Short Bowel Syndrome Research Study for Children Up To 17 Years of Age on Parenteral Nutrition

Study Overview
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Brief Summary
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Teduglutide is approved for treatment of adults with short bowel syndrome (SBS). The purpose of this study is to evaluate the safety and efficacy of teduglutide in children up to the age of 17 with SBS who are dependent on parenteral support. Subjects may choose whether to receive the study drug or to participate in a standard-of-care arm. All participants who complete the study may be eligible to receive the study drug in a long-term extension study.

Official Title
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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

Conditions
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Short Bowel Syndrome

Intervention / Treatment
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* Drug: Teduglutide 0.05mg/kg
* Drug: Teduglutide 0.025 mg/kg
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent by a parent or guardian or emancipated minor prior to any study-related procedures When applicable, an informed assent by the subject (as deemed appropriate by the Ethics Committee/Institutional Review Board) prior to any study-related procedures Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric and/or fluid/electrolyte needs prior to screening 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. 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 Exclusion Criteria: Subjects who are not expected to be able to advance oral or tube feeding regimens Serial transverse enteroplasty or any other bowel lengthening procedure performed within 3 months of screening Known clinically significant untreated intestinal obstruction contributing to feeding intolerance and inability to reduce parenteral support Unstable absorption due to cystic fibrosis or known DNA abnormalities Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected to limit the advancement of enteral feeding. Evidence of clinically significant obstruction on upper GI series done within 6 months prior to screening. Major GI surgical intervention including significant intestinal resection within 3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, minor intestinal resections ≤ 10 cm, or endoscopic procedure is allowed). Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects who had undergone ventricular or atrial septal defect repair, and patent ductus arteriosus (PDA) ligation. History of cancer or clinically significant lymphoproliferative disease, not including resected cutaneous basal or squamous cell carcinoma, or in situ non aggressive and surgically resected cancer. Pregnant or lactating female subjects (in the teduglutide treatment arm only). Participation in a clinical study using an experimental drug (other than glutamine or Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to screening, and for the duration of the study. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2) Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months prior to screening Previous use of octreotide, or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior to screening Subjects with active Crohn's disease who had been treated with biological therapy (eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit Subjects with inflammatory bowel disease (IBD) who require chronic systemic immunosuppressant therapy that had been introduced or changed during the 3 months prior to screening More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 3 months prior to the screening visit Any major unscheduled hospital admission which affects parenteral support requirements within 1 month prior to or during screening, excluding uncomplicated treatment of bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise stable subject Body weight < 10 kg at the screening and baseline visits Signs of active severe or unstable, clinically significant hepatic impairment during the screening period, as indicated by any of the following laboratory test results : Total bilirubin (TBL) ≥ 2 x upper limit of normal (ULN) Aspartate aminotransferase (AST) ≥ 7x ULN Alanine aminotransferase (ALT) ≥ 7x ULN For subjects with Gilbert's disease: Indirect (unconjugated) bilirubin ≥ 2x ULN Signs of known continuous active or unstable, clinically significant renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the study visit schedule and other protocol requirements Unstable, clinically significant active, untreated pancreatic or biliary disease Any condition, disease, illness, or circumstance that in the investigator's opinion puts the subject at any undue risk, prevents completion of the study, or interferes with analysis of the study results.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.025 mg/kg/day Teduglutide<br>0.025 milligrams per kilogram per day (mg/kg/day) of teduglutide for 24 weeks. | Drug: Teduglutide 0.025 mg/kg<br>* 0.025 mg/kg<br>|
| Experimental: 0.05 mg/kg/day Teduglutide<br>0.05 mg/kg/day of teduglutide for 24 weeks. | Drug: Teduglutide 0.05mg/kg<br>* 0.05 mg/kg<br>|
