study. There are no formal exclusion criteria for participation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Morbidity and mortality endpoints:
•Proportion of infants and children with newly diagnosed (after 28 days post EDD) chronic medical conditions by type of condition will be recorded and include the following:
•Respiratory conditions
•Neurological conditions
•Sensory conditions
•Gastrointestinal conditions
•Cardiovascular conditions
•Renal conditions
•Growth parameters (only up to 24 months chronological age)
•Proportion of infants and children with newly diagnosed (after 28 days post EDD) congenital anomalies
•Proportion of neonatal and infant and child deaths after 28 days post EDD and until the end of the study
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
collection of neonatal morbidity data and will occur at 28 days after the estimated date of delivery (EDD) and the infant's parent/legal guardian will be asked to complete a Child Health Inventory at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age |
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E.5.2 | Secondary end point(s) |
Neurodevelopment endpoints:
•Neurodevelopment endpoints assessed at ages 9, 18, and 24 months, corrected for prematurity:
•Proportion of infants with an ASQ-3 score in the black zone in any domain
•Proportion of infants with an ASQ-3 score in the black zone for gross motor skills
•Proportion of infants with an ASQ-3 score in the black zone for fine motor skills
•Proportion of infants with an ASQ-3 score in the black zone for communication
•Proportion of infants with an ASQ-3 score in the black zone for problem solving
•Proportion of infants with an ASQ-3 score in the black zone for personal-social skills
•Proportion of infants referred for developmental evaluation (using BSID III)
•Proportion of infants with a BSID-III score >2 SDs below the mean score for the cognitive impairment (<70)
•Proportion of infants with BSID-III score >2 SDs below the mean score for the gross motor scale (<70)
•Proportion of infants with BSID-III score >2 SDs below the mean score for the fine motor scale (<70)
•Proportion of infants with a BSID-III score >2 SDs below the mean score for the language scale (<70)
•Proportion of infants referred for an additional behavioral assessment using the CBCL/1.5-5 and M-CHAT-R/F
•Proportion of infants with a CBCL/1.5–5 score at or above the 97th percentile for a subset of prespecified questions that relate to attention and hyperactivity problems
•Proportion of infants indicated as needing further evaluation after completion of the M CHAT R/F
•Proportion of infants referred for neurological evaluation to determine diagnosis of cerebral palsy
•Proportion of infants with at least 1 of the following indicators of neurodevelopmental impairment at the end of the study:
•Hearing impaired, uncorrected even with aids (at 24 months chronological age)
•Blindness in 1 or both eyes, or sees light only (at 24 months chronological age)
•Cerebral palsy (moderate and severe) ( at 24 months corrected age)
•Cognitive impairment: BSID-III Cognitive Scale Score of <2 SDs below mean score (<70) (at 24 months corrected age)
•Motor impairment: BSID-III Motor Composite Scale Score of <2 SDs below mean score (<70) ( at 24 months corrected age)
Proportion of infants and children with at least 1 of the following
indicators of neurodevelopmental impairment at the end of the study:
•Hearing impaired, uncorrected even with aids
•Blindness in 1 or both eyes or sees light only
•Cerebral palsy (moderate and severe)
•Diagnosis of ASD, attention deficit disorder (ADD), or attention deficit
hyperactivity disorder (ADHD)
Resource utilization endpoints:
•Number of hospital admissions, proportion of infants and children with
any hospital admission, post-birth hospitalization discharge, by principal
and secondary discharge diagnosis, type of hospital unit admitted to
(e.g., NICU, Pediatric, PICU, Nursery level 3, ICU), and length of hospital
stay per unit after 28 days post EDD and until the end of the study.
•Combined length of hospital stay in days for all hospital admissions (for
infants discharged from the delivery hospitalization and for babies who
were never discharged home post-delivery) after 28 days post EDD and
until the end of the study.
•Number of surgical procedures (details of type and whether performed
on an inpatient basis or at an outpatient/surgical center will be collected
up to 24 months chronological age only) after 28 days post EDD and until
the end of the study.
•Number of ER/UC visits and proportion of infants with any ER/UC visit
after 28 days post EDD and up to 24 months chronological age.
•Number of specialty care or therapy visits and proportion of infants
referred for specialty care or therapy by type of care/therapy after 28
days post EDD and up to 24 months chronological age.
•Parental productivity loss related to infant hospital admissions, ER/UC
visits, or specialist care after 28 days post EDD and up to 24 months
chronological age. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
28 days after the estimated date of delivery (EDD) and the infant's parent/legal guardian will be asked to complete a Child Health Inventory at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 |
Infants will be assigned to the same treatment group to which mothers were assigned |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
study treatment given to mothers in 200721 study will remain. No drug will be given to the infants |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
France |
Germany |
Israel |
Italy |
Korea, Republic of |
Mexico |
Spain |
Sweden |
United Kingdom |
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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
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The infants and children will be followed from after 28 days EDD up to
5 years chronological age. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |