Follow up Study to Assess Long Term Safety and Outcomes in Infants and Children Born to Mothers Participating in Retosiban Treatment Studies

Obstetric Labour, Premature Clinical Trial

— ARIOS  

Official title:

Follow-Up Study to Assess Long-Term Safety and Outcomes in Infants and Children Born to Mothers Participating in Retosiban Treatment Studies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02292784
• Other study ID #: 200722
• Status: Completed
• Phase: Phase 3
• Start date: June 1, 2015
• Est. completion date: September 2, 2019

Study information

• Verified date: June 2020
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to assess the safety and outcomes of infants and children who were exposed to retosiban or comparator in utero in the Phase III spontaneous preterm labor (SPTL) treatment studies, to provide assurance that treatment is not associated with significant adverse outcomes in early childhood. The enrolled infants and children will be followed at pre-specified intervals until they reach 24 months chronological age. This study does not require medical interventions or study visits to an investigational site, instead, parents or legal guardians will be prompted at certain time points to complete developmental questionnaires and other data on their children's health status via an electronic device. Data collected during the infant and child follow up study will be managed by a centralized research coordinating center (RCC). Regionally based pediatricians will serve as study principal investigators (referred to as RCC-PIs) for this study. All communications the RCC-PI has with the parent/legal guardian or the child's health care provider (HCP) will occur remotely; there will be no clinic visits.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: September 2, 2019
• Est. primary completion date: September 2, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Weeks to 20 Weeks

Eligibility

Inclusion Criteria:

• Mother is randomly assigned and dosed (retosiban or comparator) in 1 of the Phase III SPTL retosiban clinical studies.

• Infant is alive at 28 days post EDD.

• Written informed consent is obtained from the parent(s) or legal guardian(s) of the infant. The parent/legal guardian of subjects 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.

Exclusion Criteria:

• There are no formal exclusion criteria for participation.

Related Conditions & MeSH terms

• Obstetric Labor, Premature
• Obstetric Labour, Premature

Intervention

Drug:
• Retosiban
This is a safety follow-up study of infants and children exposed to retosiban during their mother's participation in a Phase III treatment study for SPTL. Infants enrolled in this study will not be administered any investigational product.
• Atosiban
This is a safety follow-up study of infants and children exposed to atosiban comparator during their mother's participation in a Phase III treatment study for SPTL. Infants enrolled in this study will not be administered any investigational product.
• Placebo
This is a safety follow-up study of infants and children exposed to matching placebo for retosiban/ atosiban during their mother's participation in a Phase III treatment study for SPTL. Infants enrolled in this study will not be administered any investigational product

Locations

Country	Name	City	State
Belgium	GSK Investigational Site	Gent
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Jena
Israel	GSK Investigational Site	Hadera
Israel	GSK Investigational Site	Haifa
Israel	GSK Investigational Site	Holon
Israel	GSK Investigational Site	Kfar Saba
Israel	GSK Investigational Site	Petach Tikva
Israel	GSK Investigational Site	Safed
Israel	GSK Investigational Site	Tel-Aviv
Italy	GSK Investigational Site	Monza
Italy	GSK Investigational Site	Siena	Toscana
Japan	GSK Investigational Site	Miyagi
Japan	GSK Investigational Site	Miyazaki
Korea, Republic of	GSK Investigational Site	Seongnam
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Mexico	GSK Investigational Site	Ciudad Obregon	Sonora
Mexico	GSK Investigational Site	Guadalajara	Jalisco
Mexico	GSK Investigational Site	Monterrey	Nuevo León
Spain	GSK Investigational Site	Zaragoza
Sweden	GSK Investigational Site	Uppsala
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Sunderland	Tyne & Wear
United States	GSK Investigational Site	Galveston	Texas
United States	GSK Investigational Site	Park Ridge	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
GlaxoSmithKline	PPD

