Safety and Durability of RBX2660 (Microbiota Suspension) for Recurrent Clostridium difficile Infection: Results of the PUNCH CD Study.

BACKGROUND: Managing recurrent Clostridium difficile infection (CDI) presents a significant challenge for clinicians and patients. Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent CDI, yet availability of a standardized, safe, and effective product has been lacking. Our aim in this study was to assess the safety and effectiveness of RBX2660 (microbiota suspension), a commercially prepared FMT drug manufactured using standardized processes and available in a ready-to-use format. METHODS: Patients with at least 2 recurrent CDI episodes or at least 2 severe episodes resulting in hospitalization were enrolled in a prospective, multicenter open-label study of RBX2660 administered via enema. Intensive surveillance for adverse events (AEs) was conducted daily for 7 days following treatment and then at 30 days, 60 days, 3 months, and 6 months. The primary objective was product-related AEs. A secondary objective was CDI-associated diarrhea resolution at 8 weeks. RESULTS: Of the 40 patients enrolled at 11 centers in the United States between 15 August 2013 and 16 December 2013, 34 received at least 1 dose of RBX2660 and 31 completed 6-month follow-up. Overall efficacy was 87.1% (16 with 1 dose and 11 with 2 doses). Of 188 reported AEs, diarrhea, flatulence, abdominal pain/cramping, and constipation were most common. The frequency and severity of AEs decreased over time. Twenty serious AEs were reported in 7 patients; none were related to RBX2660 or its administration. CONCLUSIONS: Among patients with recurrent or severe CDI, administration of RBX2660 via enema appears to be safe and effective. CLINICAL TRIALS REGISTRATION: NCT01925417.

Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study.

OBJECTIVE: Interferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC. DESIGN: In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure-response relationship and histological improvement. RESULTS: 109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108-235 µg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events. CONCLUSIONS: Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose-response studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00656890.

Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.

BACKGROUND & AIMS: Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. METHODS: We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 µg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 µg/g. Secondary outcomes were continued remission with FC <100 µg/g or <200 µg/g (among patients with pre-randomization values above these levels). RESULTS: The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 µg/g (P = .04) and 200 µg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 µg/g compared with those with FC <200 µg/g (P = .01). CONCLUSIONS: Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145.

Computer-assisted personalized sedation for upper endoscopy and colonoscopy: a comparative, multicenter randomized study.

BACKGROUND: The SEDASYS System is an investigational computer-assisted personalized sedation system integrating propofol delivery with patient monitoring to enable endoscopist/nurse teams to safely administer propofol. OBJECTIVE: To compare the safety and effectiveness of the SEDASYS System to the current standard of care for sedation during routine endoscopic procedures. DESIGN: Nonblinded multicenter randomized comparative study. SETTING: Four ambulatory surgery centers, 3 endoscopy centers, and 1 academic center in the United States. PATIENTS: One thousand American Society of Anesthesiologists physical status class I to III adults undergoing routine colonoscopy or EGD. INTERVENTIONS: Sedation with the SEDASYS System (SED) and sedation with each site's current standard of care (CSC; benzodiazepine/opioid combination). MAIN OUTCOME MEASUREMENTS: Area under the curve of oxygen desaturation was the primary endpoint. Secondary endpoints included patient satisfaction, clinician satisfaction, level of sedation, and patient recovery time. RESULTS: Four hundred ninety-six patients were randomized to SED and 504 to CSC. Area under the curve of oxygen desaturation was significantly lower for SED (23.6 s·%) than for CSC (88.0 s·%; P = .028). Patients were predominately minimally to moderately sedated in both groups. SED patients were significantly more satisfied than CSC patients (P = .007). Clinician satisfaction was greater with SED than with CSC (P < .001). SED patients recovered faster than CSC patients (P < .001). The incidence of adverse events was 5.8% in the SED group and 8.7% in the CSC group. LIMITATIONS: Nonblinded. CONCLUSIONS: The SEDASYS System could provide endoscopist/nurse teams a safe and effective on-label means to administer propofol to effect minimal to moderate sedation during routine colonoscopy and EGD.

