Ulcerative Colitis Trials Research Articles

Histological Remission in Ulcerative Colitis: Under the Microscope Is the Cure.

In recent years, the therapeutic goals in ulcerative colitis (UC) have become increasingly stringent. Histological features seem to be a reliable predictor of disease outcomes after therapy, and histological remission (HR) is the new frontier in the treatment of UC. Here, we first provide a historical perspective before reviewing indexes in the era of biologics; histology as a treatment goal in UC trials; the poor correlation between symptoms, endoscopy, and histology; and the impact of histology on disease outcomes. HR seems to be a promising end point for the treatment of UC because it is typically associated with better outcomes. Two new validated indexes are available to assess histology more accurately in trials, and they may also be applicable to clinical practice. Additional interventional trials are now necessary to establish definitions of HR and its potential for disease modification.

770 Relationship Between Protocol Specified Corticosteroid Tapering Regimens and Achieving Outcome Measures in Patients With Moderate-Severe Ulcerative Colitis and Crohn's Disease

INTRODUCTION: Corticosteroid-free clinical remission is an important clinical outcome, yet is inconsistently defined and reported in clinical trials. We summarized the protocol specified corticosteroid tapering regimens in clinical trials of moderate-severe ulcerative colitis (UC) and Crohn's disease (CD), and calculated differences in rates of clinical remission versus corticosteroid-free clinical remission (CSF-CR). METHODS: Through a systematic literature review through February 28, 2019, we identified 16 randomized controlled trials (RCTs) of biologics or small molecules in patients with moderate-severe UC or CD that reported CSF-CR as an outcome. We estimated relative risk (RR) [and 95% confidence interval (CI)] of achieving CSF-CR vs. overall clinical remission in patients treated with active intervention or placebo, through random effects meta-analysis. RESULTS: Across trials of UC (11 trials) and CD (5 trials), median 53% (range, 28-81%) and 49% (range, 42-56%) participants were on corticosteroids at time of trial entry, respectively. Participants were allowed to enter trials at median corticosteroid dose 35 mg/d (range, 20-40 mg/d). Doses were kept stable for median 8 weeks (range, 5-10 weeks) during induction therapy, after which a mandatory and structured tapered was implemented, albeit with investigators discretion depending on clinical status. For maintenance trials, pooled rates of CSF-CR in patients with UC (n = 11) treated with placebo was 9.7% (95% CI, 6.8-13.6% vs. overall clinical remission: 14.2%; 95% CI, 10.6-18.7) and with CD (n = 5), 19.1% (95% CI, 11.3-30.2 vs. overall clinical remission: 25.7%; 95% CI, 16.4-37.7). In UC trials, the rate of CSF-CR was 24% lower than the rate of overall clinical remission (RR, 0.76; 95% CI, 0.67-0.86; placebo: RR, 0.74; 95% CI, 0.56-0.97). In patients with CD, rate of CSF-CR was 18% lower than rate of overall clinical remission (RR, 0.82; 95% CI, 0.72-0.94; placebo: RR, 0.75; 95% CI, 0.57-0.98). CONCLUSION: This is the first systematic review and meta-analysis to study corticosteroids handling across clinical trials. Protocol specified corticosteroid tapering regimens varies across trials with considerable investigator discretion. Rates of CSF-CR is 20-25% lower than overall clinical remission. These findings will help to inform design and interpretation of future clinical trials and highlight the need for standardization.

835 Can Ustekinemab Relieve the Symptoms of IBD-Associated Arthropathy?

INTRODUCTION: Arthropathy is the most common extra intestinal manifestation observed in patients with Inflammatory Bowel Disease (IBD). Various studies have shown that up to 40% or more of patients with IBD may experience arthropathy. Ustekinemab is a relatively new drug approved for the management of moderate to severe Crohn’s disease (Oct 2016) and phase 3 trials for ulcerative colitis have now been completed. It is also FDA approved for management of psoriatic arthritis. The purpose of this study was to determine if a small cohort of patients with enteroarthropathy had symptom improvement while receiving ustekinemab in a longitudinal retrospective cohort. METHODS: Adult patients with IBD and arthropathy with who were treated with ustekinumab were included in the cohort. We followed the minimal disease activity index (MDA) which includes 7 broadly accepted parameters. We chose to collect data on 5 of those parameters including 1) joint tenderness, 2) swollen joint count, 3) tender points, 4) standardized graphic pain scales (VAS or GRS), and 5) a global assessment score from 0-5 (GAS). Two parameters (psoriatic area and severity index and health disability index) were not assessed. At each visit outcome measures were evaluated for changes in arthritic symptoms. RESULTS: 15 patients were included for review. 11 had Crohn’s disease and 4 had ulcerative colitis. Patients were followed for an average of 12 months (range 9-16). Eleven of 15 patients had joint tenderness on palpation at the start of therapy with 1 to 3 affected joints per patient while the others had subjective tenderness. Five patients had visibly swollen joints and 1 had both. The mean GAS was 3 with a range of 2 to 4. The pain GRS had a mean score of four out of 10 with a range of 2 to 8. The mean number of tender points was 3. After ustekinumab therapy, 14 of 15 patients had a drop in the global assessment score and the pain GRS score. Fourteen patients had resolution of joint swelling and tenderness. At the conclusion of the study, 6 of 15 patients complete resolution of all five scales. Four patients had resolution in three of the five scales, while 4 patients had resolution of two of the five scales. 1 patient did not exhibit improvement in any area. CONCLUSION: In this small observational cohort, ustekinumab improved arthropathy in 14 of 15 patients. We hope this stimulates interest in trials observing larger number of patients with this debilitating extra international manifestation of IBD.

