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Cost-Effectiveness of Laparoscopic Ileocecal Resection Versus Infliximab Treatment of Terminal Ileitis In Crohn's Disease: The LIR!C Trial
AGA Abstracts
4 consecutive days concurrently with 500 mg/kg mitoT or vehicle daily for 7 days. Ileal IEC mitochondrial function was assessed by electron microscopy (EM) and expression of the mitochondrial unfolded protein response (mtUPR). Defects in Paneth cell function were measured by Lysozyme staining, EM, and expression of antimicrobial peptides produced by Paneth cells. Since TEMPO has been shown to affect the microbiota, which in turn modulates intestinal homeostasis, we also administered mitoT in vitro to eliminate effects of the microbiota as a confounder. Organoids cultured from ileal crypts of PHB∆IEC and PHBfl/fl mice were treated with 10 nM mitoT or vehicle for 16 hr and assayed for mtUPR, mitochondrial-derived reactive oxygen species (ROS), and expression of antimicrobial peptides produced by Paneth cells. Results: Ileal IECs from PHB∆IEC mice treated with vehicle exhibited increased mtUPR expression and swollen, damaged mitochondria; mitoT ameliorated mitochondrial morphological damage and mtUPR expression. PHB∆IEC mice treated with vehicle exhibited Paneth cell defects including diffuse Lysozyme staining and decreased expression of the antimicrobials Cryptdin 3, Cryptdin 5, Angiogenin 4, and Lysozyme, all of which after mitoT treatment resembled PHBfl/fl mice. Organoids derived from PHB∆IEC mice treated with mitoT exhibited Paneth cell antimicrobial expression, mitochondrialderived ROS, and mtUPR similar to PHBfl/fl control organoids. Conclusions: mitoT prevents IEC mitochondrial dysfunction and Paneth cell defects independent of microbiota since effects are evident in organoid cultures, indicating that mitochondrial-derived ROS contributes to disease progression during loss of PHB. Our results suggest that mitochondrial-derived antioxidants have therapeutic potential in Paneth cells, the dysfunction of which plays a central role in the pathogenesis of CD.
981 FISTULA HEALING IN PIVOTAL STUDIES OF USTEKINUMAB IN CROHN'S DISEASE Bruce E. Sands, Christopher Gasink, Douglas Jacobstein, Long-Long Gao, Jewel Johanns, Jean Frederic Colombel, Willem J. de Villiers, William J. Sandborn
980 Background: The efficacy and safety of IV induction and SC maintenance with ustekinumab (UST), the fully human monoclonal antibody to human IL12/23p40, in Phase 2 and 3 studies of moderately to severely active Crohn's disease (CD) has been previously reported. Results for fistula healing in the subsets of patients with active perineal fistulas has not been previously reported. Methods: In the UNITI-1, UNITI-2 and CERTIFI studies, almost 40% of patients had a history of fistulizing CD, but only 10.8 to 15.5% of patients across the studies had active perineal fistulas at baseline; these patients had their fistulas assessed by physical exam (including gentle compression) at study visits, and were analyzed for fistula response (≥ 50% reduction in draining fistulas) and complete fistula resolution (100% reduction). Due the small sample size, data from the final induction visit at Week 8 from these patients were combined over the 3 studies and evaluated. In IM-UNITI and CERTIFI maintenance studies, observed data on fistula response are also reported. Results: Among patients with open fistulas at baseline, a numerically higher proportion of patients in the combined ustekinumab groups in the Phase 2b CERTIFI and Phase 3 UNITI-1 and 2 studies attained fistula response vs placebo, as did both low and high dose in the pooled set (from all 3 studies; Table 1). Complete fistula resolution was attained in 14.1% in the pooled placebo group vs 24.2% with 130mg/1mg/kg (p=0.13), 27.7% with 6mg/kg (p=0.052) and 24.7% of all UST (p=0.073) at Week 8. In the CERTIFI maintenance phase, IV UST responder and nonresponder patients with open fistulas at Week 0 were re-randomized to SC ustekinumab (n=24) or SC placebo (n=30) at Week 8. Fistula response occurred in 9/ 19 (47%) and 6/20 (30%) of these patients with data available at Week 22, respectively. Among randomized patients in IM-UNITI with data available at Week 44, a numerically higher proportion of patients also had fistula response in the combined ustekinumab maintenance group (80%; 12/15) compared with the placebo group (45.5%; 5/11; p=0.64). Conclusion: Across the 3 pivotal induction studies, there is a consistent signal for efficacy in fistula healing that approached statistical significance in the combined analysis of fistula resolution, despite a relatively small number of patients. A treatment effect (delta of 10-13) was seen across the 8-week induction period. It is possible that higher proportions of fistula healing would be seen with a longer duration of ustekinumab treatment. To confirm this, a dedicated, appropriately designed, and adequately powered fistula study would be needed. Table 1: Fistula Assessments at Week 8 Among Randomized Patients with Open Perineal Fistulas at Baseline in CERTIFI, UNITI-1, and UNITI-2
COST-EFFECTIVENESS OF LAPAROSCOPIC ILEOCECAL RESECTION VERSUS INFLIXIMAB TREATMENT OF TERMINAL ILEITIS IN CROHN'S DISEASE: THE LIR!C TRIAL Joline de Groof, Willem Bemelman, Emma Eshuis, Tjibbe Gardenbroek, Patrick Bossuyt, Judith Bosmans, Hanneke van Dongen, Bart van Wagensveld, Menno Brink, Esther Consten, Christianne J. Buskens, Geert R. D'Haens, Pieter Stokkers, Cyriel Ponsioen Objective: To compare laparoscopic ileocecal resection with infliximab in patients with thiopurine or steroid refractory recurrent CD of the terminal ileum, with respect to quality of life (QoL) and cost-effectiveness. Aim & methods: A multicenter randomized controlled, open-label trial was performed in 33 centers in The Netherlands and the UK. Adult patients with CD of the terminal ileum who failed >3 months of thiopurine treatment or steroids without signs of a critical stricture were randomly allocated to either laparoscopic ileocecal resection or infliximab. Patients with a prior ileocecal resection, a diseased length >40 cm, abdominal abscesses or fluid collections or an American Society of Anaesthesiologists (ASA) score of III or IV were excluded. The primary outcomes were QoL measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the SF-36, and costs per QALY at one year follow-up. The economic evaluation estimated the marginal direct medical, non-medical and time costs, costs per quality adjusted life year (QALY), and cost-utility ratio, based on the intention-to-analysis, up to one year after initiation of treatment. Dutch Trial Registry NTR1150. Results: Between May 2008 and October 2015, 143 patients were included (33% male) with a median age of 27 years (interquartile range 22 to 40). Eventually, 65 patients started with infliximab treatment and 70 patients were operated. At time of submission, 96.5% of the patients have completed follow-up. At baseline, the mean difference (MD) in IBDQ score was 4.9 points in favor of the resection group. After correction for the baseline difference, the MD at one year follow-up was 5.8 points in favor of resection (95% confidence interval (CI) -4.7 to 16.3, p=0.28). A significant difference in favor of the resection group in QoL was observed with the SF-36 general health questionnaire, on the physical scale (MD 3.2, p=0.035) and on the mental subscale (MD 4.1, p=0.036). The mean total costs associated with the index treatment per patient at one year were €19,655 in the infliximab group and €10,724 in the resection group (MD €-8,931; 95% CI € -12,087 to € -5,097). One QALY gained in the laparoscopic ileocecal resection group was associated with a societal cost reduction of €77,221. In the probabilistic sensitivity analysis, 95% of CE-pairs were located in the south-east quadrant, confirming that laparoscopic ileocecal resection was on average less costly and more effective than infliximab (Figure 1 and 2). Conclusion: Although QoL at one year was not significantly better in terms of disease-specific quality of life, laparoscopic ileocecal improved general quality of life and was associated with a reduction in costs, compared to infliximab induction and maintenance therapy.
a
6 mg/kg group includes 6 mg/kg group in C0743T26 and weight-range based ustekinumab doses approximating 6 mg/kg group: 260 mg (weight ≤ 55kg), 390 mg (weight > 55 kg and ≤ 85 kg), 520 mg (weight > 85 kg) in CNTO1275CRD3001 and CNTO1275CRD3002. b Combined treatment group includes 1mg/kg group, 3 mg/kg group, 6 mg/kg group, and 130 mg group.
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AGA Abstracts
4 consecutive days concurrently with 500 mg/kg mitoT or vehicle daily for 7 days. Ileal IEC mitochondrial function was assessed by electron microscopy (EM) and expression of the mitochondrial unfolded protein response (mtUPR). Defects in Paneth cell function were measured by Lysozyme staining, EM, and expression of antimicrobial peptides produced by Paneth cells. Since TEMPO has been shown to affect the microbiota, which in turn modulates intestinal homeostasis, we also administered mitoT in vitro to eliminate effects of the microbiota as a confounder. Organoids cultured from ileal crypts of PHB∆IEC and PHBfl/fl mice were treated with 10 nM mitoT or vehicle for 16 hr and assayed for mtUPR, mitochondrial-derived reactive oxygen species (ROS), and expression of antimicrobial peptides produced by Paneth cells. Results: Ileal IECs from PHB∆IEC mice treated with vehicle exhibited increased mtUPR expression and swollen, damaged mitochondria; mitoT ameliorated mitochondrial morphological damage and mtUPR expression. PHB∆IEC mice treated with vehicle exhibited Paneth cell defects including diffuse Lysozyme staining and decreased expression of the antimicrobials Cryptdin 3, Cryptdin 5, Angiogenin 4, and Lysozyme, all of which after mitoT treatment resembled PHBfl/fl mice. Organoids derived from PHB∆IEC mice treated with mitoT exhibited Paneth cell antimicrobial expression, mitochondrialderived ROS, and mtUPR similar to PHBfl/fl control organoids. Conclusions: mitoT prevents IEC mitochondrial dysfunction and Paneth cell defects independent of microbiota since effects are evident in organoid cultures, indicating that mitochondrial-derived ROS contributes to disease progression during loss of PHB. Our results suggest that mitochondrial-derived antioxidants have therapeutic potential in Paneth cells, the dysfunction of which plays a central role in the pathogenesis of CD.
981 FISTULA HEALING IN PIVOTAL STUDIES OF USTEKINUMAB IN CROHN'S DISEASE Bruce E. Sands, Christopher Gasink, Douglas Jacobstein, Long-Long Gao, Jewel Johanns, Jean Frederic Colombel, Willem J. de Villiers, William J. Sandborn
980 Background: The efficacy and safety of IV induction and SC maintenance with ustekinumab (UST), the fully human monoclonal antibody to human IL12/23p40, in Phase 2 and 3 studies of moderately to severely active Crohn's disease (CD) has been previously reported. Results for fistula healing in the subsets of patients with active perineal fistulas has not been previously reported. Methods: In the UNITI-1, UNITI-2 and CERTIFI studies, almost 40% of patients had a history of fistulizing CD, but only 10.8 to 15.5% of patients across the studies had active perineal fistulas at baseline; these patients had their fistulas assessed by physical exam (including gentle compression) at study visits, and were analyzed for fistula response (≥ 50% reduction in draining fistulas) and complete fistula resolution (100% reduction). Due the small sample size, data from the final induction visit at Week 8 from these patients were combined over the 3 studies and evaluated. In IM-UNITI and CERTIFI maintenance studies, observed data on fistula response are also reported. Results: Among patients with open fistulas at baseline, a numerically higher proportion of patients in the combined ustekinumab groups in the Phase 2b CERTIFI and Phase 3 UNITI-1 and 2 studies attained fistula response vs placebo, as did both low and high dose in the pooled set (from all 3 studies; Table 1). Complete fistula resolution was attained in 14.1% in the pooled placebo group vs 24.2% with 130mg/1mg/kg (p=0.13), 27.7% with 6mg/kg (p=0.052) and 24.7% of all UST (p=0.073) at Week 8. In the CERTIFI maintenance phase, IV UST responder and nonresponder patients with open fistulas at Week 0 were re-randomized to SC ustekinumab (n=24) or SC placebo (n=30) at Week 8. Fistula response occurred in 9/ 19 (47%) and 6/20 (30%) of these patients with data available at Week 22, respectively. Among randomized patients in IM-UNITI with data available at Week 44, a numerically higher proportion of patients also had fistula response in the combined ustekinumab maintenance group (80%; 12/15) compared with the placebo group (45.5%; 5/11; p=0.64). Conclusion: Across the 3 pivotal induction studies, there is a consistent signal for efficacy in fistula healing that approached statistical significance in the combined analysis of fistula resolution, despite a relatively small number of patients. A treatment effect (delta of 10-13) was seen across the 8-week induction period. It is possible that higher proportions of fistula healing would be seen with a longer duration of ustekinumab treatment. To confirm this, a dedicated, appropriately designed, and adequately powered fistula study would be needed. Table 1: Fistula Assessments at Week 8 Among Randomized Patients with Open Perineal Fistulas at Baseline in CERTIFI, UNITI-1, and UNITI-2
COST-EFFECTIVENESS OF LAPAROSCOPIC ILEOCECAL RESECTION VERSUS INFLIXIMAB TREATMENT OF TERMINAL ILEITIS IN CROHN'S DISEASE: THE LIR!C TRIAL Joline de Groof, Willem Bemelman, Emma Eshuis, Tjibbe Gardenbroek, Patrick Bossuyt, Judith Bosmans, Hanneke van Dongen, Bart van Wagensveld, Menno Brink, Esther Consten, Christianne J. Buskens, Geert R. D'Haens, Pieter Stokkers, Cyriel Ponsioen Objective: To compare laparoscopic ileocecal resection with infliximab in patients with thiopurine or steroid refractory recurrent CD of the terminal ileum, with respect to quality of life (QoL) and cost-effectiveness. Aim & methods: A multicenter randomized controlled, open-label trial was performed in 33 centers in The Netherlands and the UK. Adult patients with CD of the terminal ileum who failed >3 months of thiopurine treatment or steroids without signs of a critical stricture were randomly allocated to either laparoscopic ileocecal resection or infliximab. Patients with a prior ileocecal resection, a diseased length >40 cm, abdominal abscesses or fluid collections or an American Society of Anaesthesiologists (ASA) score of III or IV were excluded. The primary outcomes were QoL measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the SF-36, and costs per QALY at one year follow-up. The economic evaluation estimated the marginal direct medical, non-medical and time costs, costs per quality adjusted life year (QALY), and cost-utility ratio, based on the intention-to-analysis, up to one year after initiation of treatment. Dutch Trial Registry NTR1150. Results: Between May 2008 and October 2015, 143 patients were included (33% male) with a median age of 27 years (interquartile range 22 to 40). Eventually, 65 patients started with infliximab treatment and 70 patients were operated. At time of submission, 96.5% of the patients have completed follow-up. At baseline, the mean difference (MD) in IBDQ score was 4.9 points in favor of the resection group. After correction for the baseline difference, the MD at one year follow-up was 5.8 points in favor of resection (95% confidence interval (CI) -4.7 to 16.3, p=0.28). A significant difference in favor of the resection group in QoL was observed with the SF-36 general health questionnaire, on the physical scale (MD 3.2, p=0.035) and on the mental subscale (MD 4.1, p=0.036). The mean total costs associated with the index treatment per patient at one year were €19,655 in the infliximab group and €10,724 in the resection group (MD €-8,931; 95% CI € -12,087 to € -5,097). One QALY gained in the laparoscopic ileocecal resection group was associated with a societal cost reduction of €77,221. In the probabilistic sensitivity analysis, 95% of CE-pairs were located in the south-east quadrant, confirming that laparoscopic ileocecal resection was on average less costly and more effective than infliximab (Figure 1 and 2). Conclusion: Although QoL at one year was not significantly better in terms of disease-specific quality of life, laparoscopic ileocecal improved general quality of life and was associated with a reduction in costs, compared to infliximab induction and maintenance therapy.
a
6 mg/kg group includes 6 mg/kg group in C0743T26 and weight-range based ustekinumab doses approximating 6 mg/kg group: 260 mg (weight ≤ 55kg), 390 mg (weight > 55 kg and ≤ 85 kg), 520 mg (weight > 85 kg) in CNTO1275CRD3001 and CNTO1275CRD3002. b Combined treatment group includes 1mg/kg group, 3 mg/kg group, 6 mg/kg group, and 130 mg group.
S-185
AGA Abstracts