A Clinical Efficacy and Safety Study of SHP607 in Preventing Chronic Lung Disease in Extremely Premature Infants

• ClinicalTrials.gov Identifier: NCT03253263
• Recruitment Status: Active, not recruiting
• First Posted: August 17, 2017
• Last Update Posted: July 15, 2021
• Sponsor: Shire
• Information provided by (Responsible Party): Takeda ( Shire )

Tracking Information

• First Submitted Date: August 15, 2017
• First Posted Date: August 17, 2017
• Last Update Posted Date: July 15, 2021
• Actual Study Start Date: May 9, 2019
• Estimated Primary Completion Date: February 28, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 5, 2020)

Time to Final Weaning off Respiratory Technology Support (RTS) From Day 1 Through 12 Months Corrected age (CA) [ Time Frame: Baseline through 12 months Corrected Age (CA) ]

RTS is defined as any one of the following: (1) supplemental oxygen less than (<) 2 Liter per minute (L/min) without positive pressure (including nasal cannula), (2) positive pressure support (including continuous positive airway pressure [CPAP], nasal cannula oxygen greater than (>) 2 L/min), (3) positive pressure ventilation (high frequency oscillation ventilation and technologies with positive pressure tidal volume breaths, such as mechanical ventilation, nasal intermittent positive pressure ventilation [NIPPV]). Time to final weaning off RTS as compared to a standard neonatal care group will be reported.

Original Primary Outcome Measures (submitted: August 15, 2017)

Incidence of Chronic Respiratory Morbidity (CRM) Through 12 Months Corrected Age (CA) [ Time Frame: Baseline through 12 months Corrected Age (CA) ]

CRM is a common adverse outcome of premature birth resulting in recurrent respiratory symptoms requiring treatment with pulmonary medications such as bronchodilators, need for supplementary home oxygen, frequent emergency room visits or hospital readmissions, especially during the first year of life. CRM will be measured by respiratory health care utilization and respiratory symptoms.

Current Secondary Outcome Measures (submitted: June 5, 2020)

• Incidence of Bronchopulmonary Dysplasia (BPD) or Death through Postmenstrual age (PMA) 36 Weeks [ Time Frame: Baseline through 36 weeks postmenstrual age (PMA) ]
  BPD will be assessed by modified NICHD severity grading and standardized by oxygen challenge testing for all participants. Incidence of BPD (yes/no) (as diagnosed by modified NICHD severity grading at PMA 36 weeks or discharge home, and confirmed by oxygen challenge testing) or death through PMA 36 weeks will be reported.
• Total Number of Days on Respiratory Technology Support (RTS) From Birth Through 12 Months Corrected age (CA) [ Time Frame: Birth through 12 months CA ]
  RTS is defined as any one of the following: (1) any fraction of inspired oxygen (FiO2) greter than (>) 21 percent (%), (2) noninvasive respiratory support delivered via a nasal interface (e.g., continuous positive airway pressure [CPAP], bilevel positive airway pressure [BiPAP], high flow therapy, nasal intermittent positive pressure ventilation [NIPPV], nasal cannula), (3) invasive respiratory support (mechanical ventilation) via an endotracheal tube or tracheostomy. Total number of days on RTS from birth through 12 months CA will be reported.
• Duration of Re-hospitalizations [ Time Frame: From neonatal intensive care unit (NICU) discharge through 12 months CA ]
  Duration of re-hospitalizations due to respiratory diagnoses will be reported.
• Number of Emergency Room Visits [ Time Frame: From NICU discharge through 12 months CA ]
  Number of emergency room visits associated with a respiratory diagnosis will be reported.
• Number of Days of Respiratory Medication use [ Time Frame: From NICU discharge through 12 months CA ]
  Number of days of respiratory medication use (for example, bronchodilators, steroids, leukotriene inhibitors, diuretics) will be reported.
• Incidence of Signs and Symptoms of Respiratory Disease as Assessed by a 28-day Caregiver-administered Diary Ending at 12 Months Corrected age (CA) [ Time Frame: 11 months CA through 12 months CA ]
  Incidence of signs and symptoms of respiratory disease (yes/no) at 12 months CA as assessed by a 28-day caregiver-administered diary recording episodes of wheezing, coughing, and respiratory medication will be reported.
• Incidence of Chronic Respiratory Morbidity (CRM1) Through 12 Months Corrected age (CA) [ Time Frame: From NICU discharge through 12 months CA ]
  A participant will be defined as having CRM1 if he or she experienced/required at least 1 of the 3 following clinical/treatment events, as reported by parents/caregivers and captured by the pulmonary morbidity assessment on at least two 3-month quarters over a 12-month time period: 1. Emergency room visit or hospitalization associated with a respiratory diagnosis, 2. Home RTS, 3. Daily use of respiratory medications (e.g., bronchodilators, steroids, leukotriene inhibitors, diuretics) as reported by caregivers on the pulmonary morbidity assessment. Incidence of CRM1 through 12 months CA will be reported.
• Incidence of Chronic Respiratory Morbidity Including Symptoms of Respiratory Disease (CRM2) Through 12 Months Corrected age (CA) [ Time Frame: From NICU discharge through 12 months CA ]
  A participant will be defined as having CRM2 if he or she experienced/required at least 1 of the 4 following clinical/treatment events, as reported by parents/caregivers and captured by the pulmonary morbidity assessment on at least two 3-month quarters over a 12-month time period: 1. Emergency room visit or hospitalization associated with a respiratory diagnosis, 2. Home RTS, 3. Daily use of respiratory medications (e.g., bronchodilators, steroids, leukotriene inhibitors, diuretics) as reported by caregivers on the pulmonary morbidity assessment, 4. Symptoms of respiratory disease as defined by presence of cough without cold, or wheeze at least once per week. Incidence of CRM2 through 12 months CA will be reported.
• Severity of Chronic Respiratory Morbidity (CRM3) Through 12 Months Corrected age (CA), as Determined by the Chronic Lung Disease (CLD) of Infancy Severity Score [ Time Frame: From NICU discharge through 12 months CA ]
  Severity of chronic respiratory morbidity (CRM3) through 12 months CA will be reported, as determined by the CLD of infancy severity score that will include components such as respiratory hospitalizations, RTS use, and use of respiratory medications.
• Incidence of Intraventricular Haemorrhage (IVH) Through Postmenstrual age (PMA) 40 weeks, as Assessed by Cranial Ultrasound [ Time Frame: Baseline through 40 Weeks PMA ]
  Incidence of IVH through PMA 40 weeks, as assessed by cranial ultrasound, will be reported.
• Motor Function at 12 Months Corrected age (CA), as Measured by Alberta Infant Motor Scales (AIMS) [ Time Frame: At 12 months CA ]
  The AIMS is a measure of early motor maturation used for assessment of infants at risk for motor delay, focusing on attainment of motor milestones and development of postural control. It consists of 58 items, including assessments in 4 postural positions: prone (21 items), supine (9 items), sitting (12 items) and standing (16 items). Each item is scored as 'observed' or 'not observed'. The scorer identifies the least and most mature item observed. Motor function at 12 months CA, as measured by AIMS will be reported.
• Functional Status as Assessed by PREMature Infant Index (PREMII) at Postmenstrual Age (PMA) 36 Weeks [ Time Frame: At 36 weeks PMA ]
  PREMII is a Clinician-Reported Outcome (ClinRO) assessment used to capture overall functional maturation of extremely preterm neonates. Functional Status is defined as what the infant can do with respect to 8 key functional areas (feeding, weight gain, thermoregulation, respiratory support, apnea, bradycardia, desaturation events, and oxygen administration), as a reflection of the infant's overall health and development.
• Incidence of Retinopathy of Prematurity (ROP) [ Time Frame: 31 weeks through 40 weeks PMA ]
  The ROP examination will consist of a dilated fundus examination. Typically ROP is classified according to the International Classification and is subdivided into Stage 1 (demarcation line), Stage 2 (ridge), Stage 3 (ridge with extraretinal fibrovascular proliferations), Stage 4 (subtotal retinal detachment), and Stage 5 (total retinal detachment). Incidence of ROP will be reported.
• Incidence of Mortality [ Time Frame: From birth through 12 months CA ]
  Mortality from birth through 12 months CA will be reported.
• Exposure-response of Insulin-like Growth Factor-1 (IGF-1) [ Time Frame: Up to 12 months CA ]
  Exposure response of IGF-1 will be evaluated using (Pharmacokinetic/Pharmacodynamic [PK/PD]) relationship of IGF-1 between respiratory and neurologic endpoints.

