Clinical and observational trials in inflammatory bowel diseases – Room A3____________________
LB01 DEMOGRAPHICS AND PROGNOSIS OF INCIDENT PATIENTS WITH MICROSCOPIC COLITIS–FIRST RESULTS OF THE EUROPEAN PRO-MC COLLABORATION, A LINK-AWARD PROJECT
B. Verhaegh1, A. Münch2, W. Cebula3, S. Wildt4, A.D. Diac3, S. Meisner5, N. Pedersen5, F. Fernández-Bañares6, D. Guanozzi7, A.J. J. Lucendo Villarin8, J. Bohr9, G. Macaigne10, G.E. Tontini11, J. Kupcinskas12, M.A. Al-Khalaf13, P. Penchev14, S. Miehlke15, H. Hjortswang16, M.J. Pierik17, L.K. Munck18
1Maastricht University Medical Center, Maastricht/Netherlands
Introduction: Microscopic colitis (MC) is a major cause of chronic watery diarrhoea. The international incidence rates are variable. Currently, the exact disease course and predictive markers for disease activity remain unknown. Small retrospective studies point towards an intermittent or chronic course with low rates of spontaneous remission, but prospective studies are lacking. Therefore, the PRO-MC Collaboration, a European prospective registry for MC1, was initiated.
Aims & Methods: Only incident cases of MC were eligible for inclusion. Patient characteristics and baseline data on pathology, disease activity, medical history, performed diagnostics and treatment strategies were registered. Patients will be followed prospectively at 3, 6, 12 months and then yearly.
Results: By august 2017, 193 individuals were included, mean age 65 (±14 (SD)) years, 69% females and 28% current smokers. In total, 87 had collagenous colitis (CC), 79 lymphocytic colitis (LC) and 27 incomplete MC (MCi). The mean time between endoscopy and baseline visit was 57 ± 82 days. Diarrhoea persisted for >6 months before diagnosis in 43%. Macroscopic abnormalities were present during index colonoscopy in 23%. At baseline visit, urgency was reported by 80%, nightly defecation by 46%, faecal incontinence and abdominal pain by 48%, and moderate to severe functional impairment by 52% of patients. Four out of 10 had bile acid diarrhoea by SeHCAT. At the baseline visit, 75% had active disease according to the Hjortswang criteria 2. Treatment to induce clinical remission was initiated in 54% of patients, of which 94% were treated with budesonide. In 26% of patients no medical treatment was initiated. Patients scored 4–5 out of 10 on the Short Health Scale (SHS) items (symptom severity, interference with daily activity, worry about MC and general wellbeing). Three months later, 53% of 103 patients had disease activity, 33% urgency, 6% faecal incontinence, 8% nightly defecation, and 19% reported moderate to severe functional impairment. SHS scores improved to 2.5–3. After three months, 52% of patients were without treatment, 11% on induction therapy (in 83% with budesonide), 13% on maintenance therapy (29% budesonide, others with fibers, loperamide and/or colestyramine), 14% were tapering the dose (mainly budesonide, 93%) and 10% had treatment on demand. Oral budesonide was stopped due to absence or loss of response in 9% of treated patients.
Conclusion: The PRO-MC Collaboration is accumulating incident cases of MC. Initial symptoms resemble those of previous single site cohort and confirm that disease activity causes major functional impairment. Follow-up data of this cohort will provide data on long-term prognosis and may help to identify predictive factors for disease activity and response to treatment in real life.
Disclosure of Interest: All authors have declared no conflicts of interest.
LB02 ETROLIZUMAB INDUCTION THERAPY IMPROVED ENDOSCOPIC SCORE, PATIENT-REPORTED OUTCOMES, AND INFLAMMATORY BIOMARKERS IN PATIENTS WITH MODERATE TO SEVERE UC WHO HAD FAILED TNF ANTAGONIST THERAPY: RESULTS FROM THE HICKORY OPEN-LABEL INDUCTION (OLI) TRIAL
L. Peyrin-Biroulet1, D. T. Rubin2, B. G. Feagan3, Y.S. Oh4, U. Arulmani4, H. Tyrrell5, R. Maciuca4, S. Williams5, S. Tole4, J. Thommes4
1Université de Lorraine, Vandoeuvre-lès-Nancy/France
2Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago/United States of America/IL
3University of Western Ontario, London/Canada/ON
4Genentech, Inc., South San Francisco/United States of America/CA
Introduction: Patients with moderate-severe ulcerative colitis (UC) who are intolerant or refractory (IR) to TNF antagonists (aTNFs) are a difficult-to-treat population with an important unmet medical need. Accurate endoscopic assessments of drug efficacy for UC now rely on independent reading of endoscopic videos by expert readers blinded to patient information. Centrally read endoscopy has reduced placebo endoscopic remission rates in this population to as low as 0%–8%.1,2 HICKORY OLI evaluates the safety and efficacy of etrolizumab in patients IR to aTNFs.
Aims & Methods: This study evaluates response to etrolizumab OLI via centrally read endoscopy, patient-reported outcomes, and inflammatory biomarkers in patients who are IR to aTNFs. All patients received etrolizumab 105 mg subcutaneously every 4 weeks in a 14-week induction period. Mayo subscores based on endoscopic score (ES), and patient-reported rectal bleeding (RB) and stool frequency (SF) were assessed at baseline (BL) and week 14. Clinical response: ≥3-point and 30% reduction of Mayo Clinic score (MCS) from BL and ≥1-point decrease in RB or RB ≤ 1. Remission: MCS ≤ 2 with individual subscores ≤ 1 and RB = 0. Endoscopic improvement: ES ≤ 1. RB remission: RB = 0; SF remission: SF ≤ 1 with ≥1-point reduction from BL. The percentage declines from BL in RB and SF at week 14 were also calculated.
Results: HICKORY OLI enrolled 130 aTNF-experienced patients with UC; 45% had previously failed >1 aTNF. BL disease activity included a mean MCS of 9.4, median C-reactive protein (CRP) of 6.6 g/dL, and median faecal calprotectin (FC) of 1778 mg/kg. At week 14, etrolizumab treatment was associated with clinical response in 50.8% of patients, remission in 12.3%, ES ≤ 1 in 23.9%, RB remission in 52.3%, and SF remission in 35.4%. 43.9% of patients had ≥1-point improvement from BL in the ES, and improved ES were associated with increased rates of RB and SF remission. Among patients with ES = 0, 100% reported RB ≤ 1, and 90% reported SF ≤ 1 (Table 1). Patients who achieved SF remission, RB remission, or ES ≤ 1 also demonstrated >50% geometric mean reduction in CRP (BL ≥ 2.87 mg/L) and >70% geometric mean reduction in FC.
Lower ES at week 14 was associated with higher SF and RB remission rates (N = 130)
Improvement in ES From BL (n = 57)
No Improvement From BL (n = 73)
Week 14
ES = 0 (n = 10)
ES = 1 (n = 21)
ES = 2 (n = 26)
ES = 2 (n = 15)
ES = 3 (n = 58)
RB = 0
90%
81%
62%
33%
36%
RB = 1
10%
19%
27%
40%
41%
RB ≥ 2
0
0
12%
27%
22%
SF = 0
30%
33%
8%
7%
2%
SF = 1
60%
33%
23%
27%
22%
SF ≥ 2
10%
33%
69%
67%
76%
Conclusion: aTNF-experienced patients with moderate-severe UC and high disease burden treated with open-label etrolizumab for 14 weeks achieved clinically meaningful clinical response, remission, and endoscopic improvement. Patients who had a decline in ES ≥ 1 achieved higher rates of RB and SF remission and greater reductions in inflammatory biomarkers. Recruitment to HICKORY continues in a randomised, placebo-controlled induction cohort, and a randomised maintenance phase is also ongoing.
Disclosure of Interest: L. Peyrin-Biroulet: Honoraria from MSD, AbbVie, Jansen, Takeda, Pfizer, Genentech, Celltrion, and Ferring.
D.T. Rubin: Research grants from Abbvie, Genentech/Roche, and Janssen Pharmaceuticals. Consultant/Advisor for Abbvie, Boehringer Ingelheim, Genentech/Roche, Janssen Pharmaceuticals, Pfizer, and Samsung Bioepis.
Introduction: Etrolizumab, a humanised anti-β7 monoclonal antibody currently undergoing Phase 3 evaluation in ulcerative colitis (UC) and Crohn’s disease (CD), was well tolerated and efficacious in patients with moderate to severe UC in the Phase 2 trial EUCALYPTUS. BERGAMOT (NCT02394028), a Phase 3 study, was designed with 3 sequential induction cohorts and a single maintenance cohort to evaluate the safety and efficacy of etrolizumab in patients with moderate to severe CD. This abstract describes results for the exploratory induction cohort of 300 patients.
Aims & Methods: In this multicentre, randomised, double-blind study, eligible patients with moderate to severe CD (confirmed at baseline with centrally read ileocolonoscopy) who were refractory or intolerant to anti–tumor necrosis factor α agents (aTNFs), immunosuppressants, and/or corticosteroids were assigned in a 2:2:1 ratio to receive etrolizumab 105 mg subcutaneously every 4 weeks, etrolizumab 210 mg at weeks 0, 2, 4, 8, and 12, or placebo during a 14-week induction period. End point assessments included CDAI remission (CDAI < 150), CDAI-100 response, CDAI-70 response, PRO2 remission (weighted combined score ≤11, based on patient report of liquid/very soft stool frequency [SF] and abdominal pain [AP]), symptomatic remission (unweighted SF ≤ 3 and AP ≤ 1), and endoscopic improvement (≥50% reduction from baseline SES-CD using central reading) at week 14.
Results: 300 patients (73% aTNF-experienced) with moderate to severe CD (mean CDAI [SD], 315.6 [60.0]; mean SES-CD [SD], 14.1 [7.3]; median faecal calprotectin [range], 918 [30–15451] µg/g; median C-reactive protein [range], 9.75 [0.2–148.0] mg/L) received etrolizumab 105 mg (n = 120), etrolizumab 210 mg (n = 121), or placebo (n = 59). Symptomatic remission (SF ≤ 3 and AP ≤ 1) was observed in a greater proportion of patients treated with etrolizumab 105 mg and 210 mg compared with placebo at weeks 6, 10, and 14 (Table 1). A greater proportion of patients achieved endoscopic improvement with etrolizumab 105 mg and 210 mg compared with placebo at week 14 (Table 1). CDAI remission was achieved at week 14 in 23.3% (17.6, 30.2) of patients receiving etrolizumab 105 mg, 28.9% (22.7, 36.1) of those receiving 210 mg, and 16.9% (10.4, 26.4) of those receiving placebo; PRO2 remission was achieved at week 14 in 28.3% (22.1, 35.5), 28.9% (22.7, 36.1), and 20.3% (13.1, 30.2) of patients, respectively. Etrolizumab was well tolerated. The frequency of adverse events was comparable with placebo, and no deaths, anaphylaxis, or progressive multifocal leucoencephalopathy occurred.
Proportion of patients achieving symptomatic remission or endoscopic improvement, % (90% CI)
Placebo (n = 59)
Etrolizumab 105 mg (n = 120)
Etrolizumab 210 mg (n = 121)
Symptomatic remission (SF ≤ 3 and AP ≤ 1)
Week 6
8.5% (4.2, 16.4)
15.0% (10.4, 21.1)
25.6% (19.7, 32.6)
Week 10
8.5% (4.2, 16.4)
15.8% (11.1, 22.1)
27.3% (21.2, 34.4)
Week 14
11.9% (6.6, 20.5)
20.8% (15.4, 27.5)
24.8% (18.9, 31.8)
Endoscopic improvement (≥50% reduction from baseline SES-CD)
Conclusion: In this exploratory induction cohort, treatment with etrolizumab was well tolerated and resulted in clinically meaningful endoscopic improvement, with rapid symptomatic remission as early as week 6 that was sustained through week 14. These early results are indicative of the efficacy of etrolizumab in treating CD. Enrolment into subsequent induction cohorts and into the maintenance phase of BERGAMOT is ongoing.
Disclosure of Interest: W.J. Sandborn: Dr. Sandborn reports grants/personal fees from Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic, Janssen, Bristol-Myers Squibb, Genentech, Nutrition Science Partners, personal fees from Kyowa Hakko Kirin, Millennium, Celgene Cellular Therapeutics, Santarus, Salix, Catabasis, Vertex, Warner Chilcott, Gilead Sciences, Cosmo, Ferring, Sigmoid Biotechnologies, Tillotts, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood, Index, Nestle, Lexicon, UCB, Orexigen, Luitpold, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune, Celgene, Arena, Ambrx Inc., Akros, Vascular Biogenics, Theradiag, Forward, Regeneron, Galapagos, Seres Health, Ritter, Theravance, Palatin, Biogen, Western University (owner of Robarts Clinical Trials)
J. Panes: Research grants from Ministerio de Economia y Competitividad, Spain, Helmsley Charitable Trust, Abbvie, MSD. Speaker for Abbvie, Biogen, Ferring, MSD, Takeda. Consultant/advisor for Abbvie, Boehringer Ingelheim, Celgene, Genentech, Janssen, MSD, Novartis, Oppilan, Pfizer, Robarts Research, Roche, Shire, Takeda, TiGenix, Topivert.
J. Jones: PI at QE II Health Sciences Center, Dalhousie University
A. Hassanali: Employee of Genentech, Inc.; equity interest in Roche.
R. Jacob: Employee of Roche; equity interest in Roche.
Z. Sharafali: Employee of Genentech, Inc.; equity interest in Roche.
Y.S. Oh: Employee of Genentech, Inc.; equity interest in Roche.
S. Tole: Employee of Genentech, Inc.; equity interest in Roche.
LB04 Phase III Randomized Controlled Trial to Compare Biosimilar Infliximab (CT-P13) with Innovator Infliximab in Patients with Active Crohn’s Disease: 1-year maintenance and switching results
Y. Kim1, B.D. Ye2, M. Pesegova3, O. Alexeeva4, M. Osipenko5, A. Lahat6, A. Dorofeyev7, A. Salamon8, S. Fishman9, O. Levchenko10, J.H. Cheon11, M.L. Scribano12, R. Mateescu13, K.M. Lee14, C.S. Eun15, S.J. Lee16, S.Y. Lee16, A. Kudrin16
11Severance Hospital at Yonsei University Health System, Seoul/Korea, Republic of
12Azienda Ospedaliera San Camillo Forlanini, Rome/Italy
13ColentinaClinical Hospital AND "Carol Davila" University of Medicine and Pharmacy, Bucharest/Romania
14St Vincent's Hospital, Suwon/Korea, Republic of
15Hanyang University Guri Hospital, Guri/Korea, Republic of
16CELLTRION, Incheon/Korea, Republic of
Contact E-mail Address: Alex.Kudrin@celltrion.com
Introduction: Efficacy, pharmacokinetics, and safety between CT-P13 and reference infliximab (INX) were similar in the phase 3 randomized controlled trial (CT-P13 3.4; NCT02096861) up to 30 weeks in moderate to severe CD patients1.
Aims & Methods: This report is to investigate efficacy and safety of CT-P13 throughout 1-year treatment period and following switching from INX at Week 30. Patients were randomly assigned to 4 groups; maintenance group (56 for CT-P13, 54 for INX) and switching group (55 for CT-P13 to INX and 55 for INX to CT-P13), and received study drug as maintenance or switch in a double-blinded manner. Crohn’s Disease Activity Index (CDAI)-70 response, clinical remission (CDAI score<150), Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and safety including immunogenicity were evaluated.
Results: Of 220 patients randomized, 180 patients completed Week 30 visit and 166 patients completed the study. CDAI-70 response and clinical remission rates were similar between CT-P13 and INX up to Week 30. At Week 54, clinical remission as well as CDAI-70 response rates were maintained and similar in 4 treatment groups even after switching of study drug. Furthermore, SIBDQ score increased and was similar among 4 treatment groups up to Week 54 even following switching of study drug (Table 1). One-year safety including adverse drug reactions, serious adverse events and infections was similar among all treatment groups and all safety profiles were also similar after Week 30 in maintenance and switching groups (Table 1). At Week 30, only 1 infusion-related reaction (IRR) was reported to CT-P13 to INX group after switching of study drug and this patient was anti-drug antibody (ADA) positive at Week 30. No further IRR was reported for switching groups after Week 30. There were no clinically meaningful differences in immunogenicity results throughout the study period among treatment groups up to Week 54.
Conclusion: Efficacy, safety and immunogenicity were satisfactorily shown during 1-year treatment of CT-P13. The switch group from INX to CT-P13 was comparable to CT-P13 or INX maintenance groups in terms of efficacy and safety profiles.
Disclosure of Interest: Y. Kim: CELLTRION consultant
B.D. Ye: Consultunt: Ferring Korea, Abbvie Korea, Janssen Korea, CELLTRION, Inc., Takeda Korea, Shire Korea, Kuhnil Pharm, Kangstem Biotech, Robarts Clinical Trials Inc., Quintiles. Support for travel to meetings: Ferring Korea, CELLTRION, Inc., Fees for participation in review activities: CELLTRION, Inc.,
J.H. Cheon: CELLTIRON consultant
M.L. Scribano: consulting fee from Abbvie, Jannsen, Pfizer, Takeda
R. Mateescu: Consulting from Abbvie, Egis Pharmaceuticals, Takeda, Alfa Wassermann, Alvogen
K.M. Lee: Lecture fee from Shire, Janssen, Abbvie Consulting from Shire, CELLTRION, Inc.
C.S. Eun: CELLTRION consultant
S.J. Lee: Employee of CELLTRION
S.Y. Lee: Employee of CELLTRION
A. Kudrin: CELLTRION consultant
All other authors have declared no conflicts of interest.
Reference
1. Kim YH et al., Journal of Crohn’s and Colitis 11.Suppl_1(2017):S62
LB05 V565, A Novel Oral Domain Antibody to TNF, Reduces Colonic Mucosal Inflammation after 7 Days Oral Dosing to Patients with Ulcerative Colitis
S. Nurbhai1, G. Parkes2, M. West1, K. Ray1, A. Vossenkaemper3, P. Round1, T. Macdonald3, S. Crowe1
1VHsquared Ltd, Cambridge/United Kingdom
2Barts Health NHS Trust, London/United Kingdom
3Blizard Institute, Queen Mary University of London, London/United Kingdom
Introduction: Monoclonal antibodies to TNF have transformed the treatment options for patients with Inflammatory Bowel Disease (IBD). V565 is a novel oral domain antibody (Vorabody) to TNF engineered to be resistant to intestinal proteases and formulated to be delivered effectively to inflammation in the ileum and colon. It is being developed as a potential oral treatment for IBD. It has previously been shown to suppress phosphorylation of multiple receptor tyrosine kinases and cytoplasmic signalling proteins, and inhibit the release of inflammatory cytokines following culture with biopsies taken from patients with active CD (Crowe et al. 18th International Congress of Mucosal Immunology, July 19-22 2017, Washington DC, USA). In an earlier clinical study V565 was safe and well tolerated after high single and multiple doses given to healthy volunteers and patient volunteers with Crohn’s disease. In addition, after a single oral dose, high concentrations of active compound were detected in the ileal fluid and faeces of human volunteers, and it was also detected in the urine of a patient with Crohn’s disease indicating passage through the lamina propria.
Aims & Methods: The present study was designed to translate the preclinical anti-inflammatory findings to the clinical situation and demonstrate that V565 exerts a beneficial effect on inflammatory processes following oral dosing for seven days to patients with Ulcerative Colitis (UC). In this open label study patients with a Mayo score of 3–10, including an endoscopy score of at least 1 had a pre-treatment sigmoidoscopy with biopsies, followed by 7 days of oral dosing with 555 mg tid V565. After completion of dosing a further sigmoidoscopy with biopsies was performed. The biopsies were analysed for presence of V565 in the mucosa using immunohistochemistry and reduction in phosphorylation of a panel of receptor tyrosine kinases and signalling molecules using PathScan RTK signalling arrays.
Results: Four subjects have completed the study. V565 was demonstrated in the lamina propria and co-localisation with CD14 indicated binding to mTNF on macrophages. The reduction in overall protein phosphorylation following treatment was approximately 50% in each patient. This indicates a reduction in activation of kinase signalling, and is similar to the reduction seen in Crohn’s disease and UC ex vivo biopsy cultures with infliximab at a concentration of 10 µg/ml (67 nM) in an earlier study.
Conclusion: V565, an oral domain antibody to TNF engineered to be resistant to intestinal proteases, was demonstrated co-located with CD14 macrophages in the intestinal lamina propria and resulted in inhibition of mucosal inflammatory processes after seven days oral dosing to patients with ulcerative colitis. The reduction in overall phosphorylation after oral dosing in this study was comparable to that seen in an earlier experiment with a biopsy culture with infliximab at a concentration of 10 µg/ml, a serum concentration associated with mucosal healing (Ungar et al., 2016). This is the first demonstration of biological effect in patients following oral dosing of a domain antibody to TNF engineered to be resistant to intestinal proteases and with minimal systemic exposure. The data provide encouragement that V565 has the potential to be a safe and effective treatment option in IBD.
Disclosure of Interest: S. Nurbhai: Employee of sponsor company
G. Parkes: Personal payments/honoraria/fees from Janssen, Takeda, Abbvie Travel grant or fellowship from Takeda, Abbvie, Janssen, Tillott’s
M. West: Employee of sponsor company
K. Ray: Consultant to sponsor company
A. Vossenkaemper: Research funding from GSK and VHsquared
P. Round: Consultant to sponsor company
T. MacDonald: Research funding from J&J and GSK Stock options in Topivert
S. Crowe: Employee of sponsor company
References
Crowe et al. 18th International Congress of Mucosal Immunology, July 19-22 2017, Washington DC, USA
Ungar et al., Clin Gastroenterol Hepatol. 2016 Apr;14(4):550–557
LB06 BIOSIMILAR INFLIXIMAB (CT-P13) IS NOT INFERIOR TO ORIGINATOR INFLIXIMAB: EXPLORATIVE SUBGROUP-ANALYSES IN CROHN’S DISEASE AND ULCERATIVE COLITIS IN THE NOR-SWITCH EXTENSION TRIAL
K. K. Kaasen Jørgensen1, G. L. Goll2, J. Sexton2, I. C. Olsen2, N. Bolstad3, K. E. ., A. Lundin4, I. P. Berset5, E. A. Haavardsholm2, C. Mørk6, T. K. Kvien2, J. Jahnsen7
1Department Of Gastroenterology, Akershus University Hospital, Lørenskog/Norway
2Department Of Rheumatology, Diakonhjemmet Hospital, Oslo/Norway
3Oslo University Hospital, Radiumhospitalet, Oslo/Norway
4Gastroenterology, Oslo University Hospital, Oslo/Norway
5Ålesund Hospital, Ålesund/Norway
6NTNU, Trondheim/Norway
7Dept. Of Gastroenterology, Akershus University Hospital, Lørenskog/Norway
Introduction: TNF-inhibitors have improved treatment of Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis, spondyloarthritis, psoriatic arthritis and chronic plaque psoriasis. The NOR-SWITCH 52-week, double blind, non-inferiority trial showed that switching from originator (Remicade®, IFX) to biosimilar (Remsima®, CT-P13) infliximab was not inferior to continued treatment with IFX regarding efficacy, safety and immunogenicity.1 Though explorative subgroup analyses in CD demonstrated an estimated difference close to the non-inferiority margin for CT-P13, the trial was not powered for demonstrating non-inferiority in the individual diagnoses.1
Aims & Methods: In the 26-week open label NOR-SWITCH EXTENSION trial treatment efficacy, safety and immunogenicity were assessed in patients on CT-P13 throughout the 78-week study period (maintenance group) compared to patients switched from IFX to CT-P13 at week 52 (switch group). The primary endpoint was disease worsening during follow-up according to disease-specific indices. Explorative subgroup analyses were performed to examine disease worsening within each of the six diagnoses.
Results: In total, 380 of 451 patients in the main trial entered the extension phase (Full Analysis Set). Overall disease worsening occurred in 16.8% (32/190) and 11.6% (20/173) in the maintenance and switch arms, respectively, and the 95% confidence interval (CI) of the adjusted difference was within the pre-specified 15% non-inferiority margin (−5.9%; 95% CI −12.9,1.1) (Per Protocol Set, PPS). The incidence of adverse events and anti-drug antibodies (ADAb) were comparable between arms. In CD, disease worsening occurred in 20.6% and 13.1% (−7.9%; 95% CI −21, 5.2) and in UC in 15.4% and 2.9% (−12.4%; 95% CI −25, 0.1) of patients in the maintenance and switch group, respectively (PPS) (table). These results were within the non-inferiority margin. The baseline characteristics in CD and UC when entering the extension trial at week 52 showed no difference between arms regarding age, gender, previous biologic therapy, use of immunosuppressants, trough drug levels, disease duration, extension, behaviour and activity (Harvey-Bradshaw Index (HBI) and Partial Mayo Score (PMS)), bowel surgery, smoking, CRP, faecal calprotectin, and EQ-5D. Changes in disease measures from baseline to study end in CD and UC, respectively, showed similarity between treatment arms regarding HBI, PMS, HBI and PMS remission, CRP, faecal calprotectin and Patient’s and Physician’s global assessment of disease activity (PPS)(table). Comparable results were also seen for reported adverse events, trough serum levels and presence of ADAb.
Conclusion: The open label NOR-SWITCH EXTENSION trial did not show any difference between patients who maintained CT-P13 vs. those who switched from IFX to CT-P13. In the same way, explorative subgroup analyses of CD and UC showed similarity between groups with regard to efficacy, safety and immunogenicity.
Disclosure of Interest: K.K. Kaasen Jørgensen: I have received personal fees from Intercept, Sandoz and Celltrion outside the submitted work.
G.L. Goll: Dr. Goll reports personal fees from Orion Pharma, personal fees from Pfizer, personal fees from Novartis, personal fees from AbbVie, outside the submitted work;.
I.C. Olsen: Dr. Olsen reports personal fees from Pfizer Inc, outside the submitted work;.
N. Bolstad: Dr. Bolstad reports personal fees received from Orion Pharma (adv.board), Napp Pharmaceuticals (lecture), Pfizer (adv. board), Takeda (lecture, booklet co-authorship).
K.E..A. Lundin: Dr. Lundin reports grants and personal fees from MSD, personal fees from Abbvie, personal fees from Hospira, personal fees from Orion, personal fees from Takeda, personal fees from Janssen, outside the submitted work;.
I.P. Berset: Dr. Berset reports personal fees from AbbVie, personal fees from MSD, personal fees from Takeda, personal fees from Hospira, personal fees from Ferring, outside the submitted work;.
E.A. Haavardsholm: Dr. Haavardsholm reports grants from AbbVie, grants from Pfizer, grants from UCB, grants from Roche, grants from MSD, outside the submitted work;.
C. Mørk: Dr. Mørk reports personal fees from Novartis Norge AS, personal fees from LEO Pharma AS, personal fees from ACO Hud Norge AS, personal fees from Cellgene AS, personal fees from Abbvie, personal fees from Galderma Nordic AB, outside the submitted work;.
T.K. Kvien: Dr. Kvien reports personal fees from AbbVie, personal fees from Biogen, personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from Celltrion, personal fees from Eli Lilly, personal fees from Epirus, personal fees from Janssen, personal fees from Merck-Serono, personal fees from MSD, personal fees from Mundipharma, personal fees from Novartis, personal fees from Oktal, personal fees from Orion Pharma, personal fees from Hospira/Pfizer, personal fees from Roche, personal fees from Sandoz, personal fees from UCB Pharma, outside the submitted work;.
J. Jahnsen: Dr. Jahnsen reports personal fees from Celltrion, personal fees from Orion Pharma, personal fees from Pfizer, personal fees from Sandoz, personal fees from Astro Pharma, personal fees from AbbVie, personal fees from Janssen, personal fees from Takeda, outside the submitted work; and Has served as a speaker, consultant or advisory board member for MSD, AbbVie, Celltrion, Orion Pharma, Takeda, Napp Pharm, AstroPharma, Hikma, Sandoz, Janssen, Mundipharma and Pfizer..
All other authors have declared no conflicts of interest.
Reference
1. Jørgensen KK et al. Switching from originator infliximab to biosimilar CT-P13 compared to maintained treatment with originator infliximab (NOR-SWITCH): a 52-week randomised double-blind non-inferiority trial. Lancet, 2017 Jun10;389:2304−2316.
Abstract No: (LB06)
Table: Primary and secondary efficacy endpoints in CD and UC in the NOR-SWITCH EXTENSION trial (Per Protocol Set)
Physician's global assessement of disease activity
−0.27 (1.73)
−0.32 (1.49)
0.13 (−0.37, 0.63)
0.16 (1.49)
−0.06 (1.23)
0.48 (−0.11, 1.06)
Patient's global assessement of disease activity
−0.29 (1.95)
−0.31 (1.44)
0.19 (−0.35, 0.73)
0.51 (2.5)
−0.23 (1.26)
0.9 (0.19, 1.62)
Patients treated with CT-P13 during the 52-week NOR-SWITCH trial and the 26-week EXTENSION trial. ¥Patients treated with IFX during the 52- week NOR-SWITCH trial and then switched to CT-P 13 in the 26-week EXTENSION trial. Data are in mean (SD) in change from baseline (follow-up at week 78 minus baseline at week 52) and in N (%) in disease worsening and HBI/PMS remission at follow-up (week 78). Difference is adjusted treatment difference of change from baseline (week 52) with 95% confidence intervals.
on behalf of the Nor-Switch study group
LB07 Ustekinumab IV Induction Results in Crohn’s Disease Symptom Improvement within the First Week in Anti-TNF Refractory Patients
W.J. Sandborn1, B. Yeager2, C. Gasink3, T. Hoops2, L. Gao2, Y. Wang3, D. Jacobstein4, S. Lee5, S.B. Hanauer6
1UCSD, La Jolla/United States of America
2Janssen Scientific Affairs, LLC, Horsham/United States of America
3Janssen Scientific Affairs, LLC, Horsham/United States of America/PA
4Janssen Research & Development, LLC, Spring House/United States of America/PA
5University of Washington, Medical Center, Seattle/United States of America
6Feinberg School of Medicine, Northwestern University, Chicago/United States of America
Contact E-mail Address: wsandborn@ucsd.edu
Introduction: In both the UNITI-1&2 Crohn’s disease (CD) studies, a single 6 mg/kg Ustekinumab (UST) IV infusion showed significantly greater rates of clinical response & remission vs placebo, and significant reductions in CDAI (and >70 pt reduction)1 by the first post-baseline visit at Wk 3.2 It remains to be determined how soon patients see benefit (ie. before Wk 3).
Aims & Methods: Patient (pt) CDAI diary daily data (day −7 to +14) from the UNITI-1 study of pts who had previously failed TNF antagonists were compiled and analyzed post-hoc for the 3 pt-reported CDAI components (stool frequency[SF], abdominal pain[AP], & general well-being[WB]). Mean change in these daily scores with IV UST 6 mg/kg and 130 mg were compared vs. placebo (PBO), as were 2-item SF + AP PRO2 weekly, over the 7d prior, weighted either 1:1 or as a CDAI subscore (assessed by mean change, and as % of pts with >50 pt improvement). Ranked transformation was used to compare groups for all analyses.
Results: IV UST induced significant improvement in all 3 components within the first 2 wks, with AP first significantly better than PBO on d2 for both UST doses, and consistently significantly better than PBO from d6 through d14 for 6 mg/kg and from d8 through d14 for 130 mg. Mean improvement in SF was first significantly better than PBO on d7 for UST both doses, while this occurred on d8 for WB. Week 1 and 2 SF + AP with CDAI weighting was significantly improved for both UST doses vs PBO at d7 and d14, & SF + AP added with equal 1:1 weight was significantly improved for both UST doses at d14. 29.3% of 6 mg/kg & 31.4% of 130 mg groups attained ≥50 pt improvement in CDAI solely based on SF&AP components over the second week vs 18.8% in the PBO group (p < 0.05 and p < 0.01, respectively).
Conclusion: Even in the refractory CD population of previous anti-TNF failures in UNITI-1, symptom relief based on individual pt-reported CDAI components began to show significant improvement as early as 1 day post UST infusion, and was seen consistently among all 3 components by d8 with both IV UST doses, confirmed by consistent PRO2 benefit in the second week. These findings support previously reported significant early efficacy seen at the post-baseline (Wk3) visit in the UNITI induction studies.2
Disclosure of Interest: W.J. Sandborn: Dr. Sandborn reports grants and personal fees from Pfizer; grants and personal fees from Prometheus Laboratories, grants and personal fees from AbbVie, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Takeda, grants and personal fees from Atlantic Pharmaceuticals, grants and personal fees from Janssen, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech, grants and personal fees from Nutrition Science Partners, personal fees from Kyowa Hakko Kirin, personal fees from Millennium Pharmaceuticals, personal fees from Celgene Cellular Therapeutics, personal fees from Santarus, personal fees from Salix Pharmaceuticals, personal fees from Catabasis Pharmaceuticals, personal fees from Vertex Pharmaceuticals, personal fees from Warner Chilcott, personal fees from Gilead Sciences, personal fees from Cosmo Pharmaceuticals, personal fees from Ferring Pharmaceuticals, personal fees from Sigmoid Biotechnologies, personal fees from Tillotts Pharma, per
B. Yeager: employee of Janssen Scientific Affairs, LLC, and has stock ownership at Johnson & Johnson,LLC
C. Gasink: employee of Janssen Scientific Affairs, LLC, and has stock ownership at Johnson & Johnson,LLC
T. Hoops: employee of Janssen Scientific Affairs, LLC, and has stock ownership at Johnson & Johnson,LLC
L. Gao: employee of Janssen Scientific Affairs, LLC, and has stock ownership at Johnson & Johnson,LLC
Y. Wang: employee of Janssen Scientific Affairs, LLC, and has stock ownership at Johnson & Johnson,LLC
D. Jacobstein: employee of 3Janssen Research & Development, LLC. and stock ownership at Johnson & Johnson, LLC
S. Lee: Research support and consultant for Janssen
S.B. Hanauer: Consultant, advisory boards, speaker and institutional research support for Janssen
References
1. Best WR, et al. Gastroenterology 1976;70:439−44
2. Feagan BG, et al. N Engl J Med 2016;375:1946−60.
Monday, October 30, 2017 15:45−17:15
Malignant and premalignant lesions: Detection, diagnosis and monitoring – Room A3____________________
LB08 NEEDLE-BASED CONFOCAL LASER ENDOMICROSCOPY: THE IMPACT ON DIAGNOSIS AND MANAGEMENT OF PANCREATIC CYSTIC LESIONS
M. Palazzo1, G. Vanbiervliet2, I. Borbath3, A. Sauvanet4, R. Gincul5, R. Bourdariat6, A.I. Lemaistre7, B. Pujol8, F. Caillol9, L. Palazzo10, A. Aubert11, F. Maire11, L. Buscail12, M. Giovannini9, B. Napoléon8
Introduction: The management of pancreatic cystic lesions (PCL) depends on cyst type: surgical resection or surveillance is considered for premalignant lesions (mucinous cystadenoma (MCA), intraductal papillary mucinous neoplasm (IPMN), neuroendocrine neoplasm (NEN)) whereas the absence of surveillance is proposed for asymptomatic benign cysts (serous cystadenoma (SCA), pseudocyst (PC)). After inconclusive cross-sectional imaging, the diagnosis of PCL type relies on endoscopic ultrasound fine needle aspiration (EUS-FNA) with cyst fluid analysis (cytohistology, biochemistry). Needle-based confocal laser endomicroscopy (nCLE) allows in vivo microscopic imaging of the inner wall of cyst during an EUS-FNA procedure. Several studies evaluated the feasibility, the safety and described specific nCLE criteria for the characterization of PCL1,2. The first phase of the CONTACT2 study prospectively validated an overall nCLE accuracy >95% on the 78 cysts with an histological proof. This second phase of the study aimed to evaluate nCLE impact on diagnosis and management strategy of PCL of the entire population of the CONTACT2 study.
Aims & Methods: Five independent pancreatic experts (3 endoscopists, 2 pancreato-biliary surgeons) had a phone consensus meeting on the management strategy of PCL depending on the diagnosis and confidence level. Then, they independently reviewed the medical records (clinical and demographic data, EUS-FNA reports with cyst fluid analysis). For each case, they proposed the diagnosis, the confidence level and the management strategy. Two sequential evaluations were done: the first one without nCLE data and the second one including nCLE data. Patients were randomly reordered between the two evaluations. Final consensus for diagnosis and management strategy was determined at the majority of experts. The impact of nCLE on diagnosis, and management strategy with interobserver agreements (IOA) calculations for both, were assessed.
Results: Between April 2013 and March 2016, 209 patients with a large (>20 mm) solitary non-communicating PCL were prospectively enrolled in 5 centers. EUS-FNA with cyst fluid analysis and nCLE were performed. Three pancreatitis (1.4%) were reported. nCLE was successfully performed in 99% (206/209) and was contributive in 85% of the cases (175/206). EUS-FNA cytohistology was contributive in 30% of the cases (61/206) and CEA was available in 76% of the cases (157/206), >192 ng/mL in 35% (55/157) and <5 ng/mL in 38% (59/157) of the cases. Diagnoses without nCLE were distributed as following: 7 NEN, 48 IPMN, 16 MCA, 35 indeterminate mucinous lesions (IML), 70 SCA, 8 PC, 4 others and 18 indeterminate cysts; after including nCLE outcomes diagnoses were 9 NEN, 67 IPMN, 24 MCA, 8 IML, 77 SCA, 10 PC, 3 others and 8 indeterminate cysts. Overall, nCLE changed 30% of the diagnosis (61/206), while improving its IOA from 0.45 (95% CI = 0.43–0.47) to 0.76 (95% CI = 0.74–0.78) and increasing high confidence diagnoses from 57% (95% CI = 0.43–0.70) to 79% (95% CI = 0.73–0.84). nCLE changed 28% (58/206) of the management strategy while improving its IOA from 0.36 (95% CI = 0.33–0.39) to 0.64 (95% CI = 0.61–0.67). nCLE prevented from any surveillance in 42% of the SCA (32/77) and reversed the choice between surveillance and surgery in 15% of the mucinous lesions (15/99) by refining their sub-classification in IPMN and MCA.