| Active Comparator: Standard of care<br>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. | Other: Standard of Care<br>* Observational cohort for the 24-week treatment period and 4 week follow-up.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved at Least a 20 Percent (%) Reduction in Weight-Normalized Average Daily Parenteral Nutrition Intravenous (PN/IV) Volume at Week 24 | Reduction in weight-normalized PN/IV volume was performed using both participant diary and investigator prescribed data. Number of participants who achieved at least a 20% reduction in weight-normalized PN/IV volume between the baseline and week 24/EOT visit were reported. | Baseline through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. TEAEs were defined as AEs that started or worsened on or after the date of first dose for treatment groups and those that started or worsened on or after the baseline visit for standard of care group. | From start of study treatment up to 28 weeks | 
| Number of Participants Who Were Completely Weaned Off Parenteral Nutrition Intravenous (PN/IV) Support at Week 24 | A participant was considered to have achieved independence from PN/IV support (completely weaned off PN/IV) if the investigator prescribed no PN/IV at EOT and there was no use of PN/IV recorded in the participant diary during the week prior to EOT. | Week 24 | 
| Change From Baseline in Parenteral Nutrition Intravenous (PN/IV) Volume at Week 24 | Change in PN/IV volume was reported based on the participant diary and the investigator prescribed data. | Baseline, Week 24 | 
| Change From Baseline in Parenteral Nutrition Intravenous (PN/IV) Caloric Intake at Week 24 | Change in PN/IV caloric intake was reported based on the participant diary and the investigator prescribed data. | Baseline, Week 24 | 
| Change From Baseline in Plasma Citrulline Levels at Week 24 | Plasma citrulline level was reported. | Baseline, Week 24 | 
| Change From Baseline in Enteral Nutrition Volume at Week 24 | Enteral nutrition was defined as specialized formula taken orally or by tube feeding, and excluded table foods and other fluids. Change in enteral nutrition volume was reported. | Baseline, Week 24 | 
| Change From Baseline in Enteral Nutrition Caloric Intake at Week 24 | Enteral nutrition was defined as specialized formula taken orally or by tube feeding, and excluded table foods and other fluids. Change in enteral nutrition caloric intake was reported. | Baseline, Week 24 | 
| Change From Week 24 in Parenteral Nutrition Intravenous (PN/IV) Volume at Week 28 | Change in PN/IV volume was reported. | Week 24, Week 28 | 
| Change From Week 24 in Parenteral Nutrition Intravenous (PN/IV) Caloric Intake at Week 28 | Change in PN/IV caloric intake was reported. | Week 24, Week 28 | 
| Change From Week 24 in Plasma Citrulline Levels at Week 28 | Change in plasma citrulline level was reported. | Week 24, Week 28 | 
| Change From Week 24 in Enteral Nutrition Volume at Week 28 | Enteral nutrition was defined as specialized formula taken orally or by tube feeding, and excluded table foods and other fluids. Change in enteral nutrition volume was reported. | Week 24, Week 28 | 
| Change From Week 24 in Enteral Nutrition Caloric Intake at Week 28 | Enteral nutrition was defined as specialized formula taken orally or by tube feeding, and excluded table foods and other fluids. Change in enteral nutrition caloric intake was reported. | Week 24, Week 28 | 
| Change From Baseline in Body Weight Z-score at Week 28 | Body weight z-score is a measure of relative weight adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. | Baseline, Week 28 | 
| Change From Baseline in Body Height Z-score at Week 28 | Body height z-score is a measure of relative height adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. | Baseline, Week 28 | 
| Change From Baseline in Head Circumference Z-score at Week 28 | Head circumference z-score is a measure of relative head circumference adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. Head circumference was collected only for participants of less than or equal to (<=) 36 months of age at the time of measurement. | Baseline, Week 28 | 
| Change From Baseline in Body Mass Index (BMI) Z-score at Week 28 | BMI z-score is a measure of relative BMI adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. | Baseline, Week 28 | 
| Change From Baseline in Participants' Stool Consistency at Week 28 | Stool consistency was assessed by typical stool form based on Bristol Stool Form Scale: 1 - Separate hard lumps, hard to pass, 2 - Sausage-shaped, but lumpy, 3 - Like a sausage but with cracks on the surface, 4 - Like a sausage or snake, smooth and soft, 5 - Soft blobs with clear-cut edges, 6 - Fluffy pieces with ragged edges, a mushy stool, 7 - Watery, no solid pieces, entirely liquid. | Baseline, Week 28 | 
| Change From Baseline in Hours Per Day of Parenteral Nutrition Intravenous (PN/IV) Support at Week 24 | The mean duration of the PN/IV infusions in hours, on the days when PN/IV was administered was reported. | Baseline, Week 24 | 
| Change From Baseline in Days Per Week of Parenteral Nutrition Intravenous (PN/IV) Support at Week 24 | The number of days per week of PN/IV infusions were reported. | Baseline, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Teduglutide, pediatric, GLP-2, parenteral support, Short Bowel Syndrome, short gut syndrome, short gut, SBS, parenteral nutrition