A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study Investigating Two Doses of Teduglutide in Pediatric Subjects Through 17 Years of Age with Short Bowel Syndrome who are Dependent on Parenteral Support
- Children’s Medical Center (Dallas, Plano, Southlake)
Nandini Channabasappa, M.D.
This will be a double-blind, 2-arm study in which subjects will be randomized in a 1:1 ratio to receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks followed by 4 weeks of no active therapy. Dosing regimens will be blinded to both investigators and subjects. in addition, an attempt will be made to enroll subjects in a separate standard of care group, which will serve as an observational cohort for the 24-week treatment period and 4-week follow-up. The subjects in the standard of care group will follow the same visit schedule as the randomized subjects.
all subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the requirements for nutritional support for each subject and to ensure adherence to eligibility parameters. after screening, the 24-week treatment period will consist of site visits at baseline, weekly for the first 2 weeks (Weeks 1 and 2), and then every other week through Week 12 (Weeks 4, 6, 8, 10, and 12). For the remainder of the treatment period, visits at the sites will be conducted every 3 weeks (at Weeks 15, 18, 21, and 24). Telephone contacts will be made on all other weeks during the treatment period. at all site visits and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. a final visit will be
scheduled at Week 28, 4 weeks following the end of treatment (eoT). Telephone contact will be made during the interim weeks from eoT to end of study (eoS) to monitor safety and any changes in nutritional support.
To maintain consistency across all centers, sites and subjects (treated and standard of care) must follow the nutritional support adjustment guidelines (developed with SBS expert input and provided in the protocol) for decisions regarding Pn/iV support reduction and advances in enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability.
Safety and tolerability results will be evaluated by a Data Safety Monitoring Board (DSMB) approximately every 3 months during the active study period (date of the first subject's first dose to date of the last subject's last dose). The DSMB review will include all cumulative safety data (ie, adverse events, laboratory assessments, physical examinations, etc.) from study assessments through each cutoff period period.
The primary pharmacodynamic (PD) parameter is Pn/iV volume reduction of at least 20% at 24 weeks (or eoT) compared to baseline.
analysis of additional PD endpoints will include:
* 100% reduction in Pn/iV support (any subjects who are able to completely wean off Pn/iV support) compared to baseline at eoT
* Change from baseline (absolute and percent change) in Pn/iV support (volume and calories), citrulline, and enteral nutritional support (volume and calories) over time
* Change from Week 24 (or eoT) (absolute and percent change) in Pn/iV support (volume and calories), citrulline, and enteral nutritional support (volume and calories) at Week 28 (or eoS)
* Change in body weight, height (or length) and head circumference (up to 36 months of age).
Derived variables will include height Z-score, weight Z-score, body mass index (BMi), and BMi Z-score
* Fecal output (by volume or number of bowel movements per day)
* Change in hours per day and days per week of Pn/iV support
* Proportion of responders (ie, subjects who achieve at least a 20% reduction in Pn/iV volume) over time
To maintain consistency across all centers, sites and subjects (treated and standard of care) must follow the nutritional support adjustment guidelines (developed with SBS expert input) for decisions regarding Pn/iV support reduction and advances in enteral feeds based on weight gain,
urine, and stool output in the setting of clinical stability.
Male and female children and adolescents through 17 years of age, who satisfy all of the following inclusion criteria and none of the following exclusion criteria are eligible to be enrolled in this study..
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related procedures
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics Committee/Institutional Review Board) prior to any study-related procedures
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or advance in feeds) for at least 3 months prior to and during screening, as assessed by the investigator. Transient instability for events such as interruption of central access or treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to the event.
6. Sexually active female subjects of child-bearing potential (in the teduglutide treatment arm only) must use medically acceptable methods of birth control during and 4 weeks after the treatment period