Multitasking Kinase RIPK1 Regulates Cell Death and Inflammation.

Receptor-interacting serine threonine kinase 1 (RIPK1) is a widely expressed kinase that is essential for limiting inflammation in both mice and humans. Mice lacking RIPK1 die at birth from multiorgan inflammation and aberrant cell death, whereas humans lacking RIPK1 are immunodeficient and develop very early-onset inflammatory bowel disease. In contrast to complete loss of RIPK1, inhibiting the kinase activity of RIPK1 genetically or pharmacologically prevents cell death and inflammation in several mouse disease models. Indeed, small molecule inhibitors of RIPK1 are in phase I clinical trials for amyotrophic lateral sclerosis, and phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. This review focuses on which signaling pathways use RIPK1, how activation of RIPK1 is regulated, and when activation of RIPK1 appears to be an important driver of inflammation.

The Impact of Raising the Bar for Clinical Trials in Ulcerative Colitis.

In order to identify the practical implications for both health care practitioners and patients in understanding differences between the results of trials assessing therapies for ulcerative colitis [UC], we reviewed clinical trials of therapies for moderate to severe UC, with a focus on trial design. Over time, patient populations in UC trials have become more refractory, reflecting that patients are failing treatment with additional and different classes of drug, including conventional therapies, immunosuppressant drugs, and anti-tumour necrosis factor therapies. Outcomes used to measure efficacy have become increasingly stringent in order to meet the expectations of patients and physicians, and the requirements of regulatory bodies. Trial design has also evolved to integrate induction and maintenance therapy phases, so as to facilitate patient recruitment and to answer clinically important questions such as how efficacious therapies are in specific subpopulations of patients and during long-term use. As UC clinical trial design continues to evolve, and with limited head-to-head trials and real-world comparative effectiveness studies evaluating UC therapies, careful judgment is required to appreciate the differences and similarities in trial designs, and to understand how these variances may affect the observed efficacy and safety outcomes.

Factors Affecting Clinical and Endoscopic Outcomes of Placebo Arm in Trials of Biologics and Small Molecule Drugs in Ulcerative Colitis: A Meta-Analysis.

Previous systematic cumulative analyses of the placebo arm in ulcerative colitis (UC) were limited by the wide heterogeneity in the scores and definitions of response. We aimed at estimating the placebo rates of remission, response, and mucosal healing (MH) in phase 2 and 3 randomized placebo-controlled trials of biologics and small molecule drugs that used homogeneous criteria for the assessment of outcomes. PubMed Central, Embase, and reference lists of articles were systematically searched through July 2017. Only studies that employed the Mayo score were included. Thirty-one randomized placebo-controlled trials consisting of 2702 patients met the inclusion criteria. At induction, the pooled estimates of the placebo rates of remission, response, and MH were 9% (95% confidence interval [CI], 7%-12%; range: 0%-29%; I2 = 75.0%), 34% (95% CI, 31%-38%; range: 12%-75%; I2 = 61.3%), and 26% (95% CI, 22%-30%; range: 2%-65%; I2 = 77.7%), respectively. At maintenance, the pooled estimates of the placebo rates of remission, response, and MH were 14% (95% CI, 10%-18%; range: 6%-30%; I2 = 73.0%), 23% (95% CI, 20%-27%; range: 18%-36%; I2 = 53.0%), and 19% (95% CI, 15%-23%; range: 12%-30%; I2 = 65.0%), respectively. Among the variables assessed by logistic regression analysis, multiple factors influenced the outcomes of placebo arms, including concomitant systemic steroids at baseline, endoscopic central reading, being naïve or non-naïve to anti-TNFs, and disease duration. Despite the wide use of homogeneous criteria for the assessment of clinical and endoscopic outcomes, a high heterogeneity among placebo arms of modern trials in UC still exists.