Original Secondary Outcome Measures (submitted: August 15, 2017)

• Incidence of Bronchopulmonary Dysplasia (BPD) at Postmenstrual Age (PMA) 36 Weeks [ Time Frame: PMA Week 36 ]
  BPD is a chronic lung disorder characterized by pulmonary immaturity, undifferentiated alveoli with the presence of hyaline membrane and atelectasis, dilated capillaries immersed in the mesenchyme, and a distorted deposition of the extracellular matrix. BPD results in residual effects on pulmonary function and is linked to neurodevelopmental problems during later childhood.
• Incidence of Severe Intraventricular Hemorrhage (IVH) Grade III or IV Through Postmenstrual Age (PMA) 40 Weeks [ Time Frame: Baseline Through PMA 40 Weeks ]
  IVH is characterized by hemorrhage into the germinal matrix tissues of the developing brain. IVH is associated with substantial mortality and morbidity and may result in long-term neurodevelopmental impairments. It has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature and secondary periventricular venous infarction. It will be assessed by cerebral ultrasound.
• Incidence of Bronchopulmonary Dysplasia (BPD) at Postmenstrual Age (PMA) 40 Weeks [ Time Frame: PMA Week 40 ]
  BPD is a chronic lung disorder characterized by pulmonary immaturity, undifferentiated alveoli with the presence of hyaline membrane and atelectasis, dilated capillaries immersed in the mesenchyme, and a distorted deposition of the extracellular matrix. BPD results in residual effects on pulmonary function and is linked to neurodevelopmental problems during later childhood.
• Incidence of Chronic Respiratory Morbidity (CRM) or Death Through 6 Months Corrected Age (CA) [ Time Frame: Baseline through 6 Months Corrected Age (CA) ]
  CRM is a common adverse outcome of premature birth resulting in recurrent respiratory symptoms requiring treatment with pulmonary medications such as bronchodilators, need for supplementary home oxygen, frequent emergency room visits or hospital readmissions, especially during the first year of life. CRM will be measured by respiratory health care utilization and respiratory symptoms.
• Functional Status as Assessed by PREMature Infant Index (PREMII) at Postmenstrual Age (PMA) 40 Weeks [ Time Frame: PMA Week 36 ]
  PREMII is a Clinician-Reported Outcome (ClinRO) assessment used to capture overall functional maturation of extremely preterm neonates. Functional Status is defined as what the infant can do with respect to 8 key functional areas (feeding, weight gain, thermoregulation, respiratory support, apnea, bradycardia, desaturation events, and oxygen administration), as a reflection of the infant's overall health and development.
• Incidence of Retinopathy of Prematurity (ROP) [ Time Frame: PMA Week 31 up to Week 40 ]
  The ROP examination will consist of a dilated fundus examination. Typically ROP is classified according to the International Classification (International Committee for the Classification of Retinopathy of Prematurity 2005) and is subdivided into Stage 1 (demarcation line), Stage 2 (ridge), Stage 3 (ridge with extraretinal fibrovascular proliferations), Stage 4 (subtotal retinal detachment), and Stage 5 (total retinal detachment).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Clinical Efficacy and Safety Study of SHP607 in Preventing Chronic Lung Disease in Extremely Premature Infants
• Official Title: A Phase 2b, Multicenter, Randomized, Open-label, Controlled, 3-Arm Study to Evaluate the Clinical Efficacy and Safety of SHP607 in Preventing Chronic Lung Disease Through 12 Months Corrected Age Compared to Standard Neonatal Care in Extremely Premature Infants
• Brief Summary: The purpose of this study is to determine if an investigational drug can reduce the burden of chronic lung disease in extremely premature babies through 12 months corrected age (CA), as compared to extremely premature babies receiving standard neonatal care alone.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention

Condition

• Retinopathy of Prematurity (ROP)
• Intraventricular Hemorrhage
• Bronchopulmonary Dysplasia
• Chronic Lung Disease of Prematurity

Intervention

Drug: SHP607

Participants will receive intravenous infusion of SHP607 at doses of 250 mcg/kg/24 hours and 400 mcg/kg/24 hours from birth up to PMA 29 weeks + 6 days.

Other Name: Mecasermin Rinfabate

Study Arms

• Experimental: SHP607 250 mcg/kg/24 hours
  Participants will receive continuous intravenous (IV) infusion of SHP607 250 micrograms per kilogram per 24 hours (mcg/kg/24 hours) from birth up to postmenstrual age (PMA) 29 weeks +6 days.
  Intervention: Drug: SHP607
• Experimental: SHP607 400 mcg/kg/24 hours
  Participants will receive continuous IV infusion of SHP607 400 mcg/kg/24 hours through from birth up to PMA 29 weeks +6 days.
  Intervention: Drug: SHP607
• No Intervention: Standard Neonatal Care
  Standard neonatal care alone will be provided.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 14, 2021): 81
• Original Estimated Enrollment (submitted: August 15, 2017): 1053
• Estimated Study Completion Date: February 28, 2025
• Estimated Primary Completion Date: February 28, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Written informed consents and/or assents must be signed and dated by the participant's parent(s) prior to any study related procedures. The informed consent and any assents for underage parents must be approved by the institutional review board (IRB)/independent ethics committee (IEC).
2. Written informed consents and/or assents must be signed and dated by the participant's birth mother prior to providing study-related information related to birth mother medical history, pregnancy and the birth of the participant. The informed consent and any assents for underage birth mothers must be approved by the IRB/IEC.
3. Initially, participants must be between gestational age (GA) of 26 weeks +0 days and 27 weeks +6 days, inclusive. After approximately 75 participants (approximately 25 participants in each treatment group) have completed the postmenstrual age (PMA) 40 weeks visit, an independent data monitoring committee (DMC) will assess safety data and may authorize enrollment of participants of GA between 23 weeks +0 days and 27 weeks +6 days, inclusive.

Exclusion Criteria:

1. Detectable major (or severe) congenital malformation identified before randomization.
2. Known or suspected chromosomal abnormality, genetic disorder, or syndrome, identified before randomization, according to the investigator's opinion.
3. Hypoglycemia at Baseline (blood glucose less than (<) 45 milligrams per deciliter [mg/dL] or 2.5 milli moles per liter [mmol/L]) which persists in spite of glucose supplementation, to exclude severe congenital abnormalities of glucose metabolism.
4. Clinically significant neurological disease identified before randomization according to cranial ultrasound (hemorrhages confined to the germinal matrix are allowed) and investigator's opinion.
5. Any other condition or therapy that, in the investigator's opinion, may pose a risk to the participant or interfere with the participant's potential compliance with this protocol or interfere with interpretation of results.
6. Current or planned participation in a clinical study of another investigational study drug, device, or procedure (participation in observational studies is permitted on a case-by-case basis).
7. The participant or participant's parent(s) is/are unable to comply with the protocol or is unlikely to be available for long-term follow-up as determined by the investigator.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 1 Day (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Finland, Israel, Italy, Japan, Portugal, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: Korea, Republic of

Administrative Information

• NCT Number: NCT03253263
• Other Study ID Numbers: SHP607-202; 2018-001393-16 ( EudraCT Number ); jRCT2071200076 ( Registry Identifier: jRCT )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: De-identified individual participant data from this particular study will not be shared in order to minimize the risk that individual patients could be re-identified, given that there are limited numbers of study participants at each study site per year.

• Responsible Party: Takeda ( Shire )
• Study Sponsor: Shire
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Shire

• PRS Account: Takeda
• Verification Date: July 2021