LB01 SAFETY AND EFFICACY OF USTEKINUMAB INDUCTION THERAPY IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 3 UNIFI STUDY
B.E. Sands1, W.J. Sandborn2, R. Panaccione3, C. O'Brien4, H. Zhang4, J. Johanns4, L. Peyrin-Biroulet5, G. van Assche6, S. Danese7, S. Targan8, M.T. Abreu9, T. Hisamatsu10, P. Szapary4, C.W. Marano4
1Icahn School of Medicine at Mount Sinai, New York, United States
2University of California San Diego, La Jolla, United States
3University of Calgary, Calgary, Canada
4Janssen Research & Development, LLC, Spring House, United States
5Nancy University Hospital, Department of Gastroenterology, Vandoeuvre les Nancy, France
6University of Leuven, Louvain, Belgium
7Humanitas Research Hospital, Inflammatory Bowel Diseases Center, Milano, Italy
8Cedars Sinai Medical Center, Los Angeles, United States
9University of Miami Miller School of Medicine, Miami, United States
10Kyorin University, Tokyo, Japan
Contact E-Mail Address:bruce.sands@mssm.edu
Introduction: The purpose of this study was to evaluate the safety and efficacy of intravenous (IV) ustekinumab (UST) induction therapy in patients with moderately to severely active ulcerative colitis (UC) who demonstrated an inadequate response to or were unable to tolerate conventional (ie, corticosteroids, immunomodulators) or biologic therapies (ie, 1 or more TNF blockers or vedolizumab).
Aims and Methods: UNIFI was a Phase 3 randomized, double-blind, placebo-controlled study in which patients were randomized 1:1:1 at Week (Wk) 0 to receive a single IV induction dose of UST 130 mg or a dose approximating UST 6 mg/kg [∼6 mg/kg]: 260 mg [weight ≤55 kg], 390 mg [weight >55 kg and ≤85 kg], or 520 mg [weight >85 kg]) or placebo (PBO). At Wk 8, patients were evaluated for clinical remission, endoscopic healing, clinical response, change from baseline in the IBDQ score, and mucosal healing (an endpoint that includes both endoscopic healing and histologic healing).
Results: Nine hundred sixty-one patients, of which about 50% had failed biologic therapy and 16.6% had failed both anti-TNF and vedolizumab, were randomized to treatment in the primary analysis population; 941 patients (98%) completed through Wk 8. Baseline demographics, UC disease characteristics and concomitant UC medications were generally similar among treatment groups. Significantly (p < 0.001) higher proportions of patients receiving UST IV 130 mg and ∼6 mg/kg achieved clinical remission, endoscopic healing, clinical response, and mucosal healing at Wk 8 and significant improvement from baseline in IBDQ was achieved (Table 1) compared to PBO. Significant (p < 0.05) decreases in median levels of fecal biomarkers (calprotectin and lactoferrin) were also observed at Wk 8. Similar proportions of patients reported adverse events (41.4%, 50.0%, and 48.0%), serious adverse events (3.7%, 3.1%, and 6.6%), infections (15.9%, 15.3%, and 15.0%) and serious infections (0.6%, 0.3%, and 1.3%) in the UST IV 130 mg, ∼6 mg/kg and PBO groups, respectively. No malignancies, opportunistic infections or tuberculosis were reported through Wk 8. One death from esophageal varices hemorrhage was reported for a patient with no known history of cirrhosis in the UST ∼6 mg/kg group prior to Wk 8.
Conclusion: A single IV dose of UST resulted in significant improvements in clinical, endoscopic and health-related quality of life outcomes at Wk 8 compared to PBO in patients with moderate-severe UC who had previously failed conventional or biologic therapy. The therapy was well tolerated through induction.
PBO IV
UST IV 130 mg
UST IV ∼ 6 mg/kg
Number of randomized patients
319
320
322
Patients in clinical remissiona (%)
17 (5.3%)
50 (15.6%)*
50 (15.5%)*
Patients with endoscopic healingb (%)
44 (13.8%)
84 (26.3%)*
87 (27.0%)*
Patients in clinical responsec (%)
100 (31.3%)
164 (51.3%)*
199 (61.8%)*
Change from baseline in IBDQ: N, Median (IQ range)
317, 10.0 (−2.0; 34.0)
316, 31.5 (7.5; 53.5)*
321, 31.0 (11.0; 56.0)*
Mucosal healingd: N, Patients with mucosal healing (%)
316, 28 (8.9%)
316, 64 (20.3%)*
315, 58 (18.4%)*
aA Mayo score ≤2 points, with no individual subscore >1. bMayo endoscopy subscore of 0 or 1. cA decrease from induction baseline in the Mayo score by ≥30% and ≥3 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. dCombined endoscopic healing (Mayo endoscopy subscore of 0 or 1) and histologic healing (defined as 0-<5% neutrophils in epithelium, no crypt destruction, and no erosions or ulcerations or granulations). *p < 0.001
[Primary and other multiplicity-controlled endpoints at Week 8]
Disclosure: This study was supported by Janssen Research & Development, LLC
LB02 PTG-100, AN ORAL GUT-RESTRICTED PEPTIDE α4β7 ANTAGONIST, INDUCES CLINICAL AND HISTOLOGIC REMISSION IN PATIENTS WITH MODERATE TO SEVERELY ACTIVE ULCERATIVE COLITIS
W.J. Sandborn1, B. Bressler2, S. Lee3, R. Bhandari4, B. Kanwar5, L. Tozzi5, R. Shames5, G. D'Haens6, J.-F. Colombel7, S. Schreiber8, S. Danese9, R.K. Pai10, B.G. Feagan11
1University of California – San Diego, La Jolla, California, United States
2University of British Columbia, Vancouver, Canada
3University of Washington Dept. of Gastroenterology, Seattle, United States
4Delta Research Partners, Monroe, United States
5Protagonist Therapeutics, Newark, United States
6AMC Amsterdam Inflammatory Bowel Disease Centre – Academic Medical Center, AMC Amsterdam Inflammator, Academic Medical Center, Amsterdam, Netherlands
7Icahn School of Medicine at Mount Sinai, Gastroenterology, USA, United States
8Universität Kiel UKSH Medizinische Abt. I – UKSH, Universität Kiel UKSH Medizinische Abt. I; Kiel/DE, UKSH, Kiel, Germany
9Humanitas Research Hospital, Inflammatory Bowel Diseases Center, Rozzano, Italy
Introduction: PTG-100 is an oral, gut-restricted peptide antagonist of the α4β7 integrin. We conducted a Phase 2b randomized, double-blind, placebo-controlled induction study of PTG-100 in patients with moderate to severely active ulcerative colitis which planned to enroll up to 240 patients. A pre-specified futility assessment was conducted by an independent DMC after the first 65 patients were randomized and completed treatment on one of three active arms (150 mg, 300 mg, 900 mg once daily) or placebo followed by 12 weeks of treatment. Futility was based on rates of clinical remission (Mayo endoscopic subscore of 0/1, rectal bleeding subscore of 0, and stool frequency subscore of 0/1 with at least a 1-point reduction from baseline) at week 12. The trial was determined by the DMC to be futile due to an abnormally high placebo remission rate (4/17 = 24%). A systematic error was noted on central read endoscopy, and the entire data set (n = 83) was re-read by an independent CRO, Robarts Clinical Trials, to determine if further development of PTG-100 is warranted.
Aims and Methods: Robarts re-read all endoscopies in a blinded manner with a single reader paradigm using 2 readers with a high inter-reader correlation coefficient (κ = 0.92). Baseline and week 12 biopsies were also centrally read in a blinded manner to determine rates of histologic remission as defined by the Robarts histopathologic index (RHI) overall score ≤ 3 amongst patients who had a baseline score > 3.
Results: PTG-100 exhibited a dose-dependent increase in clinical remission, endoscopic response, and histologic remission with maximal efficacy at the 900 mg dose (See Table). Given the course of events, these efficacy results will ultimately require confirmation in subsequent trials. PTG-100 was well tolerated, with low rates of adverse events, serious adverse events, and discontinuations.
Conclusion:
Clinical Remission
Endoscopic Response
Histologic Remission
PTG-100 (150 mg QD)
2/22 (9.1%)
2/22 (9.1%)
2/13 (15%)
PTG-100 (300 mg QD)
2/21 (9.5%)
3/21 (14.3%)
2/9 (22%)
PTG-100 (900 mg QD)
3/19 (15.8%)
3/19 (15.8%)
7/16 (44%)
Placebo
1/21 (4.8%)
1/21 (4.8%)
0/13 (0%)
[Results of Efficacy]
1. An oral gut-restricted approach to α4β7 integrin antagonism may be effective in ulcerative colitis.
2. Histologic remission (e.g., mucosal healing) was achieved in a dose dependent manner with PTG-100.
3. These data support future development and PTG-100 is expected to advance to a larger induction and maintenance study in ulcerative colitis.
Disclosure: Nothing to disclose
LB03 EFFICACY AND SAFETY OF A NEW VEDOLIZUMAB SUBCUTANEOUS FORMULATION FOR ULCERATIVE COLITIS: RESULTS OF THE VISIBLE 1 PHASE 3 TRIAL
W.J. Sandborn1, F. Baert2, S. Danese3, Ž. Krznarić4, G. D'haens5, T. Kobayashi6, X. Yao7, J. Chen7, K. Kisfalvi7, S. Vermeire8
1University of California San Diego, Division of Gastroenterology, La Jolla, United States
2University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium
4Clinical Hospital Centre Zagreb, Division of Gastroenterology and Hepatology, Zagreb, Croatia
5Academic Medical Centre, Dept. of Gastroenterology, Amsterdam, Netherlands
6Kitasato University Kitasato Institute Hospital, Center for Advanced IBD Research and Treatment, Tokyo, Japan
7Takeda Development Center Americas Inc., Cambridge, United States
8University Hospitals Leuven, Department of Clinical and Experimental Medicine, Leuven, Belgium
Contact E-Mail Address:wsandborn@ucsd.edu
Introduction: Vedolizumab, a gut-selective, humanised, monoclonal α4β7 integrin antibody, is available as an intravenous (IV) formulation to adult patients (pts) with moderately to severely active ulcerative colitis (UC) or Crohn's disease. We present the first phase 3 results on a new subcutaneous (SC) formulation for maintenance treatment in UC.
Aims and Methods: A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial (VISIBLE 1; NCT02611830; EudraCT 2015-000480-14) assessed vedolizumab SC as maintenance treatment in adult pts with active UC. An open-label induction with vedolizumab IV (300 mg) was administered at Weeks (Wks) 0 and 2, with disease evaluation at Wk 6. Pts with a clinical response at Wk 6 (complete Mayo score reduction of ≥3 points and ≥30% from Baseline [Wk 0] plus reduction in rectal bleeding subscore of ≥1 point or absolute subscore of ≤1 point) were randomised (2:1:1) to receive vedolizumab SC (108 mg every 2 wks), or vedolizumab IV (300 mg every 8 wks), or placebo for up to 52 wks. The primary objective was to assess clinical remission (defined as complete Mayo score of ≤2 points and no individual subscore >1 point) with vedolizumab SC vs placebo at Wk 52. Between-group treatment effects were compared using the Cochran-Mantel-Haenszel test with stratification by study randomisation factors (concomitant corticosteroid use, Wk 6 remission status, and prior anti-tumour necrosis factor alpha [anti-TNFα] failure or immunomodulator use).
Results: A total of 383 pts received open-label vedolizumab IV induction. Of those, 216 (56.4%) experienced clinical response at Wk 6 and entered the maintenance phase. At Wk 52, 46.2% of pts on vedolizumab SC vs 14.3% on placebo were in clinical remission (p < 0.001) (Table 1). Similarly, 42.6% of vedolizumab IV pts were in clinical remission at Wk 52. Further, vedolizumab SC was significantly superior to placebo for the key secondary endpoints mucosal healing and durable clinical response (both p < 0.001; Table 1). The efficacy results on vedolizumab SC were consistent with those on vedolizumab IV. Subgroup analysis showed clinical remission rates were significantly higher with vedolizumab SC vs placebo in both anti-TNFα-naïve pts (vedolizumab 53.7% vs placebo 18.9%, p < 0.001) and anti-TNFα-failure pts (vedolizumab 33.3% vs placebo 5.3%, p = 0.023). Injection-site reactions were mild (9.4% in vedolizumab SC vs 0 in placebo pts), none leading to discontinuation. Adverse event rates, including severe adverse events and infections, were similar in the vedolizumab SC and IV groups. The rate of anti-vedolizumab antibodies (AVAs) in the vedolizumab SC group was 5.7% (consistent with 5.6% for vedolizumab IV).
Primary and Secondary Outcomes, Week 52, Maintenance-Phase ITT Population (N = 216)
52-Week Endpoint
PBOa,b (n = 56)
VDZ SC (108 mg) Q2Wa,c (n = 106)
VDZ IV (300 mg) Q8Wa,d (n = 54)
VDZ SC vs PBO P Value
Primary Endpoint: Clinical remission, % (95% CI)e
14.3 (6.4–26.2)
46.2 (36.5–56.2)
42.6 (29.2–56.8)
<0.001
Secondary Endpoints: Mucosal healing, % (95% CI)f
21.4 (11.6–34.4)
56.6 (46.6–66.2)
53.7 (39.6–67.4)
<0.001
Durable clinical response, % (95% CI)g
28.6 (17.3–42.2)
64.2 (54.3–73.2)
72.2 (58.4–83.5)
<0.001
Durable clinical remission, % (95% CI)h
5.4 (1.1–14.9)
15.1 (8.9–23.4)
16.7 (7.9–29.3)
0.076
Corticosteroid-free remission, % (95% CI)i
8.3 (1.0–27.0)
28.9 (16.4–44.3)
28.6 (11.3–52.2)
0.067
CI, confidence interval; ITT, intent-to-treat; IV, intravenous; PBO, placebo; Q2W, every 2 weeks; Q8W, every 8 weeks; SC, subcutaneous; VDZ, vedolizumab.
All patients received open-label VDZ IV induction treatment (300 mg VDZ IV at Week 0 and Week 2). Patients who achieved clinical response were randomised into treatments for the maintenance phase.
Clinical response was defined as a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
Statistical significance was calculated only between placebo and VDZ SC arms.
aMaintenance treatment was initiated at Week 6 after the open-label induction phase. The last IV injection (VDZ or PBO) was administered at Week 46, and the last SC injection (VDZ or PBO) was administered at Week 50.
bPBO IV Q8W and PBO SC Q2W.
cVDZ SC Q2W and PBO IV Q8W.
dVDZ IV Q8W and PBO SC Q2W.
eClinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point.
fMucosal healing is defined as Mayo endoscopic subscore of ≤1 point.
gDurable clinical response is defined as clinical response at Weeks 6 and 52.
hDurable clinical remission is defined as clinical remission at Weeks 6 and 52.
iCorticosteroid-free remission is defined as patients using oral corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52. PBO: n = 24, VDZ SC: n = 45, VDZ IV: n = 21.
Conclusion: Vedolizumab SC 108 mg every 2 wks was efficacious, generally safe and well-tolerated as maintenance therapy in UC pts following induction with vedolizumab IV 300 mg. The new SC formulation of vedolizumab showed an efficacy and safety profile similar to that of the currently available IV formulation and consistent with that previously reported for vedolizumab IV.1
FeaganBG, et al.Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med2013; 369(8): 699–710.
LB04 PREDICTING CLINICAL RESPONSE TO VEDOLIZUMAB THERAPY IN CROHN'S DISEASE WITH MUCOSAL BIOMARKER OF INNATE IMMUNE ACTIVATION
M. Osterman1, I. Gordon2, M. Ciorba3, S.C. Glover4, B.P. Abraham5, E. Davis6, F. Khan7, K. Young6, X. Guo8, E. Yee9, F. Allard9, B. Claggett10, B. Shen7, J. Liu6
1University of Pennsylvania, Medicine, Philadelphia, United States
2Cleveland Clinic Foundation, Pathology, Cleveland, United States
3Washington University School of Medicine, St. Louis, United States
4University of Florida, Medicine, Gainesville, United States
5Baylor College of Medicine, Houston, United States
6University of Arkansas for Medical Sciences, Medicine, Little Rock, United States
7Cleveland Clinic Foundation, Gastroenterology, Cleveland, United States
8Third Affiliated Hospital of Xi'an Jiaotong University, Gastroenterology, Xi'an, China
9University of Arkansas for Medical Sciences, Pathology, Little Rock, United States
10Brigham and Women's Hospital, Harvard Medical School, Cardiovascular Medicine, Cambridge, United States
Contact E-Mail Address:jjliu@uams.edu
Introduction: Mucosal barrier dysfunction to luminal microbes plays a crucial role in the development of intestinal inflammation in Crohn's disease (CD). Recently, intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was proposed as a possible cause of this barrier defect. We hypothesize that small bowel IEC pyroptosis, as a marker of mucosal barrier dysfunction, may have predictive value for clinical response and help to guide the selection of biologic therapy in CD patients. Vedolizumab is an anti-integrin monoclonal antibody approved for treatment of ulcerative colitis and CD.
Aims and Methods: The aim of this multi-centered study was to determine the predictive value of pre-treatment ileal biopsy IEC pyroptosis for clinical response to vedolizumab in CD. CD patients aged 18 to 78 years from five American IBD centers who had pre-vedolizumab ileal biopsies obtained during colonoscopy were enrolled. Clinical response, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from pre-treatment baseline, and clinical remission, defined as HBI < 5, was determined at ≥6 months after therapy by chart review. Biopsy samples were sectioned and stained for IEC pyroptosis using the Maximus Barrier Assay kit (Maximus Diagnostics LLC). Samples with at least 10 intact villi per patient were analyzed by blinded pathologists for quantitation of mucosal innate immune activation. The primary outcome was clinical response rate to vedolizumab stratified by pre-treatment mucosal IEC pyroptosis, using 18 positive cells/1000 IECs as a cut-point. Binary and continuous outcomes were compared using chi-squared and t-tests, respectively.
Results: A total of 78 CD patients were enrolled and 5 were excluded from further analysis due to inadequate intestinal biopsy samples for IEC pyroptosis quantification. In the remaining 73 patients (39 M, 34 F), the median age was 47 (19, 78) years; 43 (59%) had clinical response to vedolizumab therapy, and 25 (34%) were in clinical remission. There were no significant differences in baseline patient characteristics, disease characteristics, previous anti-TNF exposure, and concomitant medication use between responders and non-responders. The clinical response rate in patients with IEC pyroptosis below the critical cut-point of 18 positive cells / 1000 IECs was significantly higher compared to those above: 74% (28/38) vs. 43% (15/35), odds ratio 3.7 (1.4, 10.0), p = 0.009. IEC pyroptosis in responders and non-responders were 16.8 ± 11.8 vs. 24.5 ± 11.6 positive cells / 1000 IECs, respectively (p = 0.007). The probability of response to vedolizumab therapy was inversely related to the level of mucosal IEC pyroptosis, with IEC pyroptosis of >39 positive cells / 1000 IECs associated with a clinical response rate of 17% (1/6), while a level of < 13 positive cells / 1000 IECs was associated with a 90% (18/20) clinical response.
Conclusion: In this multi-centered study, we found that pre-treatment IEC pyroptosis on ileal biopsy was predictive of clinical response to vedolizmab in Crohn´s patients.
Disclosure: Dr. Liu and Dr. Davis are holders of a patent on the method of detecting barrier dysfunction using mucosal innate immune activation in IBD.
LB05 THE INTESTINALLY RESTRICTED, ORALLY ADMINISTERED, PAN-JAK INHIBITOR TD-1473 DEMONSTRATES FAVORABLE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND SIGNAL FOR CLINICAL ACTIVITY IN SUBJECTS WITH MODERATELY-TO-SEVERELY ACTIVE ULCERATIVE COLITIS
W.J. Sandborn1, R. Bhandari2, J. Leighton3, R. Ganeshappa4, D. Nguyen5, B. Ferslew5, A. Olmsted5, R. Graham5, J. Panés6
1University of California San Diego, San Diego, United States
2Delta Research Partners, Monroe, United States
3Mayo Clinic Phoenix, Medicine, Phoenix, United States
4Pinnacle Clinical Research, San Antonio, United States
5Theravance Biopharma, South San Francisco, United States
6Hospital Clínic Barcelona Dept. of Gastroenterology – Dept. of Gastroenterology, Hospital Clínic Bar, Dept. of Gastroenterology, Barcelona, Spain
Contact E-Mail Address:jpanes@clinic.ub.es
Introduction: A need exists for effective and safe oral therapeutic options for moderate to severe ulcerative colitis (UC). TD-1473 is an orally administered and intestinally restricted pan-Janus kinase (JAK) inhibitor that was well tolerated by healthy volunteers when administered up to 300 mg once daily for 14 days with very low systemic exposure.
Aims and Methods: To assess the safety, tolerability, and pharmacokinetics (PK) of TD-1473 in subjects with moderately-to-severely active UC. In this double-blind placebo-controlled multicenter phase 1b study, 40 subjects were enrolled and administered placebo (n = 9), 20 mg (n = 10), 80 mg (n = 10), or 270 mg (n = 11) TD-1473 once daily for 28 days after meeting eligibility criteria (including Mayo rectal bleeding subscore of ≥ 1, stool frequency subscore of ≥ 1, and centrally read endoscopic subscore of ≥ 2). Safety, PK, clinical outcomes, and biomarkers were evaluated.
Results: The mean age was 44 years with 65% of subjects being male and a median disease duration of 3.1 years. The baseline mean total Mayo Score ranged from 8.2 (80 mg) to 9.6 (20 mg), with an overall mean of 8.9. All subjects completed dosing, except for one subject at 20 mg who stopped taking TD-1473 at Day 5 due to lack of efficacy. Two serious treatment-emergent adverse events consisted of hospitalization for UC exacerbation (20 mg and 80 mg). No cases of serious or opportunistic infection or signals for abnormalities in hematologic or chemistry laboratory parameters were observed. Plasma exposures were low and consistent with those observed previously in healthy subjects. Colonic tissue concentrations of TD-1473 were higher than plasma and in the range needed for JAK inhibition. There were trends for higher rates of mucosal healing and improvement by ≥ 1 point in rectal bleeding and endoscopy, relative to placebo. C-reactive protein (CRP) decreased relative to placebo at all dose levels. Fecal calprotectin decreased in subjects treated with 80 mg and 270 mg. High variability was observed for CRP and fecal calprotectin at all dose levels.
Conclusion: TD-1473 was generally well tolerated over 4 weeks with evidence of intestinal restriction, low systemic exposure, and signals for clinical and biomarker activity in subjects with moderately-to-severely active UC.
TD-1473 Dose
Subjects with Improvement in Rectal Bleeding Subscore by ≥ 1 point (n, %)
Subjects with Improvement in Endoscopy Subscore by ≥ 1 point (n, %)
Subjects with Mucosal Healing*
Serum CRP (Placebo Adjusted Change from Baseline; %, 95% CI)
Fecal Calprotectin (Placebo Adjusted Change from Baseline; %, 95% CI)
GI Tissue TD-1473 Concentration** (nM)
Plasma TD-1473 Concentration: Ctrough (nM)
Plasma TD-1473 Concentration: Cmax (nM)
Placebo (n = 9)
4 (44%)
0 (0%)
0 (0%)
NA
NA
NA
NA
NA
20 mg (n = 10)
3 (30%)
2 (20%)
2 (20%)
−61 (−84, −1)
+62 (−76, +987)
10
NC
0.350
80 mg (n = 10)
7 (70%)
3 (30%)
2 (20%)
−57 (−83, +6)
−31 (−89, +344)
162
0.202
5.66
270 mg (n = 11)
8 (73%)
2 (18%)
1 (9%)
−70 (−88, −28)
−26 (−88, +351)
108
1.74
30.1
*: mucosal healing: endoscopic subscore ≤ 1 point **: JAK1-3 and TYK2 T-cell stimulation IC50s 32-158 nM; Beattie DT. TD-1473, a Novel, Potent, and Orally Administered, GI-targeted, Pan-Janus Kinase (JAK) Inhibitor. Poster presented at: The European Crohn's and Colitis Organisation meeting; 16-19 March 2016; Amsterdam, The Netherlands ***: Ctrough and Cmax values provided to indicate range of plasma exposures over 24 hour treatment period NA: not applicable NC: not calculated because concentrations were below limit of detection
[Key Efficacy, biomarker and PK results in subjects with moderately- to severely-active UC after 28 days of treatment with TD-1473 or placebo]
Disclosure: William Sandborn: consulting fees from Abbvie, Akros Pharma, Allergan, Ambrx Inc., Amgen, Ardelyx, Arena Pharmaceuticals, Atlantic Pharmaceuticals, Avaxia, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Conatus, Cosmo Technologies, Escalier Biosciences, Ferring, Ferring Research Institute, Forward Pharma, Galapagos, Genentech, Gilead Sciences, Immune Pharmaceuticals, Index Pharmaceuticals, Janssen, Kyowa Hakko Kirin Pharma, Lilly, Medimmune, Mesoblast, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma, Otsuka, Palatin, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Qu Biologics, Regeneron, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust or HART), Salix, Seattle Genetics, Seres Therapeutics, Shire, Sigmoid Biotechnologies, Takeda, Theradiag, Theravance, Tigenix, Tillotts Pharma, UCB Pharma, Vascular Biogenics, Vivelix; research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, Abbvie, Janssen, Takeda, Lilly, Celgene/Receptos; payments for lectures/speakers bureau from Abbvie, Janssen, Takeda; and holds stock/stock options in Escalier Biosciences, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals. Julian Panes: Consulting fees from Abbvie, Arena, Boehringer Ingelheim, Celgene, GoodGut, GSK, Janssen, MSD, Nestlé, Oppilan, Pfizer, Takeda, Theravance, and TiGenix; unrestricted research grants from Abbvie and MSD. Raj Bhandari: nothing to disclose. Jonathan Leighton: consulting fees from Medtronic; research funds from Pfizer, Shire, and Medtronic. Ravi Ganeshappa: nothing to disclose. Brian Ferslew, Deanna Nguyen, Richard Graham: employees of Theravance Biopharma and stockholders. Ann Olmsted: paid biometrics consultant to Theravance Biopharma and stockholder.
LB06 PHASE III RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, MULTICENTER, PARALLEL GROUP STUDY TO ASSESS THE EFFICACY AND SAFETY OF ADD-ON FIXED-DOSE ANTI-MYCOBACTERIAL THERAPY (RHB-104) IN MODERATELY TO SEVERELY ACTIVE CROHN'S DISEASE (MAP US)
D.Y. Graham1, R. Hardi2, T. Welton3, R. Krause4, S. Levenson5, H. Sarles6, A. Sheikh7, M. Epstein8, G. Duvall9, C. Freedland10, Z. Hebzda11, T. Arlukowicz12, A. Kopon13, G. Rydzewska14, N. Zdravkovic15, P. Svorcan16, E. Zittan17, P. Dugalic18, E. Israeli19, P. Anderson20, C. Fehrmann20, A. Bibliowicz20, P. McLean20, R. Fathi20, I. Kalfus20
1Baylor College of Medicine, Molecular Virology and Microbiology, Houston, United States
2Chevy Chase Clinical Research, Rockville, United States
3Cotton-O'Neil Clinical Research Center, Topeka, United States
4ClinSearch, Chatanooga, United States
5Digestive Care Associates, Inc., San Carlos, United States
6DHAT Research Institute / Digestive Health Associates of Texas, Richardson, United States
7Gastrointestinal Specialists of Georgia PC, Marietta, United States
8Investigative Clinical Research, Annapolis, United States
9Tyler Research Institute, Tyler, United States
10Advanced Research Institute Inc., New Port Richey, United States
11Unicardia, Krakow, Poland
12MEDICUM University of Warmia and Mazury, Olsztyn, Portugal
13Gastromed, Specialized Center of Gastrology and Endoscopy, Torun, Poland
14Gastroenterology Dept, CSK MSWiA Warsaw, Faculty of Medicine and Health Sciences, UJK, Warsaw, Poland
15University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia
16Zvezdara University Medical Center, Clinical Department of Gastroenterology and Hepatology, Belgrade, Serbia
17Emek Medical Center, Ellen and Pinchas Mamber Institute of Gastroenterology and Liver Diseases, and the IBD Unit, Afula, Israel
18Clinical Hospital Center Zemun, Department of Gastroenterology and Hepatology, Belgrade, Serbia
19Hadassah-Hebrew University, Institute of Gastroenterology and Liver Diseases, Jerusalem, Israel
20RedHill Biopharma Ltd., Tel-Aviv, Israel
Contact E-Mail Address:dgraham@bcm.edu
Introduction:Mycobacterium avium subspecies paratuberculosis (MAP), the causative organism for Johne's disease in ruminants is also suspected to cause Crohn's disease (CD). MAP US is the first global, randomized trial to assess the efficacy of anti-MAP therapy in active CD.
Aims and Methods: We investigated the efficacy and safety of add-on fixed-dose combination anti-MAP therapy or placebo in subjects with moderately to severely active CD (CDAI score of ≥ 220 and ≤450 at baseline). Entry was stratified for the use of anti-TNF agents infliximab and adalimumab. RHB-104 consists of fixed dose clarithromycin 95 mg, rifabutin 45 mg and clofazimine 10 mg administered as 5 capsules bid for up to 52 weeks. Primary endpoint was remission at week 26 defined as CDAI less than 150, with key secondary endpoints examining response at week 26 (decrease in CDAI by at least 100 points), early remission at week 16 and remission through week 52. All subjects were required to continue pre-study therapy i.e. 5-ASA, corticosteroids (tapering permitted after week 8), azathioprine, 6-MP, methotrexate, infliximab or adalimumab. 331 subjects were randomized 1:1 at 92 sites across North America, Europe, Australia/New Zealand and Israel.
Results: The proportion of subjects achieving remission at week 26, was significantly greater with standard therapy with the addition of anti-MAP therapy compared to the addition of placebo (37% vs. 23%, p = 0.007). Add on RHB-104 was also more effective than placebo at response at week 26 (44% vs. 31%, p = 0.017), and remission at week 16 (42% vs 29%, p = 0.015). RHB-104 was twice as effective as placebo in durable remission continuously from week 16 through week 52 (18% vs 9%, p = 0.019), as well as in an additional analysis of maintenance of remission at week 52 in subjects in remission at week 16 (25% vs 12%, p = 0.003). Post hoc analysis of week 16 and week 26 remission in the subgroup receiving anti-TNF agents demonstrated a favorable, though underpowered, treatment effect with RHB-104 vs placebo (39% vs 22% at week 16 and 36% vs 17% at week 26). The AE profile, laboratory values, and other safety assessments did not indicate any safety concerns.
Conclusion: The addition of anti-MAP therapy to standard therapy demonstrated a clinically meaningful and statistically significant treatment effect in the protocol defined primary endpoint of remission at week 26 along with secondary endpoints of early remission at week 16, durable remission through week 52 and an additional endpoint of remission at week 16 and week 52. RHB-104 appeared to be efficacious as add-on therapy in CD subjects treated with and without anti-TNF agents. RHB-104 was safe and well tolerated and could provide a new oral antibiotic therapy for use across a broad spectrum of Crohn's disease patients.
Primary and Key Secondary Endpoints
RHB-104 N = 166 (%)
Placebo N = 165 (%)
Treatment Effect
P-value*
Remission at Week 26
61 (37%)
38 (23%)
14%
0.007
Response at Week 26
73 (44%)
51 (31%)
13%
0.017
Early Remission at Week 16
70 (42%)
48 (29%)
13%
0.015
Additional Endpoints
RHB-104** N = 158 (%)
Placebo** N = 161 (%)
Treatment Effect
P-value*
Durable Remission Weeks 16–52
28 (18%)
14 (9%)
9%
0.019
Remission at Weeks 16 and 52
40 (25%)
20 (12%)
13%
0.003
Current Anti-TNF*** Use Subgroup
RHB-104 N = 31 (%)
Placebo N = 36 (%)
Treatment Effect
P-value****
Remission Week 16
12 (39%)
8 (22%)
17%
0.144
Remission Week 26
11 (36%)
6 (17%)
19%
0.080
No Current Anti-TNF*** Use Subgroup
RHB-104 N = 135 (%)
Placebo N = 129 (%)
Treatment Effect
P-value****
Remission Week 16
58 (43%)
40 (31%)
12%
0.045
Remission Week 26 Remission Week 26
50 (37%)
32 (25%)
12%
0.032
[MAP US Efficacy Endpoints]
Disclosure: Dr. Graham is a consultant for RedHill Biopharma regarding novel H. pylori therapies. He has also received research support for culture of H. pylori and is the PI of an international study of antimycobacterial therapy for Crohn's disease. He is also a consultant for BioGiai in relation to probiotic therapy for H. pylori infection and for Takeda in relation to H. pylori therapies. Dr. Hardi – nothing to disclose. Dr. Welton – nothing to disclose. Dr. Krause – nothing to disclose. Dr. Levenson – Speakers Bureau for Allergan, a stockholder of Gilead Sciences and Abbott Laboratories. Dr. Sarles – nothing to disclose. Dr. Shiekh – Advisory Board of Gilead and Intercept. Research Grants from Shire, Intercept, Enanta, Tobira, Novartis, Gilead, Conatus, Protagonist, Roche, Janssen, Seres and Stason. Speakers Bureau and a shareholder of Gilead. Dr. Epstein is a consultant for imhealthscience and on Speakers Bureaus for Pfizeer and Dailchi Sankyo. Dr. Duvall – nothing to disclose. Dr. Freedland – nothing to disclose. Dr. Hebzda – nothing to disclose. Dr. Arlukowicz – nothing to disclose. Dr. Adam Kopon – nothing to disclose. Prof. Grzyna Rydzewska – nothing to disclose. Dr. Natasa Zdravkovic – nothing to disclose. Prof. Svorcan – nothing to disclose. Dr. Zittan – has received research support and consulting fees from Janssen, Abbvie, Takeda, Neopharm and Pfizer. Dr. Dugalic – nothing to disclose. Prof. Eran Israeli – nothing to disclose. Patricia Anderson is VP Regulatory and an Option Holder of RedHill. Clara Fehrmann is a consultant and Option Holder of RedHill. Patrick McLean is a Product Manager, Patent Holder and Option Holder of RedHill. Dr. Kalfus is a Medical Director, Stock Owner and Option Holder of RedHill.
References: * Calculated with Cochran-Mantel-Haenszel (CMH) chi-square test with stratification according to anti-TNF agents use (yes/no) ** Number of subjects reflects those subjects who have completed week 52 assessments and are no longer receiving blinded therapy *** Current use of Anti-TNF included infliximab and adalimumab only ****Calculated with Mantel-Haenszel (MH) chi-square test.
LB07 HIGH DEFINITION WHITE LIGHT ENDOSCOPY (HDWLE) VERSUS HIGH DEFINITION VIRTUAL CHROMOENDOSCOPY (HDVCE) IN THE DETECTION OF COLONIC NEOPLASIA DURING IBD SURVEILLANCE COLONOSCOPY: A PROSPECTIVE MULTI-CENTRE RANDOMISED CONTROLLED TRIAL
K. Kandiah1, S. Subramaniam1, F.J.Q. Chedgy2, S. Thayalasekaran1, G. Longcroft-Wheaton3, S. Smith4, M. Iacucci4, P. Bhandari5
1Queen Alexandra Hospital, Gastroenterology, Portsmouth, United Kingdom
2Queen Alexandra Hospital, Gastroenterology and Hepatology, Portsmouth, United Kingdom
3Portsmouth Hospitals NHS trust, Gastroenterology, Hampshire, United Kingdom
4University Of Birmingham Queen Elizabeth Hospital, Birmingham, United Kingdom
5Portsmouth University Hospital – Dept. of Gastroenterology, Portsmouth University Hospital; Portsmou, Dept. of Gastroenterology, Portsmouth, United Kingdom
Introduction: Patients with longstanding colonic inflammatory bowel disease (IBD) are at increased risk of developing colonic neoplasia and are therefore recommended to have regular surveillance colonoscopy. It has previously been shown that there is no added gain in using high definition chromoendoscopy when surveillance is carried out with a high definition white light endoscopy (HDWLE). [1]
Aims and Methods: We aim to compare the performance of high definition virtual chromoendoscopy using Pentax iScan OE2 (HDVCE) to HDWLE in the detection of neoplastic lesions in patients with longstanding inflammatory bowel disease.
A multi-centre prospective randomised control trial was conducted. Patients with clinically inactive disease were randomly assigned to undergo surveillance colonoscopy using either HDWLE or HDVCE. All neoplastic lesions detected were resected and all patients had four quadrant random biopsies taken at 10 cm intervals.
Results: A total of 189 patients (53% male; median age 54 years, age range 20–80 years) with longstanding colonic IBD were assessed with HDWLE (n = 95) and HDVCE (n = 94) in two centres in the United Kingdom. There was no significant difference between HDWLE and HDVCE for neoplasia detection. The mean number of neoplastic lesions per colonoscopy was 0.28 for HDWLE and 0.26 for HDVCE (p = 0.24). (Table 1) The neoplasia detection rate was not significantly different for HDWLE (24.2%) and HDVCE (14.9%) (p = 0.11). All adenomas detected contained low-grade dysplasia only. A total of 6751 quadrantic biopsies detected 1 adenoma only. The total withdrawal time was similar in both arms of the study; median of 24 minutes in HDWLE and 25.5 minutes in HDVCE.
Conclusion: We could not demonstrate a significant difference in neoplasia detection in patients with long-term colonic IBD undergoing surveillance colonoscopy using HDWLE and HDVCE. However, targeted biopsies using a high definition system, detected more than 98% of all neoplasia in this study. There is no further need to carry out four quadrant random biopsies when surveillance colonoscopy is performed using a high definition system.
Per lesion neoplasia rate
HDWLE (n = 95)
HDVCE (n = 94)
Total number of lesions identified
71
78
Total neoplastic lesions
27 (Adenoma 13, SSA 13, Cancer 1
25 (Adenoma 21, SSA 4)
Percentage of lesions that were neoplastic
38.0%
32.1%
Mean neoplasia per colonoscopy
0.28
0.26
Disclosure: Nothing to disclose
Reference
MohammedNKantPAbidF, et al.OC-028 High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomised controlled trial. Gut2015; 64: A14.2-A15–A14.2-A15. doi:10.1136/gutjnl-2015-309861.28.
Monday, October 22, 201815:45-17:15
Novel endoscopic and surgical approaches – Room C____
LB08 ENDOSCOPIC VERSUS SURGICAL MYOTOMY IN PATIENTS WITH PRIMARY IDIOPATHIC ACHALASIA
Y.B. Werner1, B. Håkanson2, J. Martinek3, A. Repici4, B. Von Rahden5, A. Bredenoord6, R. Bisschops7, H. Messmann8, T. Noder1, J.F. Kersten9, C.T. Germer10, A. Pazdro11, M.P. Schijven6, P. Fockens6, G.E. Boeckxstaens7, T. Rösch1
2Ersta Hospital, Dept. of Surgery, Stockholm, Sweden
3Institute for Clinical and Experimental Medicine (IKEM), Department of Hepatogastroenterology, Praha, Czech Republic
4Ist. Clinico Humanitas Rozzano Dept. of Gastroenterology, Dept. of Gastroenterology, Milano, Italy
5Uniklinikum Salzburg, Universitätsklinik für Chirurgie, Salzburg, Austria
6Academic Medical Centre, Gastroenterology & Hepatology, Amsterdam, Netherlands
7Katholieke Universiteit Leuven, Department of Clinical and Experimental Medicine, Translational Research in Gastrointestinal Disorders, Leuven, Belgium
8Klinikum Augsburg, III. Medizinische Klinik, Augsburg, Germany
9University Hospital Hamburg-Eppendorf, Department of Medical Biometry and Epidemiology, Hamburg, Germany
10Universitätsklinikum Würzburg, Klinik und Poliklinik für Allgemein- und Viszeral-, Gefäß- und Kinderchirurgie, Würzburg, Germany
11Charles University and University Hospital Motol, 3rd Department of Surgery, 1st Faculty of Medicine, Prague, Czech Republic
Contact E-Mail Address:t.roesch@uke.de
Introduction: Endoscopic balloon dilatation (EBD) and laparoscopic Heller myotomy (LHM) have been used for in the symptomatic therapy of idiopathic achalasia; comparative results have been conflicting with one large randomized study showing equivalence with EBD being repeated. In an attempt to further minimize surgical trauma, peroral endoscopic myotomy (POEM) has been introduced with promising results in early studies and superior results to EBD in a recent randomized trial.
Aims and Methods: We randomly assigned patients with primary achalasia to either POEM or LHM with Dor hemifundoplicatio. Primary outcome was the rate of cases with clinically successful therapy at 2 years follow-up as determined by an Eckardt Score of ≤ 3 (this score ranging from 0-12 indicates combined severity of symptoms such as dysphagia, regurgitation, chest pain and weight loss). Secondary outcomes were manometric pressure of the lower esophageal sphincter, and complications including the development of reflux.
Results: The study population included 221 patients from 8 centers who were randomly assigned to POEM (n = 112) or LHM (n = 109). Demographic data at baseline in both study groups were similar for age, gender and prior therapy (botulinum toxin injection, balloon dilatation). Most common treatment related severe AE were aspiration during anaesthesia, pneumothorax, mucosal perforation requiring additional therapy and were similar in both groups (4.1% overall). Clinical follow-up is still pending in 14 patients. Clinical success at 2 years (without further therapy) was achieved in 81.9% with POEM and in 80.4% with LHM. Similarly, there was no difference in manometric assessment of the lower esophageal sphincter between POEM (mean IRP 11.3 mg) and LHM (mean IRP 11.5 mg) at 2 years. The rate of endoscopic reflux esophagitis was higher with POEM after 3 months (50.5% LA A/B and 6.3% LA C/D for POEM vs 16.5% LA A/B and 3.3% LA C/D for LHM), which was not significant anymore after two years (40.0% LA A/B and 4.7% LA C/D for POEM vs 23.7% LA A/B and 5.2% for LHM; p = 0.05). Rates of acid exposure times > 4.5% at 2 years on pHmetry were not significantly different either, but more patients took low-dose proton pump inhibitors daily (39.2% after POEM versus 18.8% after LHM, p < 0.05). Patient-reported quality of life after 2 years was similar between the groups (POEM mean GIQLI score: 117.4 versus LHM mean: 114.7).
Conclusion: POEM has a similarly high efficacy and good safety profile compared to LHM with respect for the treatment of patients with symptomatic achalasia; it can be regarded as an excellent alternative. Higher rates of mild reflux with POEM were observed especially short-term.
Disclosure: The study was supported by Olympus, several foundations as well as ECRIN for monitoring
LB09 SCRUTINIZING (IN)EFFICIENT USE OF CHOLECYSTECTOMY; A MULTICENTRE RANDOMIZED NON-INFERIORITY TRIAL COMPARING USUAL CARE TO RESTRICTIVE STRATEGY FOR THE EFFECTIVENESS OF CHOLECYSTECTOMY (SECURE TRIAL)
A.H. van Dijk1, S.Z. Wennmacker2, P.R. de Reuver2, C.S. Latenstein2, O. Buyne3, S.C. Donkervoort4, Q.A.J. Eijsbouts5, J. Heisterkamp6, K.H. in 't Hof7, J. Janssen8, V.B. Nieuwenhuis9, H.M. Schaap10, P. Steenvoorde11, H.B.A.C. Stockmann5, D. Boerma12, G.P. Westert13, J.P.H. Drenth2, M.G.W. Dijkgraaf1, M.A. Boermeester1, C.J.H.M. van Laarhoven2
1UMC Amsterdam, Amsterdam, Netherlands
2Radboud University Medical Center, Nijmegen, Netherlands
8Admiraal de Ruyter Ziekenhuis, Vlissingen, Netherlands
9Isala Zwolle, Zwolle, Netherlands
10Scheper Ziekenhuis, Emmen, Netherlands
11Medisch Spectrum Twente, Enschede, Netherlands
12St Antonius Hospital, Dr., Nieuwegein, Netherlands
13IQ Healthcare, Nijmegen, Netherlands
Contact E-Mail Address:a.h.vandijk@amc.nl
Introduction: Cholecystectomy is advised as the preferred treatment for symptomatic, uncomplicated gallstones, according to international guidelines. However, there is great practice variation in cholecystectomy rate. Previous research shows persistent abdominal pain in 10–41% of post-cholecystectomy patients, indicating inefficient use of cholecystectomy.
Aims and Methods: The aim of this trial is therefore to scrutinize (in)efficient use of cholecystectomy by evaluating the effectiveness of a restrictive standardized strategy with stepwise selection for cholecystectomy compared to usual care. Patients with ultrasound proven gallstones and abdominal symptoms were included in 24 Dutch hospitals. These patients were then randomly assigned to the restrictive strategy with a stepwise selection for cholecystectomy or usual care. The primary endpoint of the SECURE is the proportion of patients being pain free at 12 months' follow-up. Secondary endpoints included the rate of cholecystectomy, the proportion of patients with gallstone related and surgical complications and the association between patients' symptoms and treatment.
Results: Between February 2014 and April 2017, 1067 patients were included and eventually analyzed (530 in restrictive strategy and 537 in usual care). A total of 298 patients (56.2%) in the restrictive strategy were pain free at 12 months' follow-up, compared to 321 patients (59.8%) in usual care, which is an absolute difference of 3.6%. As the lower limit of the confidence interval of the percentage of pain free patients in usual care is minus 8.5%, this exceeds the 5% non-inferiority margin.
Rate of cholecystectomy was significantly higher in usual care than in the restrictive strategy (75.4% versus 67%, p = 0.005). The other secondary outcomes did not differ significantly between the two groups: median time to pain-free (median of 7.29 months versus 7.87 months, p = 0.130, patient satisfaction with treatment outcome at 12 months' follow-up (mean NRS of 8.4 in both arms, p = 0.976) and patients' health status over time (p = 0.820).
Conclusion: A restrictive strategy with a stepwise selection for cholecystectomy is not non-inferior to usual care in patients with uncomplicated, symptomatic gallstones with respect to proportion pain-free patients. However, the restrictive strategy is associated with a reduced rate of cholecystectomy and equal patient's satisfaction, when compared to usual care. This trial shows that current management in patients with abdominal symptoms and gallstones is not optimal and indication for cholecystectomy needs to be revised.
Disclosure: Nothing to disclose
LB10 ULTRASOUND-GUIDED TRANSORAL FUNDOPLICATION FOR THE TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE: RESULTS UP TO 24 MONTHS FROM A SINGLE-CENTER PROSPECTIVE STUDY
P.A. Testoni, G. Mazzoleni, G. Distefano, S.G.G. Testoni, M. Antonelli, L. Fanti, S. Passaretti
San Raffaele Scientific Institute – Vita Salute San Raffaele University, Milan, Italy
Contact E-Mail Address:testoni.pieralberto@hsr.it
Introduction: Transoral incisionless fundoplication (TIF) with the MUSE system is a new ultrasound-guided intervention for the treatment of gastroesophageal reflux disease (GERD).
Aims and Methods: Aim of this study was to assess the safety of TIF with MUSE and its effects on clinical, pathophysiological and endoscopic results. TAF with MUSE was performed in a series of consecutive patients (pts) with symptomatic GERD, in a single-center study. All pts underwent GERD-Related Quality of Life (GERD-HRQL) and Reflux Symptom Index (RSI) questionnaires, upper gastrointestinal endoscopy, 24 h esophageal pH-impedance recording and high-resolution esophageal manometry (HRM) before TIF, 6 months and 12 months after TAF (HRM only before TIF and after 6 months). Symptomatic questionnaires and proton pump inhibitors (PPIs) consumption were also investigated at 24 months. Data were compared to baseline using Fisher's exact test for frequencies and Wilcoxon signed-rank test for nonparametric data.
Results: Thirty-six pts underwent TIF (20 males). Eleven pts (31.4%) had grade A esophagitis, while 24 pts had NERD (pathological pH-impedance recording). In one case it was not possible to perform esophageal intubation with the endostapler. TIF was successful in all other cases. Esophageal perforation occurred in one case (overall complication rate: 2.8%). Clinical follow-up was completed in 26, 20 and 14 pts at 6, 12 and 24 months, respectively. One pts requested surgery six months after TIF for inefficacy of the procedure on symptoms. Compared to baseline, median GERD-HRQL and RSI scores and PPIs consumption were significantly improved at 6, 12 and 24 months after TIF, respectively. Endoscopic follow-up was completed in 25 and 20 pts at 6 and 12 months, with 3 and 4 pts which had grade A esophagitis, respectively. Pathophysiological follow-up was completed in 17 and 13 pts at 6 and 12 months, respectively. Compared to baseline, 6 months after TIF there were a significantly lower number of acid, proximal and total refluxes, detected by esophageal impedance and a significantly increase of lower esophageal sphincter length and rate of peristaltic waves, detected by HRM.
Exam
Parameter (Mean ± SD)
Before TAF
6 months after TAF
p value
12 months after TAF
p value
24-h esophageal pH-metry
DeMeester score
27.2 ± 15.7
28.7 ± 22.2
0.77
20.3 ± 16.0
0.49
AET (%)
5.8 ± 3.6
5.2 ± 4.4
0.58
4.1 ± 3.3
0.39
Longest reflux (min)
10.0 ± 7.2
16.5 ± 17.4
0.15
12.5 ± 17.1
0.46
Refluxes > 5 min (N°)
1.9 ± 1.8
2.1 ± 2.0
0.84
1.1 ± 1.4
0.3
24-h esophageal impedance
Total refluxes (N°)
61.6 ± 36.5
45.0 ± 29.7
0.007
43.7 ± 28.4
0.05
Acidic refluxes (N°)
46.3 ± 24.2
30.0 ± 21.4
0.0002
41.6 ± 21.9
0.11
Weakly acidic refluxes (N°)
14.4 ± 16.9
13.6 ± 11.1
0.82
10.9 ± 9.1
0.33
Alkaline refluxes (N°)
0.9 ± 2.0
1.4 ± 2.7
0.31
0.8 ± 1.1
1
Proximal refluxes (N°)
28.3 ± 20.1
21.3 ± 22.8
0.008
20.1 ± 18.2
0.4
Nocturnal baseline impedance (Ω)
1699 ± 940
1844 ± 822
0.32
1685 ± 877
0.85
High resolution esophageal manometry
LES basal pressure (mmHg)
27.6 ± 10.2
32.9 ± 13.9
0.2
LES length (cm)
4.2 ± 2.1
5.3 ± 2.6
0.003
IRP (mmHg)
9.1 ± 6.1
12.1 ± 6.4
0.08
DCI (mmHg*cm*s)
1477.6 ± 1632.0
1729.7 ± 1715.0
0.34
Peristaltic waves (%)
58.9 ± 38.5
73.3 ± 39.4
0.03
Weak waves (%)
6.4 ± 11.5
7.0 ± 18.5
0.88
Failed waves (%)
25.5 ± 35.9
19.0 ± 36.1
0.26
[Pathophysiological results]
Conclusion: 6, 12 and 24 months data showed TIF by MUSE safe and effective, allowing a significant improvement of symptom scores and a significant reduction of PPIs consumption and refluxes number, detected by esophageal impedance.
Disclosure: Nothing to disclose
LB11 NEXT GENERATION SEQUENCING OF IPMN CYST FLUID OBTAINED BY EUS-GUIDED FNA HAS A HIGHER DIAGNOSTIC YIELD THAN CYTOLOGY OR LABORATORY TESTING AND IDENTIFIES BOTH MULTIPLE KRAS/GNAS MUTATIONS AND DNA-MUTATION PATTERNS – FINDINGS FROM THE ZYSTEUS STUDY
D. Schmitz1, A.-L. Volckmar2, N. Weller1, M. Doll1, A.-M. Nahm1, S. Weingärtner1, N. Pelaez1, J. Rudi1, P. Schirrmacher2, A. Stenzinger2
1Theresienkrankenhaus and St. Hedwig Hospital, Academic Teaching Hospital of Heidelberg University, Gastroenterology, Oncology and Diabetology, Mannheim, Germany
2Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are the most frequent neoplastic pancreas cysts and can progress to high grade dysplasia (HGD) or invasive cancer. Normally, pancreas cysts are suspected as IPMNs in cross sectional imaging examinations with CT, MRI or EUS. Cyst fluid obtained by EUS-guided FNA can be analyzed for cytology or chemical laboratory testing (CEA, lipase) but have a low sensitivity and specificity. Hence, further diagnostic tools are needed to identify IPMNs at an early stage for appropriate patient management (follow up or surgical resection). Molecular genetic analysis of pancreatic cyst fluid is a new but rapidly evolving method to identify DNA mutations. Detection of KRAS activating mutations improves the accuracy of the diagnosis of a mucinous cyst. Recent studies observed GNAS-mutations only in branch duct IPMN but not in mucinous cystic neoplasm (MCN). Occurrence of mutations in RNF43, p16/CDKN2, TP53 or SMAD4 are found more often in IPMNs with HGD or invasive carcinoma. Furthermore to the diagnostic yield of DNA-mutation analysis, it might shed additional light on the pathogenesis of IPMN cysts by assessing prevalence and distribution of genetic alterations.
Aims and Methods: 19 patients with suspected IPMN in cross sectional imaging underwent endoscopic ultrasound (EUS)-guided fine-needle aspiration and material was obtained for cfDNA extraction by MagMAX™ Cell-Free DNA Isolation Kit. cfDNA was sequenced with the Oncomine Colon cfDNA Panel (Thermo-Fisher) by ultra-deep ion semiconductor sequencing (S5XL, Ion Torrent), cytology and chemical laboratory testing. Clinical parameters, imaging findings in EUS and MRI, and follow-up data were collected continuously.
Results: We detected KRAS mutations in all analyzed IPMNs (3 main duct IPMN, 1 mixed type IPMN, 12 branch duct IPMN) but one, which harbored a GNAS mutation. One case showed both KRAS and GNAS mutation. Mutation allele frequencies varied between 0.03–46.67%. Five patients harbored multiple KRAS mutations. Patients with multifocal branch duct-IPMN showed identical DNA-mutation profiles in different cysts. Diagnostic yield was significantly lower in cytology and chemical laboratory testing than in DNA-mutation analysis. In three pseudocysts used as biological control, no oncogenic driver mutation could be detected.
Conclusion: DNA-mutation analysis with Next Generation Sequencing is highly sensitive in identifying IPMN cysts in comparison with non-neoplastic pancreas cysts and has a higher diagnostic yield than cytology or laboratory testing of cyst fluid. Detection of multiple KRAS-mutations in one IPMN cyst indicates a possible oligoclonal development. Identification of the same DNA-mutations in different IPMN cysts of the same patient suggests a recurrent “field defect”.
Disclosure: Nothing to disclose
References
Fischer CG, Wood LD. From somatic mutation to early detection: Insights from molecular characterization of pancreatic cancer precursor lesions. J Pathol. 2018 Aug 13. European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018 May;67(5):789–804.Wu J, Matthaei H, Maitra A et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011 Jul 20;3(92):92ra66.Kromrey ML, Bülow R, Hübner J, Paperlein C, Lerch MM, Ittermann T, Völzke H, Mayerle J, Kühn JP. Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study. Gut. 2018 Jan;67(1):138–145.Singhi AD, McGrath K, Brand RE et al. Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut. 2017 Sep 28.
LB12 DETECTION OF EARLY GASTRIC CANCER USING SECOND-GENERATION NARROW BAND IMAGING: A MULTICENTER RANDOMIZED CONTROLLED TRIAL
M. Arao1, N. Yoshida2, H. Doyama2, T. Yano3, T. Horimatsu4, N. Uedo5, Y. Yamamoto6, N. Kakushima7, H. Kanzaki8, S. Hori9, K. Yao10, I. Oda11, S. Tanabe12, C. Yokoi13, K. Ohata14, K. Yoshimura15, H. Ishikawa16, M. Muto4
1Gifu University Hospital, Gastroenterology and Hepatology, Gifu, Japan
2Ishikawa Prefectural Central Hospital, Gastroenterology, Kanazawa, Japan
3National Cancer Center Hospital East, Gastroenterology and Endoscopy, Kashiwa, Japan
4Kyoto University Graduate School of Medicine, Therapeutic Oncology, Kyoto, Japan
5Osaka International Cancer Institute, Gastrointestinal Oncology, Osaka, Japan
6Hyogo Cancer Center, Gastrointestinal Oncology, Akashi, Japan
7Shizuoka Cancer Center, Endoscopy, Shizuoka, Japan
8Okayama University Hoapital, Gastroenterology and Hepatology, Okayama, Japan
9Shikoku Cancer Center, Endoscopy, Matsuyama, Japan
10Fukuoka University Chikushi Hsopital, Endoscopy, Chikushino, Japan
11National Cancer Center Hospital, Endoscopy, Chuo-ku, Japan
12Kitasato University School of Medicine, Advanced Medicine Research and Development Center for New Medical Frontiers, Sagamihara, Japan
13Center Hospital of the National Center for Global Health and Medicine, Endoscopy, Shinjuku-ku, Japan
14NTT Medical Center Gastroenterology, Gastroenterology, Shinagawa-ku, Japan
15Kanazawa University Hospital, Innovative Clinical Research Center, Kanazawa, Japan
16Kyoto Prefectural University of Medicine, Moecular-Targleting Cancer Prevention, Kyoto, Japan
Contact E-Mail Address:aryao_poor_boy@yahoo.co.jp
Introduction: Early detection is crucial for improving survival of cancer patients. Introduction of first-generation narrow band imaging (1G-NBI) significantly improved detection of early-stage head and neck, and esophageal cancers compared to white light imaging (WLI). However, the detection of early gastric cancer (EGC) using 1G-NBI has been difficult because of insufficient brightness for observing wide gastric lumen. Development of a second-generation NBI (2G-NBI) system (EVIS LUCERA ELITE; Olympus Co., Tokyo, Japan) led to a significant improvement in the brightness and resolution of the endoscopic images during non-magnifying NBI observation. Thus, we hypothesized 2G-NBI may improve detection of EGC.
Aims and Methods: An objective of this study was to investigate whether the 2G-NBI detects significantly more EGCs compared to the WLI in patients at high-risk for EGC. This open-label, multi-institutional, randomized controlled trial was conducted in 13 hospitals in Japan. Patients with concomitant or past history of esophageal or gastric neoplasm were eligible in this study. We randomly assigned the patients to either primary WLI followed by secondary 2G-NBI (WLI) group or primary 2G-NBI followed by secondary WLI (2G-NBI) group. All endoscopic examinations were performed to detect previously undiagnosed lesions suspected of EGC (target lesions). The endoscopic findings in each examination were independently documented in a case reporting form. After the whole protocol examinations, biopsy specimens were obtained from the all target lesions to serve histological reference standard. A primary endpoint was a percentage of patients with newly detected EGC at the primary examination in the WLI or 2G-NBI groups. Secondary endpoints were positive predictive value (PPV) of the primary examination for the diagnosis of EGC, and observation time of the primary examinations.
Results: A total of 4,575 patients were enrolled from September 2014 to September 2017. Of them, 52 patients refused to participate. The remaining 4,523 patients were randomized into the WLI group (n = 2,258) or the 2G-NBI group (n = 2,265). The primary WLI examination found 45 (2.0%) patients with newly detected EGC, while the primary 2G-NBI examination detected 53 (2.3%, P = 0.47). The PPV of the primary WLI examination was 13.7% (51/372 lesions) but that of the primary 2G-NBI examination was significantly better at 21.2% (60/283 lesions, P = 0.015). The mean observation time for the primary WLI and the primary 2G-NBI examinations were 233 sec and 253 sec, respectively (P < 0.001).
Conclusion: The EGC detection rate of 2G-NBI was comparable to WLI, but it did not show statistical significance. However, the PPV of 2G-NBI was significantly higher than that of WLI, suggesting efficiency (low false-positive lesions) of the 2G-NBI in EGC detection.
Disclosure: This study was funded by the joint research funds supplied by Kyoto University and Olympus Corporation. Conflicts of interest exist between Muto M. and Olympus Corporation.
LB13 SAFETY, FEASIBILITY AND EFFECTIVENESS OF AN INDIVIDUALIZED SURVEILLANCE PROTOCOL FOR SERRATED POLYPOSIS SYNDROME: RESULTS FROM A PROSPECTIVE 5-YEAR INTERNATIONAL COHORT STUDY
A. Bleijenberg1, J. IJspeert1, Y. van Herwaarden2, S. Carballal3, M. Pellisé3, G. Jung3, T.M. Bisseling4, I.D. Nagtegaal5, M. van Leerdam6, N. van Lelyveld7, X. Bessa Casserras8, F. Rodriguez Moranta9, B.A.J. Bastiaansen1, W. de Klaver1, M.C.W. Spaander10, J.J. Koornstra11, L. Bujanda Fernández de Piérola12, F. Balaguer3, E. Dekker1
1Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam, Netherlands
2Radboud University Medical Center, Gastroenterology and Hepatology, Nijmegen, Netherlands
3Hospital Clinic Barcelona / Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) / Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology and Hepatology, Barcelona, Spain
4Radboud University Medical Centre, Gastroenterology and Hepatology, Nijmegen, Netherlands
5Radboud University Nijmegen Medical Center, Pathology, Nijmegen, Netherlands
6Netherlands Cancer Institute, Gastroenterology, Amstelveen, Netherlands
7Antonius Hospital, Dept. of Gastroenterology, Nieuwegein, Netherlands
8Hospital del Mar – Parc de Salut Mar, Gastroenterology and Hepatology, Barcelona, Spain
9University Hospital of Bellvitge (HUB-IDIBELL), Barcelona, Spain
10Erasmus Medical Center Rotterdam, Gastroenterology and Hepatology, Rotterdam, Netherlands
11UMC Groningen Dept. of Gastroenterology, University Medical Center Groningen, Groningen, Netherlands
12Universidad del País Vasco (UPV/EHU) / Instituto Biodonostia / Centro de Investigación Biomédica en Red de Enfermades Hepáticas y Digestivas (CIBEREHD), Gastroenterology, Vizcaya, Spain
Contact E-Mail Address:a.g.bleijenberg@amc.uva.nl
Introduction: Serrated polyposis syndrome (SPS) is the most prevalent polyposis syndrome known1, 2, and is associated with an increased risk of colorectal cancer (CRC). Most recent guidelines recommend surveillance every one to two years.3, 4 Some, like the influential guideline of the United States Multi-society Taskforce on CRC, even recommend annual surveillance.5 However, CRC risk in SPS patients appears to be highly variable, and annual surveillance likely leads to excessive colonoscopy burden for many. Tools to identify patients at high risk of CRC that would benefit from annual surveillance are lacking. We therefore developed and prospectively assessed a personalized surveillance protocol aiming to safely reduce the burden of colonoscopies for SPS patients.
Aims and Methods: From January 2013 to April 2018 we enrolled SPS patients (type I and/or type III) from nine hospitals in the Netherlands and Spain. Patients were surveilled using a personalized surveillance protocol, which appoints either a one or two year interval after each surveillance colonoscopy, based on polyp burden. Five or more low-risk polyps or at least one high-risk polyp led to a 1-year surveillance interval. In all other cases a 2-year interval was appointed. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance.
Results: 271 SPS patients were followed for a median of 3.6 years (inter-quartile range 2.3–4.9). The protocol led to a 2-year interval in most patients. After the 1st, 2nd and 3rd surveillance colonoscopy, a 2-year interval was appointed to 52%, 63% and 71%, respectively. During surveillance, three patients were diagnosed with CRC, corresponding to a cumulative 5-year incidence of 1.7% (95%-CI 0.5–5.6%). Two out of three CRCs occurred after a 1-year interval. One was a T1 CRC, detected at the first surveillance colonoscopy after clearing, and could be managed endoscopically. The second was a T3N0M0 tumor, treated with total colectomy and detected 1 year after removal of a high-grade dysplastic adenoma in the same segment. Six months after polypectomy the scar was not identified at endoscopy. The third was a T3N1M0 tumor, occurring after a 2-year interval. Histologically and endoscopically it was considered a local recurrence six years after primary CRC diagnosis, since it protruded from inside the anastomosis of the previous colectomy. Several colonoscopies had been performed without remarkable findings since the previous CRC diagnosis. A total colectomy was performed.
The 5-year cumulative AN incidence was 44% (95%-CI 37–52%). Following a 1-year interval recommendation, 41% had AN at the subsequent colonoscopy, compared to only 19% after a 2-year interval recommendation (p < 0.001). Patients with SPS type III had a lower risk of AN during surveillance than SPS type I (HR 0.38, 95%-CI 0.22–0.63, p < 0.001) and SPS type I & III (HR 0.41, 95%-CI 0.24–0.71, p < 0.001).
Conclusion: Using our personalized surveillance protocol, CRC incidence was low. The three CRCs that occurred during follow-up could likely not have been prevented by more stringent (annual) surveillance. In addition, the protocol adequately discriminated between patients at high and low risk of AN during subsequent surveillance colonoscopy. We therefore conclude that lengthening of surveillance intervals based on this personalized surveillance protocol is safe and effective in reducing colonoscopy burden. To further improve risk stratification, we identified SPS type III patients as a low-risk group that might benefit from even less frequent surveillance.
Disclosure: Nothing to disclose
References
IJspeert JEG, Bevan R, Senore C, et al. Detection rate of serrated polyps and serrated polyposis syndrome in colorectal cancer screening cohorts: a European overview. Gut 2016;0:gutjnl-2015-310784.Rivero-SanchezLLopez-CeronMCarballalS, et al.Reassessment colonoscopy to diagnose serrated polyposis syndrome in a colorectal cancer screening population. Endoscopy2017; 49: 44–53.East JE, Atkin WS, Bateman AC, et al. British Society of Gastroenterology position statement on serrated polyps in the colon and rectum. Gut 2017.Hassan C, Repici A, Rex DK. Serrated polyposis syndrome: risk stratification or reduction? Gut 2016;0:gutjnl-2015-311357.LiebermanDARexDKWinawerSJ, et al.Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology2012; 143: 844–857.
LB14 INTERVAL CANCERS AFTER A NEGATIVE FAECAL IMMUNOCHEMICAL TEST IN THE FIRST SCREENING ROUND IN THE NETHERLANDS: RESULTS FOR TWO CUT-OFF LEVELS
E. Toes-Zoutendijk1, A. Kooyker1, A.W.J. Opstal-van Winden1, M.C.W. Spaander2, E. Dekker3, C. Ramakers4, M. Buskermolen1, A.J. van Vuuren2, E.J. Kuipers5, F.J. van Kemenade6, M. Velthuysen6, M. Thomeer7, H. van Veldhuizen7, M. van Ballegooijen7, I.D. Nagtegaal8, H.J. de Koning1, M.E. van Leerdam9, I. Lansdorp-Vogelaar1
1Erasmus MC – University Medical Center, Public Health, Rotterdam, Netherlands
2Erasmus MC – University Medical Center, Gastroenterology and Hepatology, Rotterdam, Netherlands
3AMC, Gastroenterology and Hepatology, Amsterdam, Netherlands
4Erasmus MC – University Medical Center, Clinical Chemistry, Rotterdam, Netherlands
5Erasmus MC – University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands
6Erasmus MC – University Medical Center, Pathology, Rotterdam, Netherlands
7Erasmus MC – University Medical Center, Rotterdam, Netherlands
8Radboud University Nijmegen Medical Center Dept. of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
9Netherlands Cancer Institute, Dept. of Gastroenterology, Amstelveen, Netherlands
Contact E-Mail Address:a.kooyker@nki.nl
Introduction: This study evaluated the interval cancer incidence after the first screening round in a national organised colorectal cancer (CRC) screening program using the faecal immunochemical test (FIT) in relation to FIT cut-off.
Aims and Methods: Screenees with a negative FIT in the first screening round in 2014 in the Netherlands were included in the study. We defined interval cancers according to the internationally recommended nomenclature of the working group on interval CRC of the World Endoscopy Organization. This designated a FIT interval cancer as a CRC after a negative FIT but before the invitation of subsequent screening round with FIT. The number of interval CRCs were related to the number of persons with a negative FIT to assess the cumulative incidence and will be presented per 10,000 persons with a negative FIT. The number of screen-detected CRCs were related to the total number of CRCs as a proxy for the test sensitivity for CRC.
Results: Among the 485,112 participants with a negative FIT, 544 interval cancers were detected, 126 interval cancer after using a FIT cut-off level of 15 µg Hb/g faeces and 418 interval cancer after using a FIT cut-off level of 47 µg Hb/g faeces. The age-adjusted two year cumulative incidence of an interval cancer after negative FIT did not differ between the two cut-off levels, 9.5 interval cancers per 10,000 persons at the low cut-off level and 13.8 interval cancer per 10,000 persons at the higher cut-off level with a standardized rate ratio of 0.68 (95%CI: 0.42–1.12). Age-adjusted sensitivity of FIT for CRC at the low cut-off level was 90.5% and 82.9% at the higher cut-off level, with a standardized rate ratio of 1.09 (95%CI: 0.91–1.30).
Conclusion: The incidence of interval CRC in the two years after a negative FIT is low, irrespective of cut-off. This supports the high sensitivity of FIT for CRC, also when using a relatively high FIT cut-off level. These results are promising for all organized CRC screening programs using higher FIT cut-off levels.
Cut-off level Hb/g faeces
Negative FITs
Screen-detected CRCs
Interval CRCs
Cumulative incidence
Sensitivity
Total
n
n
n
per 10,000 persons (95% CI)
% (95% CI)
All
485,112
3,209
544
11.2 (10.3–12.2)
85.5 (84.3–86.6)
Men
231,219
1,963
282
12.2 (10.9–13.7)
87.4 (86.0–88.7)
Women
253,893
1,246
262
10.3 (9.1–11.6)
82.6 (80.6–84.5)
All
15 µg
111,800
1,101
126
11.3 (9.5–13.4)
89.7 (87.9–91.3)
Age adjusted
9.5
90.5
Men
52,025
655
73
14.0 (11.2–17.6)
90.0 (87.6–92.0)
Women
59,775
446
53
8.9 (6.8–11.6)
89.4 (86.4–91.8)
All
47 µg
373,312
2,108
418
11.2 (10.2–12.3)
83.5 (82.0–84.9)
Age adjusted
13.8
82.9
Men
179,194
1,308
209
11.7 (10.2–13.4)
86.2 (84.4–87.9)
Women
194,118
800
209
10.8 (9.4–12.3)
79.3 (76.7–81.7)
[Interval cancer after negative FIT]
Disclosure: Nothing to disclose
Tuesday, October 23, 201815:45–17:15
Advances in clincial gastroenterology and hepatology – Room G____
LB15 A RANDOMIZED TRIAL OF PROTON PUMP INHIBITORS VERSUS PLACEBO TO PREVENT UPPER GASTROINTESTINAL BLEEDING IN PATIENTS RECEIVING RIVAROXABAN OR ASPIRIN
P. Moayyedi12, J.W. Eikelboom2, J. Bosch2, S.J. Connolly2, L. Dyal2, S. Yusuf2; on behalf of the COMPASS investigators
1McMaster University Dept. of Medicine Dept. of Gastroenterology – McMaster University Dept. of Medic, Hamilton, Canada
2McMaster University, Hamilton, Canada
Contact E-Mail Address:moayyep@mcmaster.ca
Introduction: Antiplatelet and anticoagulants are associated with increased upper gastrointestinal (GI) bleeding. Proton pump inhibitors (PPI) have been shown to reduce peptic ulcer disease and peptic ulcer bleeding related to aspirin and non-steroidal use but there has been no randomized trial evaluating the efficacy of PPI in preventing upper GI complications in patients taking anticoagulants.
Aims and Methods: 17,598 participants not already taking a proton pump inhibitor with stable cardiovascular disease were randomized to pantoprazole 40 mg daily or placebo. Participants were also randomized to rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily or aspirin alone. The randomization schedules were computer-generated and delivered through an interactive web response system. The primary outcome was time to first upper GI event, defined as a composite of overt bleeding with a gastroduodenal lesion, overt upper GI bleeding of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer, GI pain of three days or more with five or more gastroduodenal erosions, upper GI obstruction or perforation.
Results: Patients were followed up for 3.02 years accounting for 53,152 patient years.
There was no difference in upper GI events in the pantoprazole (102/8791 events) compared to the placebo (116/8807 events) group (hazard ratio = 0.88; 95% confidence intervals (CI) 0.67 to 1.15) (Table). Evaluating the components of the upper GI bleeding events, there was a reduction in the bleeding gastroduodenal events in the pantoprazole compared to the placebo group (HR = 0.52; 95% CI = 0.28 to 0.94). Clinically significant upper GI events were uncommon in this trial and we explored whether this related to the strict definition of an event. In a post hocanalysis we broadened definitions. Bleeding gastroduodenal lesions were redefined as an ulcer seen at endoscopy in a patient with upper GI bleeding of gastroduodenal origin with no requirement for the lesion to be actively bleeding at the time of endoscopy. Similarly, we relaxed the requirement for documented pain when ulcer/erosions were diagnosed at endoscopy or other imaging. In this post hoc analysis pantoprazole was associated with a lower risk of bleeding gastroduodenal lesion as in the primary analysis (HR = 0.45; 95% CI = 0.27 to 0.74). Furthermore, in this post hoc analysis, pantoprazole was also associated with a lower risk of peptic ulcer (HR = 0.46; 95% CI = 0.25 to 0.83) and erosions (HR = 0.33; 95% CI = 0.13 to 0.84).
Conclusion: Routine PPI in patients receiving low dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper GI complications. PPIs may prevent peptic ulcer complications in high risk patients.
Pantoprazole 40 mg od (N = 8791)
Pantoprazole placebo (N = 8807)
Pantoprazole versus placebo
Outcome
No. of first events (%)
Annual rate (%/yr)
No. of first events (%)
Annual rate (%/yr)
Hazard ratio (95% CI)
p value
Upper GI event
102 (1.2)
0.4
116 (1.3)
0.4
0.88 (0.67 to 1.15)
0.35
Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography
16 (0.2)
0.06
31 (0.4)
0.1
0.52 (0.28 to 0.94)
Overt upper GI bleeding of unknown origin
50 (0.6)
0.2
46 (0.5)
0.2
1.09 (0.73 to 1.63)
Bleeding of presumed occult upper GI tract origin with documented decrease in Hb ≥ 2 g/dL
10 (0.1)
0.04
9 (0.1)
0.03
1.11 (0.45 to 2.74)
Symptomatic gastroduodenal ulcer
8 (<0.1)
0.03
17 (0.2)
0.06
0.47 (0.20 to 1.09)
GI pain with ≥5 gastroduodenal erosions
4 (<0.1)
0.02
7(<0.1)
0.03
0.57 (0.17 to 1.95)
Upper GI obstruction or perforation
21 (0.2)
0.08
17 (0.2)
0.06
1.24 (0.65 to 2.35)
[Primary Efficacy Outcome of clinically significant upper gastrointestinal events with pantoprazole versus placebo]
Disclosure: This study was funded by Bayer
LB16 ADVERSE EVENTS RELATED TO PROTON PUMP INHIBITOR THERAPY. RESULTS OF A RANDOMIZED TRIAL OF PANTOPRAZOLE VERSUS PLACEBO WITH 53,152 PATIENT YEARS OF FOLLOW-UP
P. Moayyedi12, J.W. Eikelboom2, J. Bosch2, S.J. Connolly2, L. Dyal2, S. Yusuf2; on behalf of the COMPASS investigators
1McMaster University Dept. of Medicine Dept. of Gastroenterology – McMaster University Dept. of Medic, Hamilton, Canada
2Population Health Research Institute, Hamilton, Canada
Contact E-Mail Address:moayyep@mcmaster.ca
Introduction: Proton pump inhibitors (PPI) are effective at treating acid related disorders such as gastro-esophageal reflux disease. They are very well tolerated drugs in the short term but have been reported in observational studies to be associated with adverse events, including pneumonia, enteric infections, fracture risk, dementia, and chronic renal disease, as well as an increase in cardiovascular events and mortality. Concerns regarding long term adverse events have relied on observational data and have not been confirmed in adequately powered randomized trials.
Aims and Methods: We randomized 17,598 participants not already taking a PPI with stable cardiovascular disease to pantoprazole 40mg daily or placebo. The primary aim was to evaluate the efficacy of pantoprazole in reducing upper gastrointestinal events in patients taking aspirin and/or rivaroxaban. The randomization schedules were computer-generated and delivered through an interactive web response system. A predefined secondary aim was to evaluate the long term safety of PPI therapy. We prospectively collected data on pneumonia, clostridium difficile infection, other enteric infections, fracture, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, GI cancer and all cause mortality. Statistical analyses were not adjusted for multiple testing.
Results: Patients were followed up for 3.02 years accounting for 53,152 patient years of follow-up. Baseline characteristics were similar between the pantoprazole and placebo arms. There was no statistically significant difference between pantoprazole versus placebo for any of the safety events except for enteric infections (odds ratio (OR) = 1.33; 95% CI = 1.01 to 1.75) (Table). Numerically event rates were similar between the two group except for clostridium difficile which was approximately twice as common in the PPI group although with only 13 events this was not statistically significant (OR = 2.26; 95% CI = 0.70 to 7.34). Approximately 20% of participants in each group permanently discontinued their PPI or placebo. Results were very similar when these participants were excluded from the analysis.
Conclusion: PPI therapy is not associated with any adverse event when used for three years with the possible exception of risk of enteric infections.
Pantoprazole 40 mg od (N = 8791)
Pantoprazole placebo (N = 8807)
Pantoprazole 40 mg od versus placebo
Outcomes
no. of incident events (%)
no. of incident events (%)
Odds ratio or Hazard ratio*(95% CI)
p value
All cause mortality
630 (7.2)
614 (7.0)
1.03 (0.92 to 1.15)*
0.63
Myocardial infarction
252 (2.9)
267 (3.0)
0.94 (0.79 to 1.12)*
0.51
Stroke
184 (2.1)
159 (1.8)
1.16 (0.94 to 1.44)*
0.16
GI cancer
86 (1.0)
83 (0.9)
1.04 (0.77 to 1.40)*
0.81
Gastric atrophy
19 (0.2)
26 (0.3)
0.73 (0.40 to 1.32)
0.30
Clostridium difficile
119 (1.4)
4 (<0.1)
2.26 (0.70 to 7.34)
0.18
Enteric infection
119 (1.4)
90 (1.0)
1.33 (1.01 to 1.75)
0.04
Chronic kidney disease
184 (2.1)
158 (1.8)
1.17 (0.94 to 1.45)
0.15
Dementia
55 (0.6)
46 (0.5)
1.20 (0.81 to 1.78)
0.36
Pneumonia
318 (3.6)
313 (3.6)
1.02 (0.87 to 1.19)
0.82
Fracture
203 (2.3)
211 (2.4)
0.96 (0.79 to 1.17)
0.71
COPD
146 (1.7)
124 (1.4)
1.18 (0.93 to 1.51)
0.17
Diabetes mellitus
513 (5.8)
532 (6.0)
0.96 (0.85 to 1.09)
0.56
CI = confidence interval
COPD = chronic obstructive pulmonary disease
[Safety outcomes of pantoprazole versus placebo]
Disclosure: This study was funded by Bayer
LB17 IMPROVEMENT IN HEARTBURN AND REGURGITATION SYMPTOMS IN PATIENTS WITH PERSISTENT GERD DESPITE PPI TREATMENT: RESULTS FROM A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF IW-3718, A NOVEL GASTRIC-RETENTIVE BILE ACID SEQUESTRANT
M.F. Vaezi1, R. Fass2, N. Vakil3, P. Kahrilas4, R.S. Mittleman5, M. Hall5, J.Z. Shao5, D. Reasner5, Y. Chen5, L. Lane5, C. O'Dea5, M.G. Currie5
1Vanderbilt University Medical Center, Nashville, United States
2MetroHealth Medical Center and Case Western Reserve University, Cleveland, United States
3University of Wisconsin School of Medicine and Public Health, Madison, United States
4Northwestern University Feinberg School of Medicine, Chicago, United States
5Ironwood Pharmaceuticals, Cambridge, United States
Introduction: Bile acid reflux plays an important role in GERD. IW-3718 is an investigational gastric-retentive bile acid sequestrant designed to improve GERD symptoms by binding bile acids in the gastro-oesophageal refluxate.
Aims and Methods: The aim of this study was to determine if IW-3718 improves heartburn (HB) and regurgitation (RG) in patients with persistent GERD symptoms despite receiving PPI once daily, per label dose. This study included screening, 2-week pretreatment and 8-week treatment periods. Eligible patients had GERD with erosive esophagitis (EE) and/or abnormal pH (pH < 4 for ≥4.2% of a daily 24-hour interval) and ongoing HB or RG symptoms ≥4 days per week for 8 weeks despite ongoing once-daily PPI. Patients were stratified by EE status and randomized to receive placebo (PBO) or IW-3718 (500, 1000 or 1500 mg) BID (1:1:1:1) while on PPI therapy. Symptoms were assessed daily via a reflux symptom questionnaire. The primary endpoint was % change from baseline to Week 8 in 6-point HB severity score (0 = none, 5 = severe). Secondary endpoints included weekly % change from baseline in HB severity score and 5-point RG frequency score (0 = never, 4 = very often) and overall HB and RG responders (≥45% decrease from baseline in weekly score for ≥4 of 8 treatment weeks including ≥1 of the 2 final weeks). Esophagogastroduodenoscopy (EGD) was performed on patients both pre- and post-treatment (EGD Subgroup), then evaluated for change in EE by LA Classification. Adverse events (AEs) were recorded.
Results: The modified ITT population included 280 patients (68–71/arm); 52% had EE at baseline. Demographics were similar across groups. Week-8 % change from baseline in HB severity scores were −46.0, −49.0, −55.1 and −58.0 for PBO, IW-3718 500, 1000 and 1500 mg groups, respectively (dose-response test P = 0.02); 1500 mg treatment difference vs PBO = −11.9 (P = 0.04). Week-8 % change from baseline in RG frequency score was significantly better for 1500 mg (−55.4) vs PBO (−37.9) (difference −17.5, P = 0.01). Numerical gains were seen starting at Week 2 for HB severity for 1500 mg vs PBO; greater improvements were seen at this dose in EE patients. Overall responder rates for HB and RG were 52.9% and 46.3% for the 1500 mg group vs 37.1% and 34.3% for PBO, respectively; greater improvements vs PBO were seen in EE patients (table). Patient-level change in LA Classification in the EGD Subgroup (N = 12): PBO – 1 (25%) improved (C to B), 2 unchanged, 1 worsened (C to D); IW-3718 (all doses) – 7 (87.5%) improved (1 A to none, 1 C to none, 1 C to A, 4 C to B), 1 unchanged, 0 worsened. Constipation was the most common AE reported (7.1% PBO, 8.1% IW-3718).
Conclusion: Adjunct treatment with IW-3718 1500 mg improved HB and RG symptoms vs PBO in patients with persistent GERD despite ongoing label-dose PPI treatment. Improvements in HB and RG symptoms were seen throughout the treatment period at the 1500 mg dose, with evidence of efficacy in EE patients. Pre- and post-treatment EGD results in a small number of patients show that IW-3718 did not worsen EE severity and may have contributed to improvement. IW-3718 was well tolerated at all doses.
% Responders
Parameter
Placebo w/PPI
IW-3718 1500 mg w/PPI
Treatment Difference
Heartburn ≥ 45% Responder:
All patients (N = 280)
37.1
52.9
15.8
EE patients (N = 145)
30.6
50.0
19.4
Regurgitation1 ≥45% Responder:
All patients (N = 277)
34.3
46.3
12.0
EE patients (N = 142)
27.8
42.9
15.1
1Patients with no regurgitation at baseline were excluded.
[Overall HB and RG Responders (mITT Population)]
Disclosure: MF Vaezi, R Fass, and N Vakil have served on medical advisory boards for Ironwood Pharmaceuticals, Inc. RS Mittleman, M Hall, DS Reasner, JZ Shao, Y Chen, L Lane, CR O'Dea, and MG Currie are Ironwood employees and may own stock or stock options in Ironwood Pharmaceuticals, Inc. P Kahrilas is a consultant for Ironwood Pharmaceuticals, Inc.
LB18 FOURTEEN-DAYS ESOMEPRAZOLE AND AMOXICILLIN CONTAINING HIGH DOSE DUAL THERAPY ACHIEVED AN EXCELLENT ERADICATION RATE IN THE TREATMENT OF FIRST-LINE ANTI-H. PYLORI THERAPY: A PROSPECTIVE RANDOMIZED TRIAL
W.-C. Tai, C.-C. Yao, C.-M. Liang, S.-K. Chuah
Kaohsiung Chang Gung Memorial Hospital, Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung, Taiwan
Contact E-Mail Address:luketai1019@gmail.com
Introduction: The first line eradication rate of standard triple therapy for Helicobacter pylori (H. pylori) infection has declined to < 80% relate to the increasing incidence of clarithromycin-resistant strains of H. pylori and novel therapies are needed.1–3 So far, it is still unclear which one is the best first-line H. pylori eradication regimen with least adverse effects. A novel high dose dual therapy is simple and involved only two drugs and the most important of all is that amoxicillin resistance is still very low globally.4,5 The key point to success for this therapy is that high dose proton-pump inhibitors (PPI) has been used in several studies for H. pylori eradication in order to increase the intra-gastric PH for optimal eradication. However, inconsistent eradication rates were reported in the literature for high dose PPI plus amoxicillin dual therapy.6, 7 A 10-day report of esomeprazole and amoxicillin containing high dose dual therapy by Zullo et al in Italy attained a near 90% eradication.8
Aims and Methods: Aims: To assess the efficacy of 14-day esomeprazole and amoxicillin containing high dose dual therapy.
Methods: We recruited 240 out of 278 eligible H. pylori-infected patients in the intention-to-treat (ITT analysis) after excluding those who had taken antibiotics, bismuth, PPI, within 4 weeks, were allergic to the medications used, had history of previous gastric surgery or serious concomitant illness, currently pregnant or those who refused to participate. They were randomly assigned to 14-day high-dose dual therapy (Esomeprazole 40 mg tid. and amoxicillin 750 mg qid. for 14 days, EA group, n = 120) or 7-day non-bismuth quadruple therapy (Esomeprazole 40 mg bid., clarithromycin 500 mg bid., amoxicillin 1 g bid. and metronidazole 500 mg bid. for 7 days, EACM group, n = 120). Eleven patients were lost during follow-up (5 in EA and 6 in EACM group, resulting in 115 for EA group and 114 in the per protocol (PP) study for EACM group. Urea breath tests were followed-up 8 weeks later.
Results: The eradication rates for EA and EACM groups were 91.7% (95% confidence interval [CI] = 85.3%–96.0%) and 86.7% (95% CI = 79.3%–92.2%) (p = 0.213) in ITT analysis; 95.7%(95% CI = 90.2%–98.6%) and 92.0%(95% CI = 85.4%–96.3%) (p = 0.255) in PP analysis. The adverse event rates were 9.6% vs. 22.8 % in the 2 groups (p = 0.006). The H. pylori culture positive rate was 91.8%. The antibiotic resistance rates were amoxicillin (0%), clarithromycin (15.5%) and metronidazole (34%). The H. pylori eradication rates for patients with dual resistant to both clarithromycin and metronidazole were 100% in the EA group and only 50% in the EACM group.
Conclusion: A 14-days high-dose dual therapy with esomeprazole and amoxicillin containing esomeprazole 40 mg thrice daily and amoxicillin 750 mg four times daily achieved an excellent eradication rate (95%) in the treatment of first-line anti-H. Pylori therapy in Taiwan with less adverse events.
The major outcomes of the two therapies
Eradication rate
EA (n = 115)
EACM (n = 114)
P-value
Intention-to-treat
91.7% (110/120)
87.5% (105/120)
0.291
Per-protocol
95.7% (110/115)
92.1% (105/114)
0.263
Adverse events
9.6% (11/115)
22.8% (26/114)
0.006
Compliance
100% (115/115)
100% (114/114)
–
Disclosure: Nothing to disclose
References
GrahamDYFischbachL. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut2010; 59: 1143–1153.GrahamDYLuHYamaokaY. Therapy for Helicobacter pylori infection can be improved: sequential therapy and beyond. Drugs2008; 68: 725–736.Tai WC, Liang CM, Lee CH, et al. Seven-day Non-Bismuth containing Quadruple Therapy Could Achieve a Grade “A” Success Rate for First-line Helicobacter pylori Eradication Biomed Res Int 2015; 62373.MegraudF. H.pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut2004; 53: 1374–84.MegraudF. Failed Eradication for Helicobacter pylori. What Should Be Done?Dig Dis2016; 34: 505–9.BayerdörfferEMiehlkeSMannesGA, et al.Double-blind trial of omeprazole and amoxicillin to cure Helicobacter pylori infection in patients with duodenal ulcers. Gastroenterology1995; 108: 1412–1417.GrahamDYJavedSUKeihanianSAbudayyehSOpekunAR. Dual proton pump inhibitor plus amoxicillin as an empiric anti-H. pylori therapy: studies from the United States. J Gastroenterol2010; 45: 816–820.ZulloA.RidolaL.FrancescoVD, et al.High-dose esomeprazole and amoxicillin dual therapy for first-line Helicobacter pylori eradication: a proof of concept study. Ann. Gastroenterol2015; 28: 448–51.
LB19 EARLY PULMONARY AND RENAL FUNCTION IN A FEASIBILITY RANDOMISED CONTROL TRIAL OF GOAL-DIRECTED FLUID THERAPY AFTER ORTHOTOPIC LIVER TRANSPLANTATION (COLT TRIAL)
F. Froghi1, V. Gopalan1, Z. Anastasiou2, R. Koti1, K. Gurusamy1, C. Eastgate3, M. McNeil3, H. Filipe3, M. Pinto3, J. Singh4, L. Longworth4, S. Mallett3, N. Schofield3, D. Thorburn5, D. Martin6, B.R. Davidson1; (COLT Study Group)
1UCL Division of Surgery & Interventional Sciences, HPB and Liver Transplantation, London, United Kingdom
2UCL Joint Research Office, Biostatistics Group, London, United Kingdom
3Royal Free Hospital, Critical Care Unit, London, United Kingdom
4PHMR, Health Economics, Pricing & Reimbursement, London, United Kingdom
5UCL Institute for Liver and Digestive Health, London, United Kingdom
6UCL Division of Surgery & Interventional Sciences, London, United Kingdom
Contact E-Mail Address:farid.froghi@nhs.net
Introduction: The safety of Goal-directed fluid therapy (GDFT) in patients with cirrhosis undergoing liver transplantation (LT) is unknown. This study reports secondary outcomes on the effect of GDFT on early pulmonary and renal function post-LT in patients recruited to Cardiac-output Optimisation following Liver Transplantation trial (COLT).
Aims and Methods: 60 patients with liver cirrhosis undergoing liver transplantation were randomised to GDFT [n = 30] or standard care (SC) [n-30] as per published COLT trial protocol1 (ISRCTN10329248). Total fluid administration and time to extubation was recorded. Pulmonary function was assessed by arterial blood gas (ABG) (pH, PaCO2, PaO2, HCO3, BE) and ventilator parameters (RR, TV, PEEP, PIP and PS) until extubation. PaO2:FiO2 ratio and pulmonary compliance were calculated. The KDIGO score was used for acute kidney injury score. Data is presented as medians and IQR for nonparametric data. Statistical analysis was performed using Minitab 17 software.
Results: GDFT group received a significantly higher total volume of fluid during the 12-hour intervention (GDFT 5316.7 ± 2334.77 mL vs. SC 3807.17 ± 1345.13 mL, p = 0.003); in particular crystalloids (GDFT 3500 ± 2750 mL vs. SC 2225 ± 1740 mL, p = 0.002) with no significant difference in volume of colloids, blood, FFP, platelets, cryoprecipitates or other infusions. No difference was demonstrated in time to extubation (GDFT 12.5 ± 39.5 hrs vs. 12 ± 33 hrs, p = NS), PaO2:FiO2 ratios, pulmonary compliance, ventilatory or blood gas parameters (table 1). There was a significant rise in creatinine on the first two post-operative days in both groups (baseline 77 µmol/L, day1 87 µmol/L p = 0.039, day2 107 µmol/L p = 0.001). There was no difference in the highest KDIGO scores for the first 7 days post-LT.
Conclusion: In this randomised feasibility study, there were no adverse effects on short-term pulmonary and renal function despite receiving more fluids in GDFT post-LT.
Parameter
GDFT (median, [IQR])
SC (median, [IQR])
P-value
PaCO2 (kPa)
ITU admission
4.960, [0.730]
5.160, [0.620]
0.274
12 hours
4.745, [0.708]
4.695, [0.625]
0.891
Day 3
5.270, [1.793]
5.220, [0.850]
0.722
PaO2 (kPa)
ITU admission
23.60, [10.320]
21.710, [14.045]
0.611
12 hours
13.260, [3.203]
13.585, [4.080]
0.435
Day 3
13.535, [4.303]
12.570, [2.930]
0.218
FiO2 (%)
ITU admission
0.440, [0.250]
0.440, [0.100]
0.861
12 hours
0.300, [0.078]
0.300, [0.078]
0.751
Day 3
0.350, [0.100]
0.290, [0.050]
0.328
PaO2:FiO2 ratio
ITU admission
417.64, [280]
373.41, [173]
0.601
12 hours
316.57, [76]
315.56, [108]
0.804
Day 3
318.03, [125]
329.73, [89]
1.00
Pulmonary Compliance (ml/cmH2O)
ITU admission
39.112, [17.325]
45.175, [27.803]
0.137
12 hours
40.670, [37.63]
49.140, [54.213]
0.493
Day 2
30.958, [14.570]
45.197 [17.848]
0.175
[Pulmonary function parameters]
Disclosure: Nothing to disclose
Reference
FroghiFKotiRGurusamyKMallettSThorburnDSelvesL, et al.Cardiac output Optimisation following Liver Transplant (COLT) trial: study protocol for a feasibility randomised controlled trial. Trials2018; 19: 1–9.
LB20 RANDOMIZED CONTROLLED CLINICAL TRIAL: FAECAL MICROBIOTA TRANSPLANTATION (FMT) IS SUPERIOR TO BOTH FIDAXOMICIN AND VANCOMYCIN MONOTHERAPIES FOR RECURRENT CLOSTRIDIUM DIFFICILE-ASSOCIATED DISEASE
C.L. Hvas1, S.M.D. Jørgensen1, S.P. Jørgensen1, M. Storgaard2, L. Lemming3, C. Erikstrup4, J.F. Dahlerup1
1Aarhus University Hospital, Department of Hepatology and Gastroenterology, Aarhus N, Denmark
2Aarhus University Hospital, Department of Infectious Diseases, Aarhus N, Denmark
3Aarhus University Hospital, Department of Clinical Microbiology, Aarhus N, Denmark
4Aarhus University Hospital, Department of Clinical Immunology, Aarhus N, Denmark
Contact E-Mail Address:chrishva@rm.dk
Introduction: Faecal microbiota transplantation (FMT) is recommended for recurrent Clostridium difficileinfection (rCDI), but its effect relative to that of new antibiotic treatments is unknown.
Aims and Methods: We investigated the clinical and microbiological effects of FMT in comparison with those of fidaxomicin and vancomycin. This was a single-centre, randomized, controlled, open label clinical trial. We randomized 64 adult patients with rCDI to 10 days of either vancomycin 125 mg QID followed by one FMT applied by colonoscopy or nasojejunal tube (n = 24), fidaxomicin 200 mg BID (n = 24), or vancomycin 125 mg QID (n = 16). Primary outcome was clinical resolution and a negative Clostridium difficile (CD) toxin test 8 weeks following the allocated treatment. Secondary endpoints included clinical resolution at week 8.
Results: All 64 patients received the allocated treatment. Combined clinical and microbiological resolution was achieved in 17 (71%) of 24 treated with vancomycin plus FMT, 8 (33%) of 24 treated with fidaxomicin, and 3 (19%) of 16 treated with vancomycin (FMT vs. fidaxomicin p = 0.009; FMT vs. vancomycin p = 0.001; fidaxomicin vs. vancomycin p = 0.31). Clinical resolution was obtained in 22/24 (92%) with vancomycin plus FMT, 10/24 (42%) with fidaxomicin, and 3/16 (19%) with vancomycin (p = 0.0002; p < 0.0001; p = 0.13). One serious adverse event could be related to FMT. No deaths occurred.
Conclusion: Vancomycin plus FMT was superior to both fidaxomicin and vancomycin monotherapies for recurrent Clostridium difficile infection, both with regard to combined clinical and microbiological resolution and to clinical resolution alone. Serious adverse events were observed but occurred infrequently.
Disclosure: Nothing to disclose
LB21 CHARACTERIZATION OF ESOPHAGEAL MICROBIOTA IN PATIENTS WITH BARRETT´S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA
L.R. Lopetuso1, G. Ianiro2, M. Severgnini3, S. Pecere4, I. Boskoski5, G. Quaranta6, T. Camboni3, F. Scaldaferri7, M.E. Riccioni8, L. Masucci9, C. Consolandi3, A. Gasbarrini10, G. Costamagna11, G. Cammarota12
1Catholic University of Rome, Gastroenterological Area, Gastroenterological and Endocrino-Metabolical Sciences Department, Rome, Italy
2Catholic University School Of Medicine, Internal Medicine, Gastroenterology and Liver Unit, Rome, Italy
3Italian National Research Council, Institute of Biomedical Technologies, Milan, Italy
4Catholic University of Rome, Gemelli Hospital, Rome, Italy
5Catholic University of Rome Digestive Endoscopy Unit, Digestive Endoscopy Unit, Rome, Italy
6Università Cattolica del Sacro Cuore, Microbiology, Rome, Italy
7Catholic University of Rome Dept. of Internal Medicine Dept. of Gastroenterology, Internal Medicine, Gastroenterology Division, IBD Unit, Rome, Italy
9Università Cattolica del Sacro Cuore, Microbiology Department, Rome, Italy
10Catholic University, Gemelli University Hospital, Internal Medicine, Gastroenterology and Liver Diseases, Rome, Italy
11Università Cattolica del Sacro Cuore, Digestive Endoscopy Unit, Roma, Italy
12Catholic Univerisity, Fondazione Policlinico Gemelli, Internal Medicine and Gastroenterology, Rome, Italy
Contact E-Mail Address:lopetusoloris@libero.it
Introduction: Despite the introduction of innovative therapies, the prognosis in patients with Esophageal Adenocarcinoma (EAC) remains poor. Thus, improved diagnostic tools to accurately dissect the risk factors that drive the transition from normal epithelium to Barrett´s Esophagus (BE) and EAC represent a clear need for new therapeutic alternatives.
Aims and Methods: The aim of our study was to characterize esophageal microbiota composition in patients with BE and EAC. In an observational prospective study, we analyzed the microbiota composition of the distal esophagus in subjects with BE and EAC. A total of 26 patients was enrolled: 10 without any endoscopic sign of pathological mucosa, as control group; 10 with a new diagnosis of BE; and 6 with a new diagnosis of distal esophageal/esophagogastric junction cancer, confirmed histologically. Genomic DNA was extracted from distal esophagus biopsies and V3-V4 regions of the 16S rRNA gene were sequenced by MiSeq Illumina platform. In patients with BE, biopsies were obtained from both the esophageal metaplastic lesion (BEM) and the normal esophageal mucosa (BEU).
Results: BE and EAC patients showed an overall higher level of biodiversity which was statistically significant between BE and control patients (Wilcoxon test for Phylogenetic Diversity Whole Tree metric p < 0.05). When evaluating β-diversity, a robust separation on the first axis was observed for unweighted Unifrac, in which control samples were significantly separated from both BE (p < 0.005) and EAC (p < 0.05), as well as BE were substantially diverging from EAC (p < 0.05). BEU samples showed significant higher values of α-diversity (PD whole tree) when compared with control patients (p < 0.05), while BEM shared similar values with EAC, being lower than BEU and higher than control patients. A substantial divergence on the first axis was registered for unweighted Unifrac with control patients significantly separated from BEU (p < 0.005) and EAC samples (p < 0.05). Among phyla, relative abundance analysis revealed a lower level of Firmicutes and a significantly higher percentage of Bacteroidetes in BEU and EAC compared with control subjects. In addition, BEU and BEM exhibited a significantly higher presence of Fusobacteria compared with control samples. At genus level, Streptococcus relative abundance showed a progressive reduction in the disease spectrum from controls to EAC with its percentage significantly lower in EAC when compared with BEM and control samples. Conversely, Veillonella exhibited a gradual abundance increase in this spectrum, being consistently higher in EAC and BEU when compared with control subjects. Porphyromonas and Prevotella resulted consistently higher in BEU, and in both BEU and EAC, respectively, compared with controls. Actinobacillus was significantly higher in both BEU and BEM compared with controls and EAC. Similarly, Fusobacterium and Leptotrichia levels were consistently increased in BEU and in both BEU and BEM, respectively, when compared with controls.
Conclusion: Taken together, these data describe a specific microbial signature for both BE and EAC and open new horizons towards the identification of potential risk factors and innovative diagnostic/therapeutic tools. Further studies are underway to determine the exact implications that sustain these findings.