Conclusion: After having prospectively validated the very high sensitivity and specificity of nCLE for the diagnosis of the nature of large solitary non-communicating PCL which represents the main diagnostic issue for clinicians, here we showed that the addition of nCLE to the EUS-FNA with cyst fluid analysis changes the diagnosis and the management strategy proposed by specialist doctors involved in pancreatic diseases in nearly one third of the cases while improving interobserver agreement for both. Strikingly, nCLE allows to stop with high confidence level unnecessary long term surveillance in more than 40% of the benign SCA. These results support the recognition of nCLE as an integral part of the standard of care of such clinical situation.
Disclosure of Interest: G. Vanbiervliet: Expert consultant for Mauna Kea Technologies
I. Borbath: Expert consultant for Mauna Kea Technologies
A. Sauvanet: Expert consultant for Mauna Kea Technologies
R. Gincul: Expert consultant for Mauna Kea Technologies
R. Bourdariat: Expert consultant for Mauna Kea Technologies
A.I. Lemaistre: Training courses for Mauna Kea Technologies Expert consultant for Mauna Kea Technologies
B. Pujol: Clinical research sponsored by Mauna Kea Technologies
F. Caillol: Clinical research sponsored by Mauna Kea Technologies
B. Napoléon: Clinical research sponsored by Mauna Kea Technologies Training courses for Mauna Kea Technologies Expert consultant for Mauna Kea Technologies
All other authors have declared no conflicts of interest.
References
1. Konda et al. Endoscopy 2013;45:1006–13.
2. Napoleon et al. Surg Endosc 2016;30:2603–12.
LB09 Assessing the Feasibility of Target Screening for Oesophageal Adenocarcinoma Based on Individual Risk Assessment: A Population-Based Cohort Study in Norway
S. Xie1, E. Ness-Jensen1, J. Lagergren2
1Department Of Molecular Medicine And Surgery, Karolinska Institutet, Stockholm/Sweden
2Division Of Cancer Studies, King's College London, London/United Kingdom
Contact E-mail Address: shaohua.xie@ki.se
Introduction: Oesophageal adenocarcinoma (OAC) has a poor prognosis, and tumour stage at diagnosis is the strongest prognostic factor. However, universal screening is not justified due to the low absolute risk in the general population. Risk prediction models have the potential of identifying high-risk individuals for targeted screening, but have rarely been evaluated for OAC.
Aims & Methods: We used data from a population-based cohort of 62,576 participants recruited in 1995–1997 in Nord-Trøndelag County, Norway and followed up until December 31th, 2015. A model for predicting individuals’ absolute risk of OAC was developed using competing-risks regression which accounted for competing-risks of mortality. Additionally, the Lorenz Curve was used to assess the concentration of OAC patients in high-risk individuals and evaluate the feasibility of targeted screening based on individual risk assessment.
Results: During a total of 1,085,137 person-years of follow-up, 29 newly diagnosed cases of OAC occurred. The model included risk factors for OAC, in which male sex, older age, gastro-oesophageal reflux symptoms, obesity, and tobacco smoking predicted higher risk of OAC. The area under the receiver operating characteristic curve for 10-year risk of OAC was 0.81 (95% confidence interval [CI] 0.70–0.91) and that for 15-year risk was 0.88 (95% CI 0.83–0.93), with good agreements between observed and predicted risks. The Lorenz Curve indicated that based on individually predicted risks, 33% of all OAC cases in 15 years would have occurred in the 5% of the population of the highest risks, and 61% of all cases in the top 10% of the population.
Conclusion: Individual risk assessment based on known risk factors for OAC has the potential of identifying individuals with high risk of OAC, who may benefit from screening for early detection.
Disclosure of Interest: All authors have declared no conflicts of interest.
LB10 Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men: a randomized trial
Ø. Holme1, M. Løberg2, M. Kalager2, M. Bretthauer2, M. A. Hernán3, E. Aas2, T. J. Eide4, E. Skovlund5, J. Lekven6, J. Schneede7, K. M. Tveit4, M.H. Vatn2, G. Ursin8, G. Hoff8
1SSK Dept. of Medicine, Kristiansand/Norway
2University of Oslo, Oslo/Norway
3Harvard T.H. Chan School of Public Health, Boston/United States of America
4Oslo University Hospital, Oslo/Norway
5Norwegian University of Science and Technology, Trondheim/Norway
6University of Bergen, Bergen/Norway
7University of Umeå, Umeå/Sweden
8Cancer Registry of Norway, Oslo/Norway
Contact E-mail Address: oyvind.holme@sshf.no
Introduction: Screening for colorectal cancer (CRC) with sigmoidoscopy with and without fecal occult blood testing (FOBT) is recommended. Its long-term effect on colorectal cancer incidence and mortality in men and women is, however, unclear.
Aims & Methods: To determine the effectiveness of flexible sigmoidoscopy screening after 15 years follow-up in men and women. Individuals aged 50–64 years without prior colorectal cancer and living in Oslo city or Telemark County, Norway, was identified through the Population Registry and randomized to once-only sigmoidoscopy screening with or without additional fecal occult blood testing or to no screening. Individuals with a positive screening test was referred for colonoscopy. The screening intervention was performed between 1999 and 2001.
Results: Of 98,678 individuals, 20,552 were randomized to screening and 78,126 to no screening. Attendance was 61.4% in men and 64.7% in women. Median follow-up was 14.8 years (maximum 17 years). We observed heterogeneity between men and women for CRC incidence (P = 0.004) and mortality (P = 0.014). In men, CRC incidence was reduced by 65.5 per 100,000 person-years (95% CI 80.8 to 36.9 reduction), and CRC mortality by 23.2 per 100,000 person-years (95% CI 32.8 to 8.7 reduction) in the screening group versus the control group. In women, screening did not reduce CRC incidence (13.5 reduction per 100,000 person-years; 95% CI 35.4 reduction to 8.5 increase) or mortality (0.43 increase per 100,000 person-years; 95% CI 11.7 reduction to 12.6 increase).
Conclusion: Once-only sigmoidoscopy screening reduces colorectal cancer incidence and mortality for up to 17 years in men, but we found little or no apparent effect in women.
Disclosure of Interest: Holme: ØH has received fess for lectures from AstraZeneca and Norgine
All other authors have declared no conflicts of interest.
LB11 Benefit of circulating methylated biomarkers inclusion in the management of metastatic colorectal cancer patients
L. Barault1, A. Amatu2, G. Siravegna1, A. Ponzetti3, S. Moran4, A. Cassingena2, B. Mussolin5, C. Falcomatà1, A. M. Binder6, C. Cristiano3, D. Oddo1, S. Guarrera7, C. Cancelliere1, S. Bustreo3, K. Bencardino2, S. Maden8, A. Vanzati9, P. Zavattari10, G. Matullo7, M. Truini2, W.B. Grady11, P. Racca3, K. B. Michels6, S. Siena2, M. Esteller4, A. Bardelli1, A. Sartore-Bianchi2, F. Di Nicolantonio1
1Oncology, University of Torino, Candiolo/Italy
2Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan/Italy
3Colorectal Cancer Unit, Medical Oncology Division 1AOU Città della Salute e della Scienza, San Giovanni Battista Hospital, Turin/Italy
4Cancer Epigenetics And Biology Program, Bellvitge Biomedical Research Institute, L’Hospitalet, Barcelona/Spain
5Candiolo Cancer Institute-FPO, IRCCS, Candiolo/Italy
6Department Of Epidemiology, UCLA Fielding School of Public Health, Los Angeles/United States of America/CA
7Medical Sciences, Italian Institute for Genomic Medicine – IIGM/HuGeF, Turin/Italy
8Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle/United States of America/WA
9Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan/Italy
10Biomedical Sciences, University of Cagliari, Cagliari/Italy
11Gastroenterology, University of Washington Medical Center School of Medicine, Seattle/United States of America
Contact E-mail Address: ludovic.barault@unito.it
Introduction: Current guidelines for the management of patients with metastatic colorectal cancer (mCRC) advise a bimonthly treatment response evaluation 1. However, growing evidence demonstrated that early tumour shrinkage is associated with long-term outcome 2,3. Cell-free circulating DNA (cfDNA) assessment offers a highly specific and minimally invasive method amenable on regular basis to patients, but is currently impaired by the lack of consensus markers 4. Early alterations in methylation patterns are highly prevalent and limited to specific regions of the genome, allowing for a universal assay design compatible for population studies.
Aims & Methods: We aimed to identify an optimal panel of cancer specific biomarkers for the purpose of monitoring therapeutic outcome in cfDNA in mCRC patients. Comparison of genome-wide DNA methylation profiles of a collection of 149 CRC cell lines with normal mucosa and blood cells identified five genes (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC) to be used as universal liquid biopsy assay for mCRC. Markers were validated in silico using methylome data from CRC specimens. Digital PCR-based assays were then designed and performed in tissue (N = 112) and cfDNA samples from mCRC patients (N = 182) and self-declared healthy donors (N = 50). Retrospective longitudinal assessment of the panel was performed and compared to current gold standards (imaging, CEA).
Results: Average methylation (and range) was 2.3% [0.2–8.4] and 55.2% [20.2–94.9] for normal tissues and for macro-dissected matched tumour tissues respectively (p < 0.001). Using cfDNA individual markers easily stratified self-declared healthy donor from mCRC patients samples (average specificity: 0.96; average specificity: 0.69). Male gender was significantly associated with lower methylation values (p = 0.023), while the presence of unresected primary tumour (p = 0.002), bulky disease (defined as massive tumour involvement of >50% of liver or lungs; p = 0.012) or multiple metastatic lesions (p = 0.023) were significantly associated with higher methylation values, while CEA levels were less informative. Longitudinal assessment in cfDNA of patients treated with chemotherapy (N = 8) recapitulated tumor burden changes as assessed by imaging, with a decrease preceding partial response, while an increase in methylation anticipated progression. For cases with known mutations in the tumor tissue, KRAS or BRAF mutant levels in cfDNA were consistent with methylation values. In patients treated with the EGFR inhibitor panitumumab (N = 5), disease progression was associated to an increase in methylation levels and the emergence of resistance causative alterations (acquired RAS mutations or MET gene amplification). Finally, drop in methylation of markers in cfDNA correlated with objective tumor response (as assessed by conventional radiological methods; PPV = 0.82; NPV = 0.79, p = 0.0048) and progression-free survival (p = 0.042, HRrelapse = 0.48 [0.17–0.88]) in 29 mCRC patients enrolled in the TEMECT clinical trial (Temozolomide).
Conclusion: This panel of methylated markers was able to monitor tumour burden in colorectal cancer patients treated with different conventional treatment regimens, including chemotherapy, anti-angiogenic agents and targeted agents. Liquid biopsy based on methylated markers could be coupled with imaging to improve timely therapeutic changes. This approach could also be useful for early pharmacodynamic assessments in clinical trials in particular for those using drugs for which no reliable biomarker of response are available (e.g.: regorafenib)5.
Disclosure of Interest: P. Zavattari: Dr. Zavattari have a patent 102017000072650 pending.
A. Bardelli: Dr. Bardelli reports personal fees (scientific advisory board member) from Horizon Discovery, personal fees (scientific advisory board member) from Biocartis, personal fees (Consultant) from Novartis, personal fees (Consultant) from Roche, personal fees (Consultant) from Illumina. Dr. Bardelli reports grants from Trovagene Inc., outside the submitted work.
F. Di Nicolantonio: Dr. Di Nicolantonio reports grants from Trovagene Inc., outside the submitted work. In addition, Dr. Di Nicolantonio have a patent 102017000072650 pending.
All other authors have declared no conflicts of interest.