Gut microbiome identifies risk for colorectal polyps.

OBJECTIVE: To characterise the gut microbiome in subjects with and without polyps and evaluate the potential of the microbiome as a non-invasive biomarker to screen for risk of colorectal cancer (CRC). DESIGN: Presurgery rectal swab, home collected stool, and sigmoid biopsy samples were obtained from 231 subjects undergoing screening or surveillance colonoscopy. 16S rRNA analysis was performed on 552 samples (231 rectal swab, 183 stool, 138 biopsy) and operational taxonomic units (OTU) were identified using UPARSE. Non-parametric statistical methods were used to identify OTUs that were significantly different between subjects with and without polyps. These informative OTUs were then used to build classifiers to predict the presence of polyps using advanced machine learning models. RESULTS: We obtained clinical data on 218 subjects (87 females, 131 males) of which 193 were White, 21 African-American, and 4 Asian-American. Colonoscopy detected polyps in 56% of subjects. Modelling of the non-invasive home stool samples resulted in a classification accuracy >75% for Naïve Bayes and Neural Network models using informative OTUs. A naïve holdout analysis performed on home stool samples resulted in an average false negative rate of 11.5% for the Naïve Bayes and Neural Network models, which was reduced to 5% when the two models were combined. CONCLUSION: Gut microbiome analysis combined with advanced machine learning represents a promising approach to screen patients for the presence of polyps, with the potential to optimise the use of colonoscopy, reduce morbidity and mortality associated with CRC, and reduce associated healthcare costs.

The validity of breath collection bags method in detecting Helicobacter pylori using the novel BreathID ® Hp Lab System: a multicenter clinical study in 257 subjects.

BACKGROUND AND AIM: The BreathID ® Hp urea breath test provides several advantages over other 13C breath analyzers for the detection of Helicobacter pylori. We evaluated the sensitivity and specificity of a new BreathID ® Hp Lab System (Exalenz Bioscience Ltd, Israel), a 13C-urea breath test system using breath sampling bags that facilitates multiple testing in a multicenter international clinical study. METHODS: A total of 257 subjects with evaluable results for urea breath test, rapid urease test, and histology were enrolled into two study groups: 189 naïve subjects were included in the pre-therapy group, and 68 subjects comprised the post-eradication therapy group. Analytical studies were conducted to evaluate the stability, reproducibility, and repeatability of the 13C-urea breath test results using a delta over baseline cut-off value of 5. RESULTS: Among the pre-therapy subjects evaluated with the composite results from the rapid urease test and histology/immunohistochemistry, 176 results matched those of the urea breath test, resulting in an overall agreement of 98.3% with a sensitivity of 100% and specificity of 97.9%. In the post-eradication therapy cohort, the overall agreement between the urea breath test and the biopsy diagnosis was 98.5%; the sensitivity of the urea breath test in this cohort was 92.3% and the specificity was 100%. There was uniformly high overall reproducibility (99.48%) of the test results over different batches of breath sample bags, when analyzed on different days and under different storage conditions, showing stability of the breath samples in the breath collection bags. CONCLUSION: The BreathID ® Hp Lab System is a highly accurate and dependable method for the diagnosis of H. pylori infection.

Safety evaluation of fospropofol for sedation during minor surgical procedures.

STUDY OBJECTIVE: To evaluate the safety of intravenous (IV) fospropofol when used to provide minimal to moderate sedation in patients undergoing minor surgical procedures. DESIGN: Phase 3, open-label, single-arm study. SETTING: Multi-center. PATIENTS: 123 ASA physical status I, II, III, and IV patients, aged>or=18 years. INTERVENTIONS: Patients were pretreated with fentanyl 50 microg before receiving an initial dose of IV fospropofol 6.5 mg/kg. Patients could receive up to 5 supplemental doses of fospropofol 1.63 mg/kg to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score

Extracorporeal photopheresis for the treatment of refractory Crohn's disease: results of an open-label pilot study.

BACKGROUND: Extracorporeal photopheresis (ECP) is effective in immune-mediated disorders. A prospective, uncontrolled pilot study was conducted to evaluate the safety and efficacy of ECP in patients with active Crohn's disease (CD) who were refractory to or intolerant of immunosuppressants and/or anti-TNF therapies. METHODS: Patients with moderate-to-severely active CD (Crohn's Disease Activity Index [CDAI] 220-450 points) underwent 12 weeks of ECP treatment (Weeks 1-4: twice weekly, every week; Weeks 5-12: twice weekly, every other week). Clinical response was defined as a decrease in the CDAI of >or=100 points or remission (CDAI <150 points) at Week 12. Patients who responded at Week 12 could receive an additional 12 weeks of ECP treatment (twice weekly, every other week) in an extension study. RESULTS: Twenty-eight patients were enrolled with a mean baseline CDAI score of 314 (range 207-457). At Week 12, 14 patients (50%) responded; 13 patients responded within 6 weeks. Seven patients (25%) attained remission by Week 12. Three of 5 patients with open fistulae at baseline had fistula closure. Response was similar among patients naïve to anti-TNF agents and patients who had previously been refractory or intolerant to anti-TNF agents. Of the 12 patients who entered the extension study, 9 (75%) maintained their response at Week 24. CONCLUSIONS: In patients with moderate-to-severely active CD who were refractory to or intolerant of immunosuppressants and/or anti-TNF agents, ECP was well tolerated and induced clinical response (50%) and remission (25%) in patients. Most patients were able to maintain a response with continued treatments.

Disseminated intravascular coagulation in an ambulatory young woman.

We are reporting the case of an ambulatory young woman with a 10-year history of recurrent venous thrombosis who presented to us with diffuse intravascular coagulation (DIC). After excluding the recognized causes of DIC, we examined the possibility that her clinically quiescent ulcerative colitis might be the underlying stimulus. We documented sepsis-range endotoxemia in this patient at a time when she was afebrile and had a normal C-reactive protein level. In vitro her serum upregulated tissue factor in cultured endothelial cells. We postulate that she had become tolerant to the systemic effects of endotoxin leaking from her inflamed colon but that the endotoxin stimulated her endothelium and/or monocytes to produce tissue factor that made her intensely hypercoagulable. Her prothrombotic state may have been compounded by the fact that she was heterozygous for prothrombin G20210A and that her plasma clotting time demonstrated resistance to activated protein C.

Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis.

OBJECTIVE: Balsalazide is a novel azo-bonded 5-aminosalicylic acid treatment for mild-to-moderate ulcerative colitis. The study objective was to compare symptomatic remission rates with balsalazide and mesalamine while controlling for extent of disease and time since diagnosis in patients with active, mild-to-moderate ulcerative colitis. METHODS: A total of 173 patients with sigmoidoscopically verified ulcerative colitis were randomized to 8 wk of double-blind treatment with balsalazide 6.75 g/day or mesalamine 2.4 g/day. Both treatments provided 2.4 g/day of oral 5-aminosalicylic acid. Patients maintained symptom diaries throughout the treatment period. RESULTS: Overall, 46% of balsalazide- and 44% of mesalamine-treated patients achieved symptomatic remission. Higher response rates were noted in newly diagnosed patients with < or = 40 cm of disease (68% vs 61%) than in recently relapsed patients with >40 cm of disease (36% vs 25%). The median time to symptomatic remission was 12 days shorter with balsalazide (25 days) than with mesalamine (37 days). Significantly more balsalazide patients showed sigmoidoscopic (p = 0.002), stool frequency (p = 0.006), rectal bleeding (p = 0.006), and physician's global assessment score (p = 0.013) improvement by 14 days than did mesalamine patients. Similar proportions of patients reported adverse events (54% vs 64%), which were most commonly related to the gastrointestinal and central and peripheral nervous systems. CONCLUSIONS: Balsalazide is an effective and safe treatment for mild-to-moderate ulcerative colitis. Improvement of symptoms occurs considerably earlier with balsalazide than with mesalamine.