Countries where clinical trial is conducted

United States,  Belgium,  Germany,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Infants and Children With Newly Diagnosed Chronic Medical Conditions (After 28 Days Post Estimated Date of Delivery)	The parents of the infants filled in an online child health inventory (CHI) questionnaire, which asked them about each condition. If they reported anything, it was then verified by a healthcare professional. Number of infants and children with newly diagnosed chronic medical conditions are presented.	From 28 days post estimated date of delivery up to 24 months
Primary	Number of Infants and Children With Newly Diagnosed Congenital Anomalies (After 28 Days Post Estimated Date of Delivery)	A congenital anomaly is a condition present at birth that results from malformation, deformation, or disruption in 1 or more parts of the body, a chromosomal abnormality, or a known clinical syndrome. Congenital anomaly serious adverse events (SAEs) were examined by the birth defect evaluator. Events were coded per centers for disease control and prevention (CDC) Metropolitan Atlanta congenital defects program (MACDP) criteria and/or European surveillance of congenital anomalies (EUROCAT) criteria. Predefined defect codes specified whether the defect was face and neck, a cleft lip or palate, cardiovascular, respiratory, upper gastrointestinal, female genitalia, male genitalia, renal and urinary system, other musculoskeletal defects, skin, a chromosome anomaly, other organ systems, or a specified syndrome. Number of infants and children with newly diagnosed congenital anomalies reported up to 1 year of chronological age and reported after 1 year of chronological age are presented.	From 28 days post estimated date of delivery up to 24 months
Primary	Number of Infant and Child Death (After 28 Days Post Estimated Date of Delivery)	Number of infant and child death that occurred after 28 days post estimated date of delivery and up to 24 months are presented.	From 28 days post estimated date of delivery up to 24 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Any Domain at 9 Months	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for communication was 13.97, gross motor was 17.82, fine motor was 31.32, problem solving was 28.72 and personal social skills was 18.91. Total score was derived by taking mean of all 5 components. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for any domains in the black zone at 9 months is presented.	At 9 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Any Domain at 18 Months	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 18 months, the pre-defined cut-off score for communication was 13.06, gross motor was 37.38, fine motor was 34.32, problem solving was 25.74 and personal social skills was 27.19. Total score was derived by taking mean of all 5 components. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for any domains in the black zone at 18 months is presented.	At 18 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Any Domain at 24 Months	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 24 months, the pre-defined cut-off score for communication was 25.17, gross motor was 38.07, fine motor was 35.16, problem solving was 29.78 and personal social skills was 31.54. Total score was derived by taking mean of all 5 components. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for any domains in the black zone at 24 months is presented.	At 24 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Gross Motor Skills	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for gross motor skills was 17.82. At 18 months, the pre-defined cut-off score for gross motor skills was 37.38. At 24 months, the pre-defined cut-off score for gross motor skills was 38.07. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for gross motor skills in the black zone at 9, 18 and 24 months is presented.	9, 18 and 24 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Fine Motor Skills	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for fine motor skills was 31.32. At 18 months, the pre-defined cut-off score for fine motor skills was 34.32. At 24 months, the pre-defined cut-off score for fine motor skills was 35.16. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for fine motor skills in the black zone at 9, 18 and 24 months is presented.	9, 18 and 24 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Communication Skills	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for communication skills was 13.97. At 18 months, the pre-defined cut-off score for communication skills was 13.06. At 24 months, the pre-defined cut-off score for communication skills was 25.17. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for communication skills in the black zone at 9, 18 and 24 months is presented.	9, 18 and 24 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Problem Solving Skills	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for problem solving skills was 28.72. At 18 months, the pre-defined cut-off score for problem solving skills was 25.74. At 24 months, the pre-defined cut-off score for problem solving skills was 29.78. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for problem solving skills in the black zone at 9, 18 and 24 months is presented.	9, 18 and 24 months
Primary	Number of Infants With Ages and Stages Questionnaire-3 (ASQ-3) Score in the Black Zone for Personal Social Skills	The ASQ-3 included 6 questions in each area, designed to assess 5 areas of development: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for personal social skills was 18.91. At 18 months, the pre-defined cut-off score for personal social skills was 27.19. At 24 months, the pre-defined cut-off score for personal social skills was 31.54. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for personal social skills in the black zone at 9, 18 and 24 months is presented.	9, 18 and 24 months
Primary	Number of Infants Referred for Developmental Evaluation Using Bayley Scales of Infant Development, Third Edition (BSID-III)	Any infant who scored below the cut-off i.e., a score greater than or equal to 2 Standard Deviations (SDs) below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was referred to a developmental specialist for a neurodevelopmental evaluation using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Total score was derived by taking mean of all the components. Number of infants referred for developmental evaluation using BSID-III is presented.	9, 18 and 24 months
Primary	Number of Infants With Bayley Scales of Infant Development, Third Edition Score Greater Than 2 Standard Deviation Below the Mean Score for the Cognitive Scale (Less Than 4)	Any infant who scored below the cut-off i.e., a score greater than or equal to 2 SDs below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was referred to a developmental specialist for a neurodevelopmental evaluation using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the cognitive scale (less than 4) is presented.	9, 18 and 24 months
Primary	Number of Infants With Bayley Scales of Infant Development, Third Edition Score Greater Than 2 Standard Deviation Below the Mean Score for the Gross Motor Scale (Less Than 4)	Any infant who scored below the cut-off i.e., a score greater than or equal to 2 SDs below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was referred to a developmental specialist for a neurodevelopmental evaluation using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the gross motor scale (less than 4) is presented.	9, 18 and 24 months
Primary	Number of Infants With Bayley Scales of Infant Development, Third Edition Score Greater Than 2 Standard Deviation Below the Mean Score for the Fine Motor Scale (Less Than 4)	Any infant who scored below the cut-off i.e., a score greater than or equal to 2 SDs below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was referred to a developmental specialist for a neurodevelopmental evaluation using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the fine motor scale (less than 4) is presented.	9, 18 and 24 months
Primary	Number of Infants With Bayley Scales of Infant Development, Third Edition Score Greater Than 2 Standard Deviation Below the Mean Score for the Language Scale (Less Than 70)	Any infant who scored below the cut-off i.e., a score greater than or equal to 2 SDs below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was referred to a developmental specialist for a neurodevelopmental evaluation using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the language scale (less than 70) is presented.	9, 18 and 24 months
Primary	Number of Infants With a Child Behavior Checklist for Ages 1.5 to 5 Years (CBCL/1.5 to 5) Score Above the 97th Percentile for a Subset of Prespecified Questions That Relate to Attention and Hyperactivity Problems	The CBCL/1.5 to 5 questionnaire is a parent-completed questionnaire used for assessing behavioral problems and social competencies. It included approximately 100 items that described specific kinds of behavioral, emotional, and social problems that characterized preschool children between the ages of 1.5 and 5 years. Each question could be answered as "not true scored as"0",somewhat or sometimes true scored as"1"or very true or often true scored as "2". There were 6 questions related to attention and hyperactivity problems. The responses to those 6 questions were summed (ranged 0 to 12). Total score of 0 to 9 indicated normal, 10 indicated borderline and 11 to 12 indicated significant attention and hyperactivity problems. Scores above the 97th percentile are in the significant range of clinical concern. Number of infants with CBCL/1.5 to 5 score above 97th percentile for subset of pre-specified questions related to attention and hyperactivity problems at 24 months is reported.	At 24 months
Primary	Number of Infants Indicated as Needing Further Evaluation After Completion of the Modified Checklist for Autism in Toddlers- Revised With Follow-up (M-CHAT-R/F)	The M-CHAT-R/F is a parent-reported autism screening tool designed to identify children 16 to 30 months of age who received a more thorough assessment for possible early signs of autism spectrum disorder (ASD) or developmental delay. The M-CHAT-R/F consisted of 20 questions that were answered with either "yes, scored as 0" or "no, scored as 1". Total scores (ranged 0 to 20) on the M-CHAT-R/F between 0 and 2 indicated a low risk, scores between 3 and 7 indicated a medium risk and triggered administration of the follow-up questionnaire, and scores between 8 and 20 indicated a high risk. Number of infants who needed further evaluation as per the M-CHAT-R/F at 18 and 24 months is presented.	18 and 24 months
Primary	Number of Infants Referred for Neurological Evaluation to Determine Diagnosis of Cerebral Palsy	Parents reported in CHI questionnaire if their infant had cerebral palsy. If the infant was not diagnosed with cerebral palsy, then this was detected as part of the ASQ-3 assessment, based on the results of the gross motor scale. To confirm the diagnosis of cerebral palsy, the healthcare practitioner referred the infant for further neurological tests if they scored in the black zone of the ASQ-3 at the month 24 assessment. Number of infants referred for neurological evaluation to determine diagnosis of cerebral palsy at 24 months is presented.	At 24 months
Primary	Number of Infants With the Indicators of Neurodevelopmental Impairment	The indicators of neurodevelopmental impairment were 'hearing impaired, uncorrected even with aids'; 'blindness in 1 or both eyes, or sees light only'; 'cerebral palsy-moderate and severe (moderate: Grade 2 or 3 using the gross motor functional classification system [GMFCS] and severe: Grade 4 or 5 using the GMFCS)'; 'cognitive impairment: BSID-III cognitive scale score of less than 2 SDs below mean score (less than 4)'; 'motor impairment: BSID-III motor composite scale score of greater than 2 SDs below mean score (less than 70)'; 'diagnosis of ASD, attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD)'. Number of infants having any 1 of these indicators is presented.	Up to 24 months