References
1. Van Cutsem E, Cervantes A, Adam R, et al. Ann Oncol 2016;27(8):1386–422. doi: 10.1093/annonc/mdw235
2. Cremolini C, Loupakis F, Antoniotti C, et al. Ann Oncol 2015;26(6):1188–94. doi: 10.1093/annonc/mdv112
3. Douillard JY, Siena S, Peeters M, et al. Eur J Cancer 2015;51(10):1231–42. doi: 10.1016/j.ejca.2015.03.026
5. Khan K, Rata M, Cunningham D, et al. Gut 2017 doi: 10.1136/gutjnl-2017-314178.
LB12 Endocuff-assisted colonoscopy significantly improves adenoma detection rate compared to Cap- assisted colonoscopy: A randomised back to back study (DETECT).
R. Rameshshanker1, Z.P. Tsiamoulos1, A. Wilson2, A. Rajendran1, B.P. Saunders1
1Wolfson Endoscopy Unit, St Mark's Hospital, Harrow, London/United Kingdom
2Wolfson Unit For Endoscopy, St. Marks Hospital, London/United Kingdom
Contact E-mail Address: r.rameshshanker@nhs.net
Introduction: Adenoma detection rates at colonoscopy are directly linked to subsequent risk of post colonoscopy cancer. One of the main reason for missing adenomas is poor visualisation of proximal folds and flexures during standard colonoscopy. Disposable distal attachments such as the cap and the Endocuff vision device have been reported to improve adenoma detection compared to standard colonoscopy. There are however no comparative randomised trials of these two devices
Aims & Methods: Aim The primary aim of this study was to compare the adenoma miss rate between Endocuff-assisted colonoscopy (EAC) and Cap-assisted colonoscopy (CAC). Methods All Patients referred for a colonoscopy via symptomatic services were invited to participate in the study. This is a randomised, single centre, tandem colonoscopy trial with both examinations performed by the same endoscopist, on the same day first with Endocuff Vision followed by cap or vice-versa. The study was approved by local research ethics committee and registered on a trial database(ISRCTN58994883) All procedures were performed by Gastroenterology Fellows who had performed more than 1500 colonoscopies each.
Results: A total of 154 patients were recruited. 78 of them had CAC as their first procedure. The mean age of participants was 61 years (male: female ratio was 1:1). The main findings of the study were shown in table 1. The polyp miss rate was significantly lower in EAC (8.4%) when compared with CAC (26.1%, p < 0.001). Adenoma miss rate was significantly lower for EAC (EAC vs CAC, 6%, vs 19%, p = 0.002). Miss rate for diminutive adenomas (<6 mm) were significantly lower in EAC group (1.8% vs 19.6%, p < 0.001), however, there was no significant differences in the miss rates for small (6–10 mm) (3.7% vs 2.9%, p = 0.69) or adenomas larger than 10 mm (2.6% vs 1.6%, p = 0.98). There was no significant difference in cancer, advanced adenoma or serrated polyps miss rate. The mean number of adenomas per procedure was significantly higher in EAC group when compared to CAC (1.5 vs 0.8, p < 0.001). Caecal intubation time was significantly shorter in the EAC group than CAC group (median 6 vs 7 mins, p = 0.01) Conversely, withdrawal time (median 10 vs 8 mins, p = 0.01) was significantly longer in the EAC group. This difference was probably due to more polyps detected and resected in the EAC group. While introducing the colonoscope via the anus the discomfort score was higher in EAC (55% vs 10%, p < 0.001). However, the majority reported only mild discomfort During the first procedure, Endocuff was removed in 5/76(6.6%) patients’ due to difficulties to pass the Endocuff through a fixed or narrowed sigmoid colon. There were no difficulties to negotiate the sigmoid colon when the cap was used. There were no other colonoscopy related complications reported during the procedure. Table: Epidemiological data and primary outcome.
CAC
EAC
P value
Total number of patients
78 (first pass)
76 (first pass)
Age (mean/SD)
60.8(13.6)
61.9(14.7)
Caecal intubation rate
78/78(100%)
71/76(93.4%)
0.02
Insertion time -mins (median/IQR)
7(5–10)
6(4–8)
0.01
Withdrawal time - mins (median/IQR)
8(6–11)
10(7–15)
0.01
Negative withdrawal time-mins(median/IQR)
6(5–8)
6(6–7)
0.01
Polyp miss rate (%) Polyps ≤5 mm Polyps 6–9 mm Polyps >10 mm
26.1 24.4 6.1 0.8
8.4 4.3 3.7 2.6
<0.001 <0.001 0.52 0.97
Adenoma miss rate (%) Adenoma ≤5 mm Adenoma 6–9 mm Adenoma >10 mm
19 19.6 2.9 1.6
6 1.8 3.7 2.6
0.002 <0.001 0.69 0.98
Cancer miss rate
0
0
Advanced adenoma miss rate
4.2
4.6
0.98
Serrated polyps miss rate
4.9
1.8
0.25
Conclusion: Our randomised, back to back study demonstrates that Endocuff-assisted colonoscopy results in a significantly lower adenoma miss rate than cap assisted colonoscopy. Although the EndoCuff Vision had to be removed in a small minority of patients and caused minor anal discomfort, its first line use appears justified in most cases.
Disclosure of Interest: B.P. Saunders: Advisory board member of Norgine Medical private limited
All other authors have declared no conflicts of interest.
LB13 Diagnostic performance of Colon Capsule Endoscopy. A prospective multicenter study in a screening setting.
C. Spada1, C. Hassan2, M. Pennazio3, Z. Adrián-De-Ganzo4, E. Rondonotti5, E. Quintero Carrion6, S. Pecere7, N. Segnan8, G. Costamagna9, C. Senore8
1Digestive Endoscopy Unit, Fondazione Poliambulanza, Brescia/Italy
2Gastroenterology, Nuovo Regina Margherita Hospital, Rome/Italy
3San Giovanni Battista University Teaching Hospital, Turin/Italy
4Endoscopy Unit, Canarias University Hospital, Las Palmas/Spain
5Ospedale Valduce, Como/Italy
6Gastroenterology, Hospital Univ. de Canarias, Santa Cruz de Tenerife/Spain
7Digestive Endoscopy Unit, Catholic University Rome, Rome/Italy
8Cancer Screening, City of Health and Science, Torino/Italy
Introduction: Colon capsule endoscopy (CCE) has been recognized as a complementary test to colonoscopy for colorectal cancer (CRC) screening in average-risk people. CCE has the potential to reduce the need for optical colonoscopy. To date, the role of CCE in FIT-based CRC screening program has been poorly evaluated.
Aims & Methods: To assess the diagnostic accuracy of the second generation colon capsule endoscopy (CCE-2) among screenees with a positive faecal immunochemical tests (FIT) result in the context of population based programmes for colorectal cancer (CRC) screening. We targeted for enrolment subjects aged 50 to 69, with a positive FIT result, examined in 4 population based programmes in Italy and Spain, using the same test (Eiken co.) and adopting the same positivity cut-off (20 µgr. Hb/gr. faeces). Screenees meeting the inclusion criteria for the study (no swallowing disorders, or chronic disease which might increase the risk of preparation side-effects, or allergy to iodine) were invited to participate. Volunteers were asked to perform the CCE-2 examination, followed by the colonoscopy (TC). The TC was performed the same day as the CCE-2, if the capsule was excreted before 2 p.m., while in the other cases the screenee was given an additional bowel preparation and the TC was scheduled for the following morning. Bowel preparation protocol for CCE-2 included a high-volume splitted PEG-based regimen and NaP and Gastographin as boosters. The CCE-2 film was read by an experienced endoscopist, blinded to the results of the TC examination. A second TC was planned, if the CCE-2 detected a polyp >9 mm not detected by the TC. All readers had previous experience with the colon and small bowel capsule and they underwent a one day training course before starting the study. Only two endoscopists in each centre were involved in the study to minimize inter-individual variability. The main outcomes were sensitivity and specificity of CCE-2 for advanced neoplasia (AN: advanced adenoma + CRC), when using different size thresholds for TC referral (i.e. >5 or >9 mm polyp).
Results: We enrolled 222 subjects and 203 completed both the CCE-2 and the TC examination. Quality of bowel preparation for CCE-2 was judged to be adequate in 88.5% of the cases. A complete examination was achieved in 96.6% (196/203) of the cases with TC and in 88.2% with CCE-2 (capsule spontaneously excreted in 179 cases). TC detected an AN in 32.4% (58/179 – 9 CRCs) of the screenees with complete CCE-2 exam. CCE-2 sensitivity for AN was 75.9% and 89.7% when using the higher (≥1 polyp >9 mm; TC referral rate; 36.3%) or the lower (≥1 polyp >5 mm; TC referral rate 52.5%); the corresponding figures for AN specificity were 82.6% and 65.3%.
Conclusion: Our results are confirming in a high-prevalence population the findings from previous reports showing a high sensitivity of CCE-2 for significant colorectal lesions. The lower CCE-2 specificity in our study as compared to previous reports is likely related to the choice of AN as the main outcome, as opposed to large polyps (any histology).
Disclosure of Interest: C. Spada: Consultant for Medtronic
C. Hassan: Consultant for Medtronic
E. Quintero Carrion: Consultant for Medtronic
G. Costamagna: Consultant for Medtronic
All other authors have declared no conflicts of interest.
LB14 CLINICAL PERFORMANCE OF A NOVEL X-RAY BASED IMAGING CAPSULE FOR COLONIC SCREENING
N. Gluck1, E. E. Half2, J. Lachter2, A. Klein3, S. Doron4, V. Bieber5, A. Melhem6, I. M. Gralnek7, M. Menachem8, N. Arber9
1Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv/Israel
2Rambam Health Care Campus Dept. of Gastroenterology, Haifa/Israel
3Department Of Gastroenterology, Rambam Health Care Campus, Haifa/Israel
4Soroka Medical Center, Beer Sheva/Israel
5Gastroenterology, Haemek Medical Center, Afula/Israel
6Rabin Medical Center, Petah Tikva/Israel
7Institute Of Gastroenterology And Hepatology, Ha'Emek Medical Center, Afula/Israel
8Tel-Aviv Sourasky Medical Center, Tel Aviv/Israel
9Sackler Faculty Of Medicine, Tel Aviv University, Tel Aviv/Israel
Contact E-mail Address: nathang@tlvmc.gov.il
Introduction: The recently described X-ray based imaging capsule (Check-cap, Israel)1 does not require bowel preparation. It may help overcome one of the major hurdles of screening.
Aims & Methods: Aim: To provide proof of concept for effective prepless CRC screening. Herein, the efficacy for polyp detection and safety is reported. Methods: In a prospective multi-center comparative study, all patients underwent the capsule procedure and FIT (OC-Light, Eiken, Japan) with subsequent colonoscopy as the gold reference. The population consisted of average risk subjects that were enriched with subjects with known non-resected polyps (previous colonoscopies or CT colonography). After swallowing the capsule, they swallowed iodine-based contrast agent (Omnipaque 350, GE Healthcare, US) necessary for generating images (15 cc TID). A tablespoon of fiber was given with the iodine to improved capsule motility. The tracking and control unit was subsequently attached to the patients' back. This unit commands the capsule to scan and collects imaging and position data. Patients continued their normal daily routine and reported their comfort level. Capsule data was analyzed post-hoc for the occurrence of colonic polyps by a trained physician and imaging engineers. The team was blinded to the results of FIT and colonoscopy. Sensitivity and specificity of the capsule findings were calculated with reference to colonoscopy. Results were analyzed as a function of the percent of colon length effectively covered by the scanning capsule.
Results: Sixty six patients (ages 37–79 yr, 40 male) were enrolled. Forty three had un-resected polyps (>10 mm) and 23 were average risk. Forty five procedures were analyzed. Dropouts included technical failures (13) and physiological/anatomical outliers (8). Average transit time was 52 ± 32 hours. All patients continued their daily routine with normal diet. No device-related serious adverse events (SAE) occurred. Infrequent, anticipated AE included soft stool, mild abdominal pain, headache and rash under the back sticker. All AE resolved without intervention within a few hours. Average calculated total body X-ray dose exposure was 50 µSv (abdominal CT scan dose exposure is 8–15X103 µSv). Two capsules were retained and needed to be retrieved by colonoscopy, despite lack of symptoms. One was retained in the appendiceal orifice, while the other was removed at the patient's request concomitantly with polypectomy. Sensitivity and specificity of capsule findings as function of the coverage of colonic length were as follows:
Coverage (of total colon length)
Number of patients
Positive for polyp
Negative for polyps
Sensitivity (%)
Specificity (%)
all analyzed procedures
45
27
18
44 (p = 0.5)
89
> 20%
35
20
15
55 (p = 0.4)
87
>50%
19
9
10
78 (p = 0.006)
90
>70%
12
5
7
100 (p = 0.001)
86
Sensitivity of FIT alone was 37% in all analyzed procedures, and p-value was calculated relative to this. The correlation between the capsule scan coverage length and sensitivity (R^2) was 0.98.
Conclusion: Prepless colonic screening, using an X-ray imaging capsule, is feasible and safe with high acceptance and no side effects. Capsules were highly specific. Those covering the majority of the colon showed excellent sensitivity in detecting polyps. Future improvements in colonic coverage are anticipated to provide even higher sensitivity.
Disclosure of Interest: N. Gluck: Consulting fees from Check-cap LTD.
V. Bieber: Consulting fees from Check-Cap LTD.
N. Arber: Consulting fees from Check-Cap LTD.
All other authors have declared no conflicts of interest.
Reference
1. Gluck N, Shpak B, Brun R, Rösch T, Arber N, Moshkowitz M. A novel prepless X-ray imaging capsule for colon cancer screening. Gut 2016; 65:371-373
Tuesday, October 31, 2017 14:00–15:30
Late breaking clinical trials in gastroenterology – Room A3____________________
LB15 Lusutrombopag for Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Who Are Undergoing Non-Emergency Invasive Procedures: Results from An International Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (L-PLUS 2)
M. Peck-Radosavljevic1, A. Duggal2, T. Ochiai3, T. Motomiya3, T. Kano3, T. Nagata3, N. Afdhal4
1Abteilungsvorstand Gastroenterologie & Hepatologie, Endokrinologie Und Nephrologie, Klinikum Klagenfurt am Wörtersee, Klagenfurt/Austria
2Shionogi Ltd, London/United Kingdom
3Shionogi & Co., Ltd, Osaka/Japan
4Beth Israel Deaconess Medical Center, Harvard Medical School, Boston/United States of America/MA
Contact E-mail Address: markus@peck.at
Introduction: Thrombocytopenia (TCP) is a common complication of chronic liver disease (CLD), which may cause delay or avoidance of invasive procedures. Lusutrombopag (LUSU) is an agonist of human thrombopoietin receptor. Here we report results from a Phase 3 study (L-PLUS 2) evaluating LUSU for treatment of TCP in patients with CLD who were undergoing non-emergency invasive procedures.
Aims & Methods: Key eligibility criteria included ≥18 years old, diagnosis of CLD, baseline platelet count <50 × 109/L, Child-Pugh Class A or B, and planned non-emergency invasive procedure. Patients were randomized 1:1 to receive oral LUSU 3 mg once daily or placebo for up to 7 days. Invasive procedures were performed between Day 9 and 14. Platelet transfusion was mandated if pre-procedure platelet count was <50 × 109/L. Primary efficacy endpoint was proportion of patients who required no platelet transfusion prior to the procedure and no rescue therapy for bleeding up to 7 days post-procedure. Safety assessment included adverse events and imaging for detection of portal vein thrombosis (PVT).
Results: 215 patients were randomized at study sites in 22 countries (ITT population, LUSU 108, placebo 107). Baseline patient characteristics were similar between two groups. The most common invasive procedures included endoscopic variceal ligation (28%), endoscopy with or without polypectomy/biopsy (27%), dental extraction (11%), and TACE (9%). The study met its primary efficacy endpoint: 64.8% of patients in LUSU group required no platelet transfusion and no rescue therapy for bleeding, compared to 29.0% in placebo group (p < 0.0001). The proportion of patients who met the definition of platelet responder (platelet count ≥50 × 109/L and increase from baseline of ≥20 × 109/L) was 64.8% in LUSU group and 13.1% in placebo group (p < 0.0001). No patient in LUSU group and 2 patients in placebo group (1.9%) required rescue therapy for bleeding. Among patients in LUSU group who received no platelet transfusion, median duration of platelet count maintained at ≥50 × 109/L was 19 days. Treatment-emergent adverse events (TEAEs) were reported for 47.7% of patients in LUSU group and 48.6% in placebo group; serious TEAEs 6.5% in each group. Three PVT events were observed, 1 in LUSU and 2 in placebo group; all were incomplete occlusion considered not clinically significant and resolved with therapy. Bleeding-related TEAEs occurred in 3 patients of LUSU group and 6 patients in placebo group.
Conclusion: In this global Phase 3 study, oral lusutrombopag 3 mg once daily was effective and safe in treating TCP in patients with CLD undergoing invasive procedures.
Disclosure of Interest: M. Peck-Radosavljevic: Shionogi: Consultancy and Honoraria AbbVie: Consultancy, Honoraria, Research Funding and Speakers Bureau Bayer: Consultancy, Honoraria, Research Funding and Speakers Bureau Bristol-Myers Squibb: Consultancy and Honoraria Boehringer-Ingelheim: Consultancy and Honoraria Lilly: Consultancy and Honoraria Gilead: Consultancy and Honoraria Jansen: Consultancy and Honoraria MSD: Consultancy, Honoraria and Research Funding Novartis: Consultancy and Honoraria Takeda: Research Funding
A. Duggal: Shionogi: Consultancy
T. Ochiai: Shionogi: Employment
T. Motomiya: Shionogi: Employment
T. Kano: Shionogi: Employment
T. Nagata: Shionogi: Employment
N. Afdhal: Shionogi: Consultancy MSD: Consultancy Gilead: Consultancy Echosens: Consultancy Ligand: Consultancy Jansen: Consultancy Spring Bank Pharmaceuticals: Employment and Equity Ownership TRIO Healthcare: Equity Ownership and Membership on an entity's Board of Directors or advisory committees Allurion: Equity Ownership
LB16 PHARMACOKINETICS, PHARMACODYNAMICS AND TOLERABILITY OF DWP14012, A NOVEL ACID PUMP ANTAGONIST, AFTER MULTIPLE ORAL ADMINISTRATIONS IN HEALTHY SUBJECTS
J. Oh1, S. Lee1, S.J. Moon2, S. Lee3, A. Lee3, S.C. Ji1, I. Jang1
1Department Of Clinical Pharmacology And Therapeutics, Seoul National University College of Medicine and Hospital, Seoul/Korea, Republic of
2Center For Clinical Pharmacology, Biomedical Research Institute, Chonbuk National University Hospital, Jeonju/Korea, Republic of
3Daewoong Pharmaceutical Co., Ltd., Seoul/Korea, Republic of
Contact E-mail Address: johan25@snu.ac.kr
Introduction: A novel potassium-competitive acid blocker (P-CAB), DWP14012, is in clinical development for the treatment of acid-related diseases as a potential alternative to proton pump inhibitors. This study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics (PDs) and tolerability of DWP14012 after a multiple oral administrations.
Aims & Methods: A randomized, double-blind, placebo- and active-controlled, multiple ascending dose study (20, 40, 80, and 160 mg) was conducted in healthy subjects. Twelve subjects for each dose group received oral dose of DWP14012 or esomeprazole (40 mg, active comparator) or placebo in a ratio of 8:2:2 for 7 days. PK of DWP14012 was evaluated up to 24 h after single dose (day 1) and after steady-state (day 7). PD of DWP14012 was evaluated through 24-h gastric pH monitoring at baseline (day -1), day 1 and day 7. Tolerability evaluation including laboratory tests was conducted throughout the study.
Results: A total of 49 subjects were enrolled and 48 subjects were completed the study. Following multiple oral administration of DWP14012, the maximum plasma concentration was observed 1.5 to 5 hours after dose and showed first-order elimination profile with a mean half-life of 7.51 to 9.52 hours. The DWP14012 did not significantly accumulate in the plasma by once daily multiple administrations. The plasma concentration of DWP14012 increased dose proportional manner. The increased gastric acid suppression according to dose of DWP14012 and clear exposure-response relationship were observed; the percentages of time pH above 4.0 at day 7 were 38.3 %, 55.7 %, 87.4 %, and 99.2 % in DWP14012 20, 40, 80, and 160 mg dose group, respectively, whereas, the values were 11.2 % and 59.4 % in placebo and esomeprazole 40 mg dose group; the mean pH at day 7 were 3.4, 4.2, 5.7, and 6.5 in DWP14012 dose groups, respectively, whereas, the value was 2.1 and 4.3 in placebo and esomeprazole group. The gastric pH parameters observed in the subjects who received DWP14012 40 mg were similar to those of who received esomeprazole 40 mg. DWP14012 showed rapid and sustained suppression of gastric acid secretion during 24 hours after dosing. There were no serious adverse events and no clinically significant changes in tolerability parameters.
Conclusion: DWP14012 was well tolerated after 7 days of oral administrations at doses up to 160 mg in healthy subjects, and the PK and PD properties evaluated in the first time in human represented the rapid and long-lasting gastric acid suppression effect of DWP14012. These results suggested that DWP14012 may be effective for the treatment of acid-related diseases.
Disclosure of Interest: J. Oh: This study was sponsored by Daewoong Pharmaceutical Co., Ltd.
S. Lee: This study was sponsored by Daewoong Pharmaceutical Co., Ltd.
S.J. Moon: This study was sponsored by Daewoong Pharmaceutical Co., Ltd.
S. Lee: This study was sponsored by Daewoong Pharmaceutical Co., Ltd., Republic of Korea. I am an employee of Daewoong Pharmaceutical Co., Ltd., and report no other conflicts of interest in this work.
A. Lee: This study was sponsored by Daewoong Pharmaceutical Co., Ltd., Republic of Korea. I am an employee of Daewoong Pharmaceutical Co., Ltd., and report no other conflicts of interest in this work.
S.C. Ji: This study was sponsored by Daewoong Pharmaceutical Co., Ltd., Republic of Korea.
I. Jang: This study was sponsored by Daewoong Pharmaceutical Co., Ltd., Republic of Korea.
LB17 DUPILUMAB EFFICACY AND SAFETY IN ADULT PATIENTS WITH ACTIVE EOSINOPHILIC OESOPHAGITIS: A RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2 TRIAL
I. Hirano1, E. S. Dellon2, J. D. Hamilton3, M. H. Collins4, K. Peterson5, M. Chehade6, A.M. Schoepfer7, E. Safroneeva8, M. E. Rothenberg9, G.W. Falk10, Y. Assouline Dayan11, Z. Qing3, B. N. Swanson12, G. Pirozzi12, L. Mannent13, N. M. Graham3, B. Akinlade3, A. Radin3
1Division Of Gastroenterology, Northwestern University, Chicago/United States of America
2University of North Carolina School of Medicine, Chapel Hill/United States of America/NC
3Regeneron Pharmaceuticals, Inc., Tarrytown/United States of America
4Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati/United States of America/OH
5University of Utah School of Medicine, Salt Lake City/United States of America/UT
6Icahn School of Medicine at Mount Sinai, New York/United States of America/NY
7Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne/Switzerland
8University of Bern, Bern/Switzerland
9Cincinnati Children's Hospital Medical Center, Cincinnati/United States of America/OH
10University of Pennsylvania Perelman School of Medicine, Philadelphia/United States of America
11University of Iowa Hospitals and Clinics, Iowa City/United States of America
12Sanofi, Bridgewater/United States of America
13Sanofi, Chilly-Mazarin/France
Contact E-mail Address: Alain.Schoepfer@chuv.ch
Introduction: Patients (pts) with eosinophilic oesophagitis (EO) have high rates of co-morbid type 2-mediated diseases. Due to limited response to standard of care and lack of approved therapies, there is a need for new treatment options for EO. Dupilumab (DPL), a fully human anti-interleukin (IL)-4Rα monoclonal antibody, inhibits signalling of IL-4 and IL-13, key drivers of type 2-mediated inflammation, and is approved in the US for treatment of adults with moderate-to-severe atopic dermatitis. This study assessed efficacy and safety of DPL in adults with moderate-to-severe EO.
Aims & Methods: This double-blind, parallel, placebo (PBO)-controlled phase 2 study (NCT02379052) randomised adults (1:1) with active EO (histologically confirmed with dysphagia symptoms) to receive weekly subcutaneous DPL 300 mg (loading dose 600 mg, Day 1) or PBO for 12 weeks. Primary endpoint was change in Straumann Dysphagia Instrument (SDI) score from baseline (BL) to Week 10. Secondary endpoints included % change in weekly Eosinophilic Esophagitis Activity Index (EEsAI) score from BL to Week 10, % change in overall peak oesophageal intraepithelial eosinophil count (eos/hpf), change in a modified visual endoscopy score (EREFS) from BL to Week 12, and safety. Exploratory endpoints included change in Histological Scoring System (HSS)1 and oesophageal distensibility from BL to Week 12.