A composite disease activity index for early drug development in ulcerative colitis: development and validation of the UC-100 score

Combining clinical, endoscopic, and histological data associated with ulcerative colitis disease activity in a composite index could be a more sensitive way to detect efficacy in small numbers of patients during early drug development. Our aim was to derive and externally validate a novel index for this purpose. Index development was done with data from a phase 2 placebo-controlled trial of ozanimod in patients with moderate-to-severe ulcerative colitis (n=179). Multivariable logistic regression modelling determined associations between candidate index items and absence of rectal bleeding (Mayo Clinic rectal bleeding subscore of 0), with items with a p value of less than 0·10 being taken forward into the final model. Model fit was internally validated and then externally validated in an independent phase 2 clinical trial dataset (MLN02, n=146) by measuring the area under the curve of the receiver operating characteristic (AUROC). In the derivation cohort, multivariable analysis indicated that the Mayo Clinic stool frequency subscore (odds ratio [OR] 0·43, 95% CI 0·30-0·61; p<0·0001) and the Robarts histopathology index (0·97, 0·93-1·01; p=0·09) were associated with absence of rectal bleeding. Although the Mayo Clinic endoscopic subscore was not significantly associated with rectal bleeding in multivariable analysis (0·74, 0·43-1·27; p=0·27), it was entered into the final model on the basis of the established diagnostic and prognostic significance of endoscopic findings. With these parameters, we established the composite UC-100 score (1 + 16 × Mayo Clinic stool frequency subscore [0 to 3] + 6 × Mayo Clinic endoscopic subscore [0 to 3] + 1 × Robarts histopathology index score [0 to 33]), which ranges from 1 (no disease activity) to 100 (severe disease activity). The UC-100 score strongly discriminated absence of rectal bleeding in both the development (AUROC 0·82, 95% CI 0·75-0·88) and validation cohorts (0·86, 0·80-0·92). A UC-100 score of 25 or less corresponds to a 95% probability of absence of rectal bleeding. We have developed and validated a novel composite disease activity index (the UC-100 score) with good discriminative performance that could used in early phase trials of ulcerative colitis. None.

Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.

Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. Fifty-six induction (placebo n=4171) and 8 maintenance trials (placebo n=1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR=0.52, [95% CI 0.29-0.92], P=0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR=1.17 [95% CI 1.08-1.26], P<0.0001, per 10% increase in corticosteroid use). Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

Issue Highlights

Issue Highlights

Combination Immunosuppression in IBD.

Whether to use biologic treatment for inflammatory bowel disease as monotherapy or in combination with immunosuppressives has been a matter of debate in the last 2 decades. Combination therapy was not superior in any of the registration trials for Crohn's disease and ulcerative colitis for TNF antagonists, vedolizumab, or ustekinumab. It needs to be mentioned, though, that none of these trials were powered to detect such differences, and that many patients entered the trial after having failed conventional immunosuppressives.Postmarketing studies revealed that patients on background immunosuppression have a lower risk of immunogenicity (often resulting in infusion/injection reactions) than patients on monotherapy. In the SONIC and UC-SUCCESS trials, superiority of the combination azathioprine-infliximab was demonstrated in Crohn's disease and ulcerative colitis, respectively. This trial design has not been used with any other biologic for IBD, so far. Meanwhile, it has also become clear that combination treatment with TNF antagonists is associated with increased toxicity, mainly infections, but also malignancy such as lymphoproliferative disease. This toxicity could perhaps be reduced by using lower doses of immunosuppressives, a strategy that has been shown to be equally potent in reducing immunogenicity. Additionally, combination treatment could be used for a limited period of time (12 months or even shorter) since most immunogenicity develops in the beginning of the biologic treatment. Patients who develop anti-drug-antibodies later on can often be rescued by reintroduction of thiopurines or methotrexate.In summary, combination treatment is certainly beneficial with infliximab, at least in the first 12 months of treatment. With other TNF antagonists, vedolizumab, and ustekinumab, the available data do not offer clear guidance. In patients without increased risk of toxicity, and certainly in those with limited treatment options, it may be wise to offer combination treatment with all biologics for the time being and at least during the initiation phase.

P047 HISTOLOGICAL AND ENDOSCOPIC HEALING AFTER QBECO TREATMENT IN AN OPEN-LABEL PHASE 2 STUDY IN PATIENTS WITH ULCERATIVE COLITIS

Current therapies for inflammatory bowel disease (IBD) are aimed at immune suppression. These have not prevented disease progression for the majority of IBD patients and come with consequent risk. There is a recognized need for new, safe and effective treatment for IBD. QBECO is a novel microbial-based immunotherapy designed to stimulate the immune response to overcