Eldelumab [anti-interferon-γ-inducible protein-10 antibody] Induction Therapy for Active Crohn's Disease: a Randomised, Double-blind, Placebo-controlled Phase IIa Study.

BACKGROUND AND AIMS: This 11-week Phase IIa induction study evaluated the efficacy and safety of eldelumab in patients with active Crohn's disease. METHODS: Adults with Crohn's Disease Activity Index 220-450 were randomised 1:1:1 to placebo or eldelumab 10 or 20 mg/kg intravenously on Days 1 and 8, and alternate weeks thereafter. All patients underwent ileocolonoscopy at baseline. Patients with active inflammation according to the Simplified Endoscopic Score for Crohn's Disease criteria [the originally planned endoscopy cohort] underwent another ileocolonoscopy at Week 11 at the investigator's discretion. All ileocolonoscopies were centrally read. The primary objective was identification of the eldelumab target exposure for induction of remission [absolute Crohn's Disease Activity Index score < 150]. Rates of clinical response [reduction of ≥ 100 from baseline or absolute score < 150 Crohn's Disease Activity Index], remission, and endoscopic improvements were also assessed. RESULTS: A total of 121 patients were randomised. The eldelumab exposure-remission relationship was not significant at Week 11. Numerically higher remission and response rates were reported with eldelumab 20 mg/kg [29.3% and 41.5%, respectively] and 10 mg/kg [22.5% and 47.5%] versus placebo [20.0% and 35.0%]. A higher proportion of patients with a baseline Simplified Endoscopic Score for Crohn's Disease > 2 who received eldelumab achieved a 50% improvement in score and greater reductions from baseline endoscopy scores overall versus placebo. Adverse events were comparable across treatment groups. CONCLUSIONS: No exposure-remission relationship was seen with eldelumab. Eldelumab induction treatment demonstrated trends towards clinical and endoscopic efficacy. Safety was consistent with that reported previously. ClinicalTrials.gov identifier: NCT01466374.

Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial.

OBJECTIVE: Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn's disease (CD). DESIGN: Seventy-eight patients (aged ≥18 and ≤75 years) with CD for ≥3 months, Crohn's Disease Activity Index (CDAI) ≥220 and ≤450 and either C-reactive protein ≥10 mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (ΔCDAI) from baseline to week 4. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment. RESULTS: Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 ΔCDAI=-16); however, there was a significant difference by week 12 (ΔCDAI=-55; p≤0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n=28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI ≥330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed. CONCLUSIONS: A single SC dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD. TRIAL REGISTRATION NUMBER: NCT01203631.

Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease. METHODS: We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. FINDINGS: Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. INTERPRETATION: Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile. FUNDING: Galapagos.

The Use of Interventional Radiology Techniques in the Treatment of Pancreatic Fistula.

One of the complications of pancreatic disease is the formation of pancreatic fistulae. The presence of fistula leads to body wasting and cachexia. The standard treatment is intubation of the Wirsung duct and in cases where there are no improvements the next proposed form of treatment is surgery. The aim of the study was to evaluate the efficacy of pancreatic fistula closure using interventional radiology techniques. In 2009 to 2014, 46 patients diagnosed with pancreatic fistula were treated with interventional radiology techniques. Treatment consisted of vascular coil implanted at the entry of the fistula and then sealed with tissue glue adhesive during endoscopic procedure. Technical success of vascular coil implantation and the use of tissue glue adhesive were reported in all patients. Pancreatic fistula recurred in 7 patients (15.2%). The latter group of patients underwent statistical analysis to determine what the risk factors in recurring pancreatic fistulas were. The results indicate a significant relationship between etiology of the fistula and treatment effect. IN CONCLUSION: (1) the use of interventional radiology methods in the closure of pancreatic fistula is an effective and safe procedure; and (2) the recurrence of fistula is dependent on the etiology and often occurs after surgery or trauma.

Clinical Effects of a Topically Applied Toll-like Receptor 9 Agonist in Active Moderate-to-Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Toll-like receptors [TLRs] are potential drug targets for immunomodulation. We determined the safety and efficacy of the TLR-9 agonist DNA-based immunomodulatory sequence 0150 [DIMS0150] in ulcerative colitis [UC] patients refractory to standard therapy. METHODS: In this randomized, double-blind, placebo-controlled trial, 131 patients with moderate-to-severe active UC were randomized to receive two single doses of the oligonucleotide DIMS0150 [30 mg] or placebo administered topically during lower GI endoscopy at baseline and Week 4. The primary endpoint was clinical remission, defined as Clinical Activity Index [CAI] ≤4, at Week 12. Secondary endpoints included mucosal healing and symptomatic remission of key patient-reported outcomes [absence of blood in stool and weekly stool frequency <35]. RESULTS: There was no statistical significant difference between the groups in the induction of clinical remission at Week 12, with 44.4% in the DIMS0150 group vs. 46.5% in the placebo group. However, the proportion of patients who achieved symptomatic remission was 32.1% in the DIMS0150 group vs. 14.0% in the placebo group at Week 4 [p = 0.020], and 44.4% vs. 27.9% at Week 8 [p = 0.061]. More patients on DIMS0150 compared with those on placebo had mucosal healing [34.6% vs. 18.6%; p = 0.09] and histological improvement regarding the Geboes score [30.9% vs. 9.3%; p = 0.0073] at Week 4. Significantly more patients on DIMS0150 were in clinical remission with mucosal healing at Week 4: 21% vs. 4.7% in the placebo group [p = 0.02]. DIMS0150 was well tolerated, and no safety signals compared with placebo were evident. CONCLUSIONS: Therapy with the topically applied TLR-9 agonist DIMS0150 is a promising and well-tolerated novel therapeutic option for treatment-refractory, chronic active UC patients, warranting further clinical trials.

Results of endoscopic and surgical fistula treatment in oesophagointestinal anastomosis after gastrectomy.

INTRODUCTION: Intestinal fistulas occur in 4-8% of cases of upper gastrointestinal tract surgery. Until now, surgery has been the standard of treating fistulas in oesophagointestinal anastomosis. The use of stents and haemoclips still causes much controversy, but more and more publications present good results with this type of treatment. AIM: To present results of endoscopic and surgical treatment of fistulas in oesophagointestinal anastomosis after gastrectomy. MATERIAL AND METHODS: A fistula in the oesophagointestinal anastomosis was observed in 23 (4.8%) patients within an 18-year period. The indications for endoscopic treatment were small fistulas (< 50 ml/day), and large (> 50 ml/day) fistulas in subjects with no symptoms of peritonitis or abscess were treated with implantation a of covered stent. Surgical treatment was performed with a large fistula leading to peritonitis and complicated gangrene of margins and/or the presence of abscess. RESULTS: Four subjects were treated endoscopically with the use of haemoclips, resulting in 50% technical and clinical success. We implanted stents in 12 patients. Technical success was achieved in all the patients, yet permanent closure of the fistula was reported for 8 (66%) subjects. The percentage of patients operated on for fistula was 33%. We recorded 4 deaths in this group. CONCLUSIONS: The use of haemoclips in treatment of small fistulas, and self-expandable, covered stents in treatment of medium and large fistulas, is an effective method that shortens the hospitalisation period and accelerates introduction of oral nutrition while reducing the number of fatal complications.

Multiple orifices are better than single in the endoscopic treatment of pancreatic pseudocysts.

BACKGROUND/AIMS: The aim of this study was to compare the surgical drainage of large, symptomatic pancreatic cysts (>5 cm) with single- and multi-channel endoscopic drainage. MATERIALS AND METHODS: In the period 2005-2010, we treated 112 patients with post-inflammatory pancreatic cysts. Thirty-six patients underwent surgical internal drainage. The remaining group of patients was treated endoscopically. In 28 of them, drainage was performed by anastomosing the cyst to the gastrointestinal tract using a single pig tail drain and then widening the channel to a diameter of 15 mm. Forty-eight patients underwent multi-channel cystic drainage. It consisted of connecting the cyst to the stomach and/or duodenum using at least 3 drains. Each connection was widened to a minimum diameter of 15 mm to ensure free drainage of the morphotic elements of the cyst. Each procedure was preceded by abdominal computed tomography to determine the exact location of the cyst in relation to the gastrointestinal tract and a Doppler ultrasound scan to determine the location of the blood vessels modeling on its surface. RESULTS: In 48 patients with multi-channel drainage, there was no obstruction of the anastomosis, and cysts closed within 4 months. The drains were removed after about 3 months. The created channels were patent for about 3-4 weeks, which was enough to completely close the cyst. CONCLUSION: Multi-channel endoscopic anastomosis of pancreatic cyst to the gastrointestinal tract is a very effective method for drainage of large post-inflammatory pancreatic cysts, comparable in terms of effectiveness with the surgical method but less invasive.

A randomized controlled trial of the efficacy and safety of CCX282-B, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn's disease.

UNLABELLED: CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn's disease. Crohn's Disease Activity Index (CDAI) scores were 250-450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn's medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥ 70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT00306215.