Results: 47 pts (DPL n = 23) received ≥1 dose of study drug. BL demographics/characteristics were balanced between groups, except for mean total IgE (DPL 217.8 kU/L; PBO 468.2 kU/L). DPL improved SDI score (−3 vs −1.3; P = 0.0304) and numerically reduced EEsAI score (−34.6% vs −11.3%; P = 0.085) vs PBO at Week 10 (Table). At Week 12, DPL reduced peak eosinophil count (eos/hpf) from BL by −94.1 (−91.8%) vs −7.4 (+15.1%) with PBO (P < 0.0001), and decreased EREFS by −1.9 vs −0.3 with PBO (P = 0.0006). Total HSS grade/stage scores and distensibility plateau were improved at Week 12 (all P < 0.001 vs PBO). Most common treatment-emergent adverse events were injection-site erythema (DPL 34.8%; PBO 8.3%) and nasopharyngitis (DPL 17.4%; PBO 4.2%).
Conclusion: Dupilumab significantly improved dysphagia and histological/endoscopic measures of disease, and was generally well tolerated in adults with EO.
Disclosure of Interest: I. Hirano: Received honoraria as consultant at: Adare Pharmaceuticals, Inc., Receptos Inc./Celgene, Regeneron Pharmaceuticals, Inc., Shire Received research funding from: Meritage, Receptos Inc./Celgene, Regeneron Pharmaceuticals, Inc., Shire
E.S. Dellon: Received honoraria as consultant from: Alivio, Adare Pharmaceuticals, Inc., Banner, Enumeral, GlaxoSmithKline, Receptos Inc./Celgene, Regeneron Pharmaceuticals, Inc., Shire Received research funding from: Meritage, Miraca, Nutricia, Receptos Inc./Celgene, Regeneron Pharmaceuticals, Inc., Shire Received educational grant from: Banner
J.D. Hamilton: Employee and shareholder at Regeneron Pharmaceuticals, Inc.
M.H. Collins: Received honoraria as consultant from: Adare Pharmaceuticals, Inc., Regeneron Pharmaceuticals, Inc., Shire Received research funding from: Receptos Inc./Celgene, Regeneron Pharmaceuticals, Inc., Shire
K. Peterson: Received research funding from: Janssen, Receptos Inc./Celgene, Regeneron Pharmaceuticals, Inc.
M. Chehade: Received honoraria as consultant from: Actelion, Shire Received research funding from: Regeneron Pharmaceuticals Inc., Nutricia, Shire
A.M. Schoepfer: Received honoraria as consultant from: Adare Pharmaceuticals, Inc., Aptalis Pharma, Inc., Dr. Falk Pharma, GmbH Received research funding from: AstraZeneca AG, Aptalis Pharma, Inc., Dr. Falk Pharma, GmbH, GlaxoSmithKline, Nestlé SA, Novartis, Receptos, Inc./Celgene, Regeneron Pharmaceuticals, Inc.
E. Safroneeva: Received honoraria as consultant from: Aptalis Pharma, Inc., Novartis
M.E. Rothenberg: Received honoraria as consultant from: Astra Zeneca, Celgene, GlaxoSmithKline, NKT Therapeutics, Novartis, Pulm One, Shire, Spoon Guru Has equity interest at: Immune Pharmaceuticals, NKT Therapeutics, Pulm One, Spoon Guru Royalties from reslizumab from: Teva Pharmaceuticals Inventor of patents owned by Cincinnati Children's Hospital Medical Center
G.W. Falk: Received honoraria as consultant from: Adare Pharmaceuticals, Inc., Banner Received research funding from: Adare Pharmaceuticals, Inc., Meritage, Receptos Inc./Celgene, Regeneron Pharmaceuticals, Inc., Shire
Z. Qing: Contract statistician at Regeneron Pharmaceuticals, Inc.
B.N. Swanson: Employee, may hold stock and/or stock options in Sanofi
G. Pirozzi: Employee, may hold stock and/or stock options in Sanofi
L. Mannent: Employee, may hold stock and/or stock options in Sanofi
N.M. Graham: Employee, may hold stock and/or stock options in Regeneron Pharmaceuticals Inc.
B. Akinlade: Employee, may hold stock and/or stock options in Regeneron Pharmaceuticals Inc.
A. Radin: Employee, may hold stock and/or stock options in Regeneron Pharmaceuticals Inc.
All other authors have declared no conflicts of interest.
#P = 0.085, *P < 0.05, **P < 0.001 vs PBO. SDI is a 2-item measure of dysphagia; total score range 0−9 (higher scores indicate worse symptoms). EEsAI is a 5-item measure of dysphagia; total score range 0−100 (higher scores indicate worse symptoms). The Histology Scoring System (HSS; Collins et al 2016) measures eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, surface epithelial alteration, dyskeratotic epithelial cells, and dilated intercellular spaces. Oesophageal distensibility plateau was measured using the Functional Lumen Imaging Probe, a probe using impedence planimetry. The continuous efficacy endpoints were analysed in the full analysis set (FAS)
LB18 Increase in plasma interleukin(IL)-2, IL-8, and IL-10 from 2 to 6 hours on oral gluten challenge differentiates between celiac disease (CeD) and non-celiac gluten sensitivity (NCGS) in patients on gluten-free diet (GFD)
K.E.A. Lundin1, V. K. Sarna1, G.I. Skodje1, S. Wang2, L. J. Williams3, J. J. Dzuris4, L. M. Sollid1, R. P. Anderson4
1K G Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo/Norway
2ImmusanT, Cambridge/United States of America/MA
3ImmusanT, Inc., Cambridge/United States of America/MA
Conclusion: In CeD there is response to gluten with concomitant villous blunting, HLA-DQ:gluten tetramer+ T cells and both “adaptive” and “innate cytokines”. Increase in IL-2, IL-8 and IL-10 after oral gluten challenge is specific for CeD, but IL-2 is most sensitive. In NCGS there is no response to gluten when this is devoid of FODMAP, but there is response to FODMAP. Measurement of circulating cytokines may assist in differentiating between CeD and NCGS and may be developed as a clinical tool to distinguish the two clinical entities.
Results: The müsli bars containing gluten induced mucosal changes in 5 of 19 treated CeD patients and mobilized HLA-DQ:gluten tetramer positive T cells in 12 of 15 evaluated patients. In the non-coeliac “gluten sensitive” patients, there were no signs of symptomatic response to the gluten bars versus placebo bars. The symptom scores after FODMAP (fructan) müsli bars were significantly higher than gluten score for overall GSRS-IBS (p < 0.05) and GSRS bloating (p = 0.0003). IL-2 fold changes from pre-challenge were significantly increased in CeD compared to NCGS after gluten challenge at 2 hours (CeD median: 1.2, 25th–75th percentiles 1.0–2.6; NCGS: 1.0, 0.94–1.0; Mann Whitney U test p = 0.0012), 4 hours (CeD: 10.0, 2.0–25.6; NCGS: 1.0, 0.94–1.0; p < 0.0001) and 6 hours (CeD: 3.6, 1.7–18.6; NCDS: 1.0, 0.96–1.1; p < 0.001). Elevations in IL-8 and IL-10 were also significantly increased in CeD compared to NCGS at 4 hours and 6 hours (p < 0.0001), but median elevations were between 1.2 to 1.8-fold. Sensitivity and specificity with optimized cutoffs for IL-2 were 74% and 98%, respectively, for IL-8 were 42% and 100%, and IL-10 were 32% and 100%. Average IL-2 fold change in CeD at 2 to 6 hours was correlated with baseline frequency of gluten-specific cells in HLA-DQ2.5+ subjects (n = 16; p = 0.0028, r = 0.70), and overall discomfort at 6 hours (n = 19; p = 0.0446, r = 0.49).
Aims & Methods: We wanted to evaluate IL-2, IL-8 and IL-10 in plasma after gluten ingestion in CeD and NCGS subjects on GFD using highly sensitive assays. Plasma had been collected before, and 2, 4 and 6 hours after participants with CeD (n = 19) or NCGS (n = 49) on GFD initially consumed gluten (5.7 grams) in one of two studies (Sarna et al., Gut 2017; and Skodje et al., submitted). Plasma cytokines were measured by Mesoscale V-plex assays. Symptoms were measured by self-administered visual analog scale. CeD subjects were assessed for serology, duodenal histology, and frequency of gluten-specific T cells in blood using HLA-DQ:gluten tetramers.
Introduction: Gluten challenge elevates circulating cytokines in CeD patients on GFD, and it is unclear if cytokine responses could differentiate between CeD and NCGS subjects adhering to GFD. We therefore performed parallel challenges of treated CeD patients and non-coeliac, but “gluten-sensitive” individuals, who also were on a gluten-free diet. The “gluten-sensitive” individuals were challenged with placebo müsli bars, with FODMAP bars and with gluten (without FODMAP) bars.
Disclosure of Interest: K.E..A. Lundin: Member of Clinical Advisory Board of ImmusanT (Boston, USA) and funded by Stiftelsen KG Jebsen.
V.K. Sarna: Funded by Stiftelsen KG Jebsen.
G.I. Skodje: Funded by Stiftelsen KG Jebsen.
S. Wang: Employee of ImmusanT
L.J. Williams: Employee of ImmusanT
J.J. Dzuris: Employee of ImmusanT.
L.M. Sollid: Member of scientific advisory board of ImmusanT, funded by Stiftelsen KG Jebsen.
R.P. Anderson: Employee of ImmusanT.
Reference
Sarna, V.K., et al., HLA-DQ:gluten tetramer test in blood gives better detection of coeliac patients than biopsy after 14-day gluten challenge. Gut, 2017.
Treatment Outcomes
Outcome
Treatment-Naive n = 21
Prior Ablation n = 19
p value
BE < 8 cm n = 34
BE > =8 cm n = 6
p value
All N = 40
CR-CA n = 4
67%
100%
.75
100%
0
.25
75%
CR-HGD n = 23
100%
92%
1.0
100%
0
0.04
95%
CR-LGD n = 13
100%
100%
1.0
100%
100%
1.0
100%
CR-dysplasia n = 40
95%
95%
.49
100%
67%
0.02
95%
CR-IM n = 40
86%
89%
1.0
88%
83%
1.0
88%
LB19 Multifocal Nitrous Oxide Cryoballoon Ablation With or Without EMR for Treatment of Neoplastic Barrett’s Esophagus Final Results of A Prospective Clinical Trial in Treatment-Naïve and Previously Ablated Patients
M.I. Canto1, J.A. Almario2, L. Voltaggio3, E. Montgomery3, N.J. Shaheen4, C. J. Lightdale5
1Gastroenterology, Johns Hopkins Medicine – Gastroenterology, Johns Hopkins Medicine; Baltimore, MD/US, Baltimore, MD/United States of America
2Gastroenterology, Johns Hopkins Medicine – Gastroenterology, Johns Hopkins Medicine; Baltimore, MD/US, Baltimore/United States of America/MD
3Pathology, Johns Hopkins Medical Institutions, Baltimore/United States of America/MD
4Center For Esophageal Diseases Abd Swallowing, University of North Carolina School of Medicine, Chapel Hill/United States of America/NC
5Digestive And Liver Disease, Columbia University Medical Center, New York/United States of America/NY
Contact E-mail Address: mcanto@jhmi.edu
Introduction: Endoscopic cryotherapy can eradicate neoplastic BE with low pain, stricture, and bleeding rates1-4. A new portable battery-powered system (cryoballoon focal ablation system (CbFAS)) freezes esophageal mucosa with nitrous oxide5-6. This is the first clinical trial evaluating the safety and efficacy of the CbFAS for curative treatment of Barrett's neoplasia.
Aims & Methods: AIM: To determine the safety and efficacy of nitrous oxide cryoballoon ablation for eradication of neoplastic Barrett's esophagus. METHODS: In a multicenter, prospective single-arm clinical trial, consecutive BE patients with confirmed neoplasia (LGD, HGD, and/or T1aECA) without prior ablation therapy (“treatment-naïve”) or persistent/recurrent disease despite prior ablative therapies (“previously ablated”) were treated with a cryogen dose of 10 seconds per site (video). EMR was performed for lesions at least 8 weeks prior to cryoablation. Patients were included if there was biopsy-proven neoplastic BE > 1 cm, with no upper limit on length. Patients were excluded if they had an esophageal mass, advanced or metastatic cancer, prior esophageal resection, esophageal varices, or uncontrolled coagulopathy. Treatments were repeated every 10-12 weeks until complete eradication, maximum of 5. Primary outcomes were complete eradication of all dysplasia (CR-D) and intestinal metaplasia (CR-IM) at 1 year (intention-to-treat analysis). Patients who were treated with alternative therapies (ablation or surgery) or developed more advanced neoplasia grade were considered failures.
