STP206 for the Prevention of Necrotizing Enterocolitis (NEC)

Study Overview
=================
Brief Summary
-----------------
This study is a sequential dose escalation study to assess the safety, tolerability, and preliminary NEC-preventative efficacy of two doses of STP206 versus control in very low birth weight and extremely low birth weight neonates.

Detailed Description
-----------------
Protocol STP206-002 is designed as a multi-center, randomized, double-blind, placebo controlled dose escalation study of the safety and tolerability of two doses of STP206 versus control in four sequentially decreasing birth weight strata. The primary objective of this study is to assess the safety and tolerability of once daily dosing of two dose levels of STP206 versus control in four different birth weight strata in premature neonates. Secondary objectives of this study include assessment of fecal shedding of STP206 throughout dosing and describing the incidence of NEC, incidence of relevant clinical events (sepsis/bacteremia, feeding intolerance, morbidity/complications of prematurity) and neonatal growth progression in the STP206 and control treatment groups. Neonates for whom informed consent is obtained and who meet eligibility criteria will be eligible to enroll in this study. All neonates enrolled will receive daily doses of blinded study treatment for between 2 and 11 weeks with the duration of dosing based upon gestational age at birth. All neonates enrolled in the study will be placed under Universal Precautions and all study personnel with subject contact are trained in appropriate neonatal intensive care unit (NICU) infection control practices. While in the NICU, neonates will be evaluated daily for signs/symptoms of NEC, feeding volumes/feeding tolerance, adverse events, and concomitant medications. Physical examinations and vital signs will be performed daily during the dosing period and at the end of dosing/NICU discharge. Growth assessments will be performed every other week while in the NICU and at the end of dosing/NICU discharge. Assessments for complications of prematurity, including retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), and bronchopulmonary dysplasia (BPD) will be performed at protocol defined timeframes. Neonates enrolled in the study will have fecal/meconium samples collected daily through 4 days following the start of dosing and weekly thereafter until NICU discharge to determine fecal shedding of STP6 and STP11. Following completion of blinded study treatment dosing, neonates will be evaluated at 1 week, 4 weeks, 3 months, and 6 months for safety and growth assessments. Neonates will be stratified into the following four birth weights: 2000-1501g, 1500 to 1000 g, 999 to 750 g and 749 to 500 g. Each birth weight stratum will contain 2 dosing groups - a low dose STP206 group and a high dose STP206 group. Within each birth weight strata/dose level, subjects will be randomized in a 2:1 ratio to the STP206 or control group. Enrollment of neonates into study groups will occur sequentially. Enrollment into the high dose group within a birth weight stratum will not proceed until after the safety data from the low dose group is reviewed by the study independent Data Safety Monitoring Committee (DSMC). Similarly, enrollment into the next lower birth weight stratum will not proceed until the safety data from the high dose group of the prior weight stratum is reviewed by the study independent Data Safety Monitoring Committee (DSMC).

Official Title
-----------------
A Phase Ib Randomized, Placebo Controlled Study of the Safety and Efficacy of Once Daily Dosing of STP206 in Premature Very Low Birth Weight and Extremely Low Birth Weight Neonates

Conditions
-----------------
Necrotizing Enterocolitis

Intervention / Treatment
-----------------
* Biological: STP206
* Other: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Neonates with birth weights between 2000-500g for Part A and 1500-500g for Part B Ability to start treatment within four days after birth. Gestational age between 23 and 32 weeks at birth Obtaining of informed consent from the subject's mother after full understanding of the study purpose and procedures. Parents who agree to allow the Principal Investigator and his/her staff to follow the procedures and assessments required by the protocol Exclusion Criteria: Infants with, or at high probability for, early onset sepsis (positive blood cultures or with clinical/histological chorioamnionitis with the expectation of empirical antimicrobial therapy for ≥5 days) Infants with persistent pulmonary hypertension of the newborn (PPHN) Congenital or chromosomal anomalies Congenital or acquired gastrointestinal pathology that preclude feeds soon after birth (e.g. cleft lip is not an exclusion criterion, but a duodenal atresia is) Infants in extremis to whom no further intensive care is offered by attending neonatologist (e.g., infant being provided only hospice/comfort care) Other conditions of the infant which, in the opinion of the attending neonatologist, preclude participation Positive maternal HIV status Participation in another interventional clinical trial For Part A of the study, the following additional exclusion criterion will apply: Small for gestational age neonates, i.e. neonates that weigh less that the 10th percentile for their gestational age according to the Estimated Fetal Weight Percentile Chart

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 4 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STP206<br>Biological | Biological: STP206<br>* Live Biotherapeutic<br>|
| Placebo Comparator: Control<br>Sterile water | Other: Control<br>* Sterile Water<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Severity of Adverse Events Experienced by Subjects in Low-dose Treatment Groups | The number and severity of adverse events, adverse events leading to study drug discontinuation, and number of deaths experienced by subjects randomized to the low-dose treatment groups | 30 days after the last dose of blinded study treatment | 
| Number and Severity of Adverse Events Experienced by Subjects in High-Dose Treatment Groups | The number and severity of adverse events, adverse events leading to study drug discontinuation, and number of deaths experienced by subjects randomized to the low-dose treatment groups | 30 days after the last dose of blinded study treatment | 
| Treatment-emergent Adverse Events Experienced by Subjects in Low-Dose Treatment Groups | Treatment-emergent adverse events experienced by subjects in low-dose treatment groups within 30 days of last exposure to study drug | 30 days after last administration of study drug | 
| Treatment-emergent Adverse Events Experienced by Subjects in High-Dose Treatment Groups | Treatment-emergent adverse events experienced by subjects in high-dose treatment groups within 30 days of last exposure to study drug | 30 days after last administration of study drug | 
| Grade 3 Treatment-emergent Adverse Events Experienced by Subjects in Low-Dose Treatment Groups | Grade 3 treatment-emergent adverse events experienced by subjects in low-dose treatment groups within 30 days of last exposure to study drug | 30 days after last administration of study drug | 
| Grade 3 Treatment-emergent Adverse Events Experienced by Subjects in High-Dose Treatment Groups | Grade 3 treatment-emergent adverse events experienced by subjects in high-dose treatment groups within 30 days of last exposure to study drug | 30 days after last administration of study drug | 
| Serious Adverse Events Experienced by Subjects in Low-Dose Treatment Groups | Serious adverse events experienced by subjects in low-dose treatment groups within 30 days of last exposure to study drug | 30 days after last administration of study drug | 
| Serious Adverse Events Experienced by Subjects in High-Dose Treatment Groups | Serious adverse events experienced by subjects in high-dose treatment groups within 30 days of last exposure to study drug | 30 days after last administration of study drug | 
| Growth Assessment Classification in Low-Dose Treatment Groups | Accelerated growth area (AGA) is defined as both body weight (g) and head circumference (cm) are between 10th percentile and 90th percentile according to the gender specific growth percentile charts in Appendix D of Protocol v3.0. Small for gestational age (SGA) SGA/Head-Spared is defined as body weight(g) is <10th percentile, and head circumference(cm) is between 10th percentile and 90th percentile according to the gender specific growth percentile charts in Appendix D of Protocol v3.0. SGA/Head-Symmetric is defined as both body weight(g) and head circumference(cm) are <10th percentile according to the gender specific growth percentile charts in Appendix D of Protocol v3.0. Large for gestational age (LGA) is defined as both body weight(g) and head circumference(cm) are >90th percentile according to the growth percentile charts in Appendix D of Protocol v3.0. | End of dosing/hospital discharge, up to 781 days | 
| Growth Assessment Classification in High-Dose Treatment Groups | AGA is defined as both body weight (g) and head circumference (cm) are between 10th percentile and 90th percentile according to the gender specific growth percentile charts in Appendix D of Protocol v3.0. SGA/Head-Spared is defined as body weight(g) is <10th percentile, and head circumference(cm) is between 10th percentile and 90th percentile according to the gender specific growth percentile charts in Appendix D of Protocol v3.0. SGA/Head-Symmetric is defined as both body weight(g) and head circumference(cm) are <10th percentile according to the gender specific growth percentile charts in Appendix D of Protocol v3.0. LGA is defined as both body weight(g) and head circumference(cm) are >90th percentile according to the growth percentile charts in Appendix D of Protocol v3.0. | End of dosing/hospital discharge, up to 781 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Suspected Necrotizing Enterocolitis in Low-Dose Treatment Groups | NEC is staged from I to III, from suspected to definite to advanced. The 3 stages are further divided into A (less severe) and B (more severe). | Start of dosing to 6 months | 
