Efficacy and Safety of Teduglutide in Parenteral Nutrition (PN)-Dependent SBS Subjects: Update of a Current Multinational Trial

Abstract

Purpose: Massive small intestinal resection creates malnutrition, diarrhea, and dehydration as a consequence of reduced intestinal capacity to absorb nutrients, and this can lead to dependence on parenteral nutrition (PN) therapy. Unfortunately use of PN is also associated with serious complications, however, it is vital for many short bowel syndrome (SBS) patients. Teduglutide, an analog of glucagon-like peptide-2 (GLP-2), is being evaluated for safety, tolerability, and efficacy in reducing PN dependency in SBS patients. We present the design and baseline characteristics of this multinational trial. Methods: Eligibility criteria included: 18 years and older; SBS resulting from major intestinal resection; PN dependency for at least 12 months; PN required at least 3 times weekly; and preserved renal and hepatic function. Subjects then entered into an intensive stabilization period to optimize PN volume before being randomized to placebo or 0.05 or 0.1 mg/kg/day of teduglutide for a 24-week treatment, with follow-up 4 weeks post-treatment. Reduction in PN usage at 24 weeks of therapy was the primary endpoint, calculated as an ordered categorical response. Additional assessments included plasma citrulline, 72-hour balance studies, villous height, crypt depth, bone density, and quality of life. Results: A total of 139 subjects were screened and 84 randomized (37 male), with 13 withdrawing. Up to 71 patients are expected to complete the study. Forty percent of subjects were recruited from the US and Canada, 60% from the EU. Subjects developed SBS due to surgical resections for: CD (37%); vascular accidents (30%); trauma (11%); and volvulus (13%). Sixty seven percent of subjects had a colon in continuity and 35% had a stoma. The average remaining length of small bowel was 66 cm and 69 cm of colon. Of the 20% of subjects with a distal/terminal ileum, 53% had an ileocecal valve. The DSMB reviewed safety throughout the study and found no specific concerns. Conclusion: The target of randomizing at least 80 PN-dependent SBS patients in the teduglutide study was achieved, making this the largest clinical trial to evaluate a treatment to decrease PN requirements in SBS patients. The ability to reduce PN by enhancing enteral function, the therapeutic goal of teduglutide, has the potential to lead to improved quality of life in the SBS population.