Results: 42 consecutive patients were enrolled, 2 excluded (no dysplasia on review). 40 patients (21 treatment-naïve, 19 previously ablated, were treated. Mean Prague C 1.7 cm, mean Prague M 4.1 cm, with low grade dysplasia (LGD n = 13), high grade dysplasia (HGD n = 23) or ImCA(n = 4). 34(85%) had a maximum BE length <8 cm, 6(15%) with ≥8 cm. All but 1 of 114 procedures were successful. Median procedure time was 32 minutes (IQ range 24-35). Mean number of ablation procedures for all patients was 2.8, range 1-5. Overall, 1 year CR-D and CR-IM rates were 95% and 88%, respectively, with no significant difference in those with or without prior ablation. CR-D rate was significantly lower (67%) in those with ultra-long BE >8 cm compared to those with <8 cm (100%, p = 0.02). One patient in the former group had a 3 mm residual ImCA in a stricture and opted for surgery, while another with BE HGD in post RFA stricture had rescue APC. Median immediate post-ablation pain score (Likert scale 1–10) was 1 (IQR 0–2.5) but rapidly decreased to 0 by 24 hours (IQR 0–2). Two (5%) patients required narcotics for post-ablation pain after day 1. 4 patients (10%) developed mild Grade 1–2 dysphagia from inflammatory stenosis requiring dilation. One patient on aspirin developed upper GI bleeding 2 weeks after treatment, not requiring therapy.
Conclusion: Multifocal nitrous oxide cryotherapy using a CbFAS is a promising, highly effective, and safe endoscopic treatment for primary or rescue therapy of BE-associated neoplasia. Device improvements are ongoing and larger multicenter comparative clinical trials are planned to assess long-term safety and efficacy.
Disclosure of Interest: M.I. Canto: Research grant for investigator-initiated clinical trial, C2 Therapeutics, Redwood City, California, USA
N.J. Shaheen: Research grant and consulting, C2 Therapeutics, Redwood City, California Research grant, consulting, advisory committee, CSA Medical, Grant, Barrx Medical-Covidien
C.J. Lightdale: Research grant and consulting, C2 Therapeutics, Redwood City, California
All other authors have declared no conflicts of interest.
References
1. Canto MI, Shin EJ, Khashab MA, et al. Safety and efficacy of carbon dioxide cryotherapy for treatment of neoplastic Barrett's esophagus. Endoscopy 2015;47:582–91
2. Gosain S, Mercer K, Twaddell WS, et al. Liquid nitrogen spray cryotherapy in Barrett's esophagus with high-grade dysplasia: long-term results. Gastrointest Endosc 2013;78:260–5.
3. Ghorbani S, Tsai FC, Greenwald BD, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett's dysplasia: results of the National Cryospray Registry. Dis Esophagus 20152.
4. Shaheen NJ, Greenwald BD, Peery AF, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc 2010;71:680–5.
5. Friedland S, Triadafilopoulos G. A novel device for ablation of abnormal esophageal mucosa (with video). Gastrointest Endosc 2011;74:182–8.
6. Scholvinck DW, Kunzli HT, Kestens C, et al. Treatment of Barrett's esophagus with a novel focal cryoablation device: a safety and feasibility study. Endoscopy 2015;47:1106–12.
LB20 Minimally Invasive versus Open Distal Pancreatectomy (LEOPARD): Multicenter Patient-Blinded Randomized Controlled Trial
T. De Rooij1, J. Van Hilst1, H.C. Van Santvoort2, P. B. Van Den Boezem3, F. Daams4, R. M. Van Dam5, C. H. Dejong5, M.G. w. Dijkgraaf6, E. B. Van Duyn7, C.H. j. Van Eijck8, S. Festen9, M.F. Gerhards9, B. Groot Koerkamp10, C. J. h.m. Van Laarhoven11, I. De Hingh12, G. Kazemier4, J. Klaase7, R. H. j. De Kleine13, M. Luyer14, G. Patijn15, P. Steenvoorde7, M. Suker16, M. Abu Hilal17, O.R. c. Busch1, M.G. h. Besselink1
1Surgery, Academic Medical Center, Amsterdam/Netherlands
2Surgery, St Antonius Hospital, Nieuwegein/Netherlands
3Surgery, Radboud University Nijmegen Medical Center, Nijmegen/Netherlands
4Surgery, VU University Medical Center, Amsterdam/Netherlands
5Surgery, Maastricht University Medical Center, Maastricht/Netherlands
6Clinical Research Unit, Academic Medical Center, Amsterdam/Netherlands
13Department Of Hepato-pancreatico-biliary Surgery And Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen/Netherlands
14Surgery, Catharina Hospital, Eindhoven/Netherlands
17Surgery, Southampton University Hospital NHS Foundation Trust, Southampton/United Kingdom
Contact E-mail Address: j.vanhilst@amc.nl
Introduction: Minimally invasive distal pancreatectomy (MIDP) is gaining popularity as observational studies suggest superior outcomes compared with open distal pancreatectomy (ODP). Randomized studies are, however, lacking.1
Aims & Methods: We aimed to assess whether MIDP reduces the time to functional recovery, as compared to ODP. In this multicenter randomized controlled trial, we assigned adult patients with tumors confined to the left-sided pancreas to MIDP or ODP by trained surgeons2 in 17 Dutch centers. Patients were blinded for 5 days with a large abdominal dressing and treated according to an enhanced recovery pathway. Primary endpoint was postoperative time to functional recovery (defined as: independently mobile, pain control with oral medication alone, maintaining >50% daily required intake, no intravenous fluids, and no infection). Follow-up was until 90 days postoperatively. Analyses were according to intention-to-treat.3
Results: A total of 108 patients were enrolled, 51 were assigned to MIDP and 57 to ODP. Time to functional recovery was 4 days (IQR 3–6) with MIDP vs. 6 days (IQR 5–8) with ODP (P < 0.001). MIDP was associated with an improvement of each individual component of the primary endpoint as well as length of hospital stay (6 vs. 8 days, P < 0.001). For MIDP, 10% was robot-assisted and 8% converted to ODP. Operative blood loss was less after MIDP (150 (IQR 50–350) vs. 400 (IQR 200–775) mL, P < 0.001), whereas operative time was longer (217 (IQR 135–277) vs. 179 (IQR 129–231) min, P = 0.005). For both groups, drain amylase/lipase level on postoperative day 3 was more than 3 times the upper limit of the normal serum amylase/lipase level in 55% of patients. Grade B/C postoperative pancreatic fistula was seen in 37% vs. 21% of patients (P = 0.06), without difference in radiological drainage (22% vs. 20%, P = 0.73) and re-operation (2% vs. 5%, P = 0.62). Grade B/C delayed gastric emptying was seen less frequently after MIDP (4% vs. 20% (P = 0.01). Clavien-Dindo grade ≥3 complications were seen in 25% vs. 38% (P = 0.21) and mortality in 0% vs. 2% (P > 0.99), for MIDP and ODP respectively.
Conclusion: Patients recover faster after MIDP, as compared to ODP. MIDP reduced operative blood loss, delayed gastric emptying and hospital stay. Clavien-Dindo grade ≥3 complications and mortality were comparable.
Disclosure of Interest: All authors have declared no conflicts of interest.
References
1. Røsok B et al. Minimally Invasive Distal Pancreatectomy. HPB (Oxford). 2017;19(3):205–14.
2. De Rooij T et al. Impact of a Nationwide Training Program in Minimally Invasive Distal Pancreatectomy (LAELAPS). Ann Surg. 2016;264(5):754–62.
3. De Rooij T et al. Minimally invasive versus open distal pancreatectomy (LEOPARD): study protocol for a randomized controlled trial. Trials. 2017;18(1):166.
LB21 Per oral endoscopic pyloromyotomy (POP) is efficious and safe for refractory gastroparesis: the first prospective study (GASTRO-POP- NCT02779920)
J. Jacques1, L. Pagnon2, F. Hure3, R. Legros4, A. Fauchais5, S. Palat5, P. Ducrotté6, B. Marin3, S. Fontaine7, N.E. Boubaddi8, M. Clement9, D. Sautereau1, V. Loustaud-Ratti2, G. Gourcerol10, J. Monteil11
6Service D´hépato-gastroentérologie, Hôpital Charles Nicolle, Rouen/France
7Endocrinology And Diabetology Unit, CHU Rangueil Toulouse, Toulouse/France
8Gastroenterology, CH Brive, Brive la gaillarde/France
9Endocrinology And Diabetology Unit, CHU Limoges, Limoges/France
10Dept. Of Digestive Physiology, CHU Rouen Hopital C. Nicolle, Rouen Cedex/France
11Nuclear Medicine, CHU Limoges, Limoges/France
Contact E-mail Address: jeremiejacques@gmail.com
Introduction: Gastroparesis is a functionnal disorder defined by delayed gastric emptying without mechanical obstruction and cardinal symptoms (nausea, vomiting, early satiety). It’s prevalence is high around 3% in USA. Treatment of gastroparesis is based on specific diet (frequent small meals with low fat and low fiber) and prokinetics drugs. However these drugs are concerned by a lot of cardiac side effect, and a lot of patients escape because of a tachyphylaxy effect. In case of failure of these treatments, there is no validated therapeutic alternative. POP has recently been reported in retrospective series1–5 as a promising endoscopic procedure to treat refractory gastroparetic patients. We report the first prospective study evaluating feasibility, safety and efficacy of POP for refractory gastroparetic patients.
Aims & Methods: 20 refractory gastroparetic patients (10 diabetic and 10 non-diabetic) has been prospectively included in this pilot trial (NCT02779920). They were treated by POP after measurement of pyloric dysfunction using Endoflip. Clinical response was evaluated by GCSI, quality of life by Pagy-Qol and GIQLI scores, at 1 and 3 months. Evolution of gastric emptying was analysed thanks to a 4 hours gastric scintigraphy at 3 months according to recommendations of American society of nuclear medicine. All procedures were performed by two operators with large expertise in Endoscopic submucosal dissection.
Results: Feasibility was 100%. Median duration of procedure was 56.5 min (48.5–67.0). No severe adverse events linked to the procedure were recorded. POP significatively improved symptoms (Figure 1) (GCSI:1,3 vs 3,5 p < 0,0001), improve quality of life(PAGY-QoL: 4,1 vs 3 p < 0,0001; GIQLI: 97 vs 63 p < 0,001) and gastric emptying (Figure 2) (T1/2:100 min vs 345 min p = 0,0007; %H2: 56% vs 81,5% p < 0,001; %H4 15% vs 57,5% p = 0,0025) at 3 months. All individual cardinal symptoms were significatively improved by POP (Figure 3). A threshold of distensibility at 9.2 mm2/mmHg with a 50 cc inflated Endoflip predict clinical success of POP with a specifity of 100%, a sensibility of 72.2% (p = 0,04; IC 95%:0,509-0,935; AUC:0,722).
Conclusion: Discussion: POP is feasible and safe when perfomed by operators with expertise in ESD. POP clearly accelerates gastric-emptying. It seems to improved symptoms and quality of life of severe refractory gastroparesis patients but prospective blinded randomized trial is needed for this subjective endpoint. Pyloric function evaluation by Endoflip seems to be very promising to best identify gastroparetics patients in which pylorospasm is involved(Distensibility <9,2 mm2/mmHg). Conclusion: We confirm in this first prospective study feasibility, safety and efficiency of POP for severe refractory gastroparesis. POP accelerate gastric emptying in gastroparetic patients and improve all individual cardinal symptoms at 3 months in particular in patients with a low pyloric ditensibility measured by Endoflip. A long term follow-up, blinded randomized trial, and large multicentre cohorts using validated tools to evaluate function are urgently needed to confirm these promising results and to best identify the adequate place of POP in the armamentarium of therapeutic procedures for refractory gastroparesis.
Disclosure of Interest: All authors have declared no conflicts of interest.
References
1. Shlomovitz E, et al. Early human experience with per-oral endoscopic pyloromyotomy (POP). Surg Endosc 2015;29(3):543–51.
2. Khashab MA, et al. Gastric per-oral endoscopic myotomy for refractory gastroparesis: results from the first multicenter study on endoscopic pyloromyotomy (with video). Gastrointest Endosc 2017;85(1):123–8.
3. Gonzalez J-M, et al. Gastric per-oral endoscopic myotomy with antropyloromyotomy in the treatment of refractory gastroparesis: clinical experience with follow-up and scintigraphic evaluation (with video). Gastrointest Endosc 2017;85(1):132–9.
4. Xue HB et al. Fluoroscopy-guided gastric peroral endoscopic pyloromyotomy (G-POEM): a more reliable and efficient method for treatment of refractory gastroparesis. Surg Endosc 2017 Apr 13.[Epub ahead of print]
5. Rodriguez JH et al. Per oral endoscopic pyloromyotomy for refractory gastroparesis: initial results from a single institution. Surg Endosc 2017 May 31. [Epub ahead of print]