| Number of Patients With Suspected Necrotizing Enterocolitis in High-Dose Treatment Groups | NEC is staged from I to III, from suspected to definite to advanced. The 3 stages are further divided into A (less severe) and B (more severe). | Start of dosing to 6 months | 
| Number of Patients With Confirmed Necrotizing Enterocolitis in Low-Dose Treatment Groups | NEC is staged from I to III, from suspected to definite to advanced. The 3 stages are further divided into A (less severe) and B (more severe). | Start of dosing to 6 months | 
| Number of Patients With Confirmed Necrotizing Enterocolitis in High-Dose Treatment Groups | NEC is staged from I to III, from suspected to definite to advanced. The 3 stages are further divided into A (less severe) and B (more severe). | Start of dosing to 6 months | 
| Number of Patients With Sepsis in Low-Dose Treatment Groups | The presence of STP6 and STP11 was assessed in peripheral blood cultures. | Start of dosing to 6 months | 
| Number of Patients With Sepsis in High-Dose Treatment Groups | The presence of STP6 and STP11 was assessed in peripheral blood cultures. | Start of dosing to 6 months | 
| Number of Patients With Feeding Intolerance in Low-Dose Treatment Groups | Feeding tolerance was evaluated by abdominal evaluation (any excessive distension beyond what is expected with a feed, redness of abdominal wall, firmness, presence of normal bowel sounds). Neonates placed on NPO status for at least 12 hours were considered to have feeding intolerance. | Start of dosing to 6 months | 
| Number of Patients With Feeding Intolerance in High-Dose Treatment Groups | Feeding tolerance was evaluated by abdominal evaluation (any excessive distension beyond what is expected with a feed, redness of abdominal wall, firmness, presence of normal bowel sounds). Neonates placed on NPO status for at least 12 hours were considered to have feeding intolerance. | Start of dosing to 6 months | 
| Number of Patients With Retinopathy of Prematurity in Low-Dose Treatment Groups | ROP in each eye was assessed by indirect ophthalmoscope after pupillary dilation. ROP is categorized in zones 1 to 3, the lower number representing the smallest area affected, and stages 0 to 5, the lowest number indicating the mildest form and the highest number indicating retinal detachment. | Start of dosing to 6 months | 
| Number of Patients With Retinopathy of Prematurity in High-Dose Treatment Groups | ROP in each eye was assessed by indirect ophthalmoscope after pupillary dilation. ROP is categorized in zones 1 to 3, the lower number representing the smallest area affected, and stages 0 to 5, the lowest number indicating the mildest form and the highest number indicating retinal detachment. | Start of dosing to 6 months | 
| Number of Patients With Intraventricular Hemorrhage in Low-Dose Treatment Groups | IVH was assessed by cranial ultrasound between the ages of 5 and 7 days and, if clinically indicated and the neonate remained hospitalized, at 28 days. IVH is graded from I to IV, with increasing severity. | From 5 days to 28 days | 
| Number of Patients With Intraventricular Hemorrhage in High-Dose Treatment Groups | IVH was assessed by cranial ultrasound between the ages of 5 and 7 days and, if clinically indicated and the neonate remained hospitalized, at 28 days. IVH is graded from I to IV, with increasing severity. | From 5 days to 28 days | 
| Number of Patients With Bronchopulmonary Dysplasia in Low-Dose Treatment Groups | Mild to Moderate = Need for < 30% O2 at 36 wk postmenstrual age (PMA) or discharge, whichever comes first. Severe = Need for ≥ 30% O2, positive pressure or both at 36 wk PMA or discharge, whichever comes first. For each event type, patients are counted only once if they had one or more events as this table tabulates the percentage of patients with one or more events. | Start of dosing to 6 months | 
| Number of Patients With Bronchopulmonary Dysplasia in High-Dose Treatment Groups | Mild to Moderate = Need for < 30% O2 at 36 wk postmenstrual age (PMA) or discharge, whichever comes first. Severe = Need for ≥ 30% O2, positive pressure or both at 36 wk PMA or discharge, whichever comes first. For each event type, patients are counted only once if they had one or more events as this table tabulates the percentage of patients with one or more events. | Start of dosing to 6 months | 
| Number of Patients With Fecal Shedding of STP6 and STP11 in Low-Dose Treatment Groups | The presence of STP6 and STP11 was assessed in fecal cultures. | Prior to Week 1 Day 4 and at end of dosing/hospital discharge, up to 781 days | 
| Number of Patients With Fecal Shedding of STP6 and STP11 in High-Dose Treatment Groups | The presence of STP6 and STP11 was assessed in fecal cultures. | Prior to Week 1 Day 4 and at end of dosing/hospital discharge, up to 781 days |