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Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study.

ABSTRACT: BACKGROUND:This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF). METHODS:A 24-week, phase III trial with 2 randomized, double-blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment-emergent adverse events (TEAEs) and growth parameters. The primary efficacy/pharmacodynamic end point was the number of patients who achieved a ?20% reduction in parenteral support (PS) from baseline at week 24. RESULTS:All 59 enrolled patients completed the study (0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9). Baseline demographics and disease characteristics were comparable among groups. TEAEs were reported by 98% and 100% of patients in the teduglutide and SOC groups, respectively. The most common TEAEs in the teduglutide-treated groups were pyrexia and vomiting. The primary end point was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg teduglutide, and SOC, respectively (P < 0.05 vs SOC). Both 0.025-mg/kg and 0.05-mg/kg teduglutide groups showed clinically significant reductions in PS volume (P < 0.05 vs SOC), PS calories, days per week and hours per day of PS infusions, and increases in enteral nutrition and plasma citrulline at week 24 compared with baseline. Two (8.3%, 0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg teduglutide) achieved enteral autonomy. CONCLUSION:The safety profile of teduglutide was similar to that reported previously in children and adults. Treatment with teduglutide was associated with significant reductions in PS for pediatric patients with SBS-IF over 24 weeks.

SUBMITTER: Kocoshis SA

PROVIDER: S-EPMC7318247 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study.

Kocoshis Samuel A SA Merritt Russell J RJ Hill Susan S Protheroe Susan S Carter Beth A BA Horslen Simon S Hu Simin S Kaufman Stuart S SS Mercer David F DF Pakarinen Mikko P MP Venick Robert S RS Wales Paul W PW Grimm Andrew A AA

JPEN. Journal of parenteral and enteral nutrition 20190908 4

<h4>Background</h4>This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF).<h4>Methods</h4>A 24-week, phase III trial with 2 randomized, double-blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment-emergent adverse events (TEAEs) and growth parameters. The primary efficacy/ ...[more]

PMID: 31495952

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Project description:Background:In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome-associated intestinal failure (SBS-IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. Methods:Safety data from four prospective clinical trials of teduglutide in patients with SBS-IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. Results:Safety data are reported for up to 2.5?years, totalling 222?person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were reported more frequently earlier in the course of treatment, with their frequency declining over time. Fewer gastrointestinal AEs were reported in patients with vascular causes of SBS-IF and patients with most of their colon-in-continuity than in other patient subgroups. Across the patient stratification subgroups, the predominant treatment-emergent AEs for which patients receiving teduglutide had a significantly increased relative risk were abdominal distension and gastrointestinal stoma complication compared with patients receiving placebo. Conclusions:Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. The most frequently reported AEs were gastrointestinal in origin, consistent with the underlying disease condition and intestinotrophic actions of teduglutide. Clinical Trial Registry information:NCT00081458/EudraCT, 2004-000438-35; NCT00798967/EudraCT, 2008-006193-15; NCT00172185/EudraCT, 2004-000439-27; NCT00930644/EudraCT, 2009-011679-65.

Project description:Background and objectivesShort-bowel syndrome (SBS) results from the loss of a significant portion of the small intestine leading to a state of malabsorption. After an intestinal loss, there is a process of adaptation involving the Glucagon-Like Peptide-2 (GLP-2), an enteroendocrine peptide also involved in nutrient absorption. Teduglutide is a recombinant analog of GLP-2 approved in 2016 to treat selected SBS pediatric patients who are dependent on parenteral support. The present systematic review aims to evaluate the efficacy of Teduglutide in pediatric patients with SBS in reducing the need for parenteral nutrition (PN).Materials and methodsWe performed a literature search on MEDLINE and Embase to include articles up to November 2021. We included articles that involved using Teduglutide in the SBS pediatric population to define its efficacy in reducing the need for PN. The key words used were GLP-2, teduglutide, child.ResultsFourteen studies completely fulfilled the inclusion criteria. Two hundred 23 patients were treated with Teduglutide, and the median duration of treatment was 45 weeks (IQR: 36-52.5 weeks). One-hundred and fifty-two patients were treated with 0.05 mg/Kg/d of subcutaneous Teduglutide, 38 received 0.025 mg/Kg/d and 8 received either 0.125 mg/Kg/d or 0.20 mg/Kg/d. A total of 36 patients achieved enteral autonomy (EA) after a median of 24 weeks of treatment (IQR: 24-48 weeks) and 149 patients showed a reduction in PN needs in terms of volume, calories, or hours per day. Eleven studies reported complications: gastrointestinal were the most common, with 89 cases reported in treated patients and 11 in non-treated patients.ConclusionTeduglutide appears safe and effective in reducing PN requirements and improving EA in the pediatric population. However, more studies are needed to understand its efficacy in the long term and after discontinuation and possible complications.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022301593].

Project description:Background and aimsGlucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity.MethodsTeduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with <50% colon in continuity (dose 0.03 mg/kg/day), and five with > or = 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre-study fasting native GLP-2 levels were determined for the five patients with > or = 50% colon in continuity.ResultsPooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (-711 (734) g/day; p = 0.001) and faecal energy excretion (-808 (1453) kJ/day (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice.ConclusionTeduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.

Dataset Information

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study.

Publications

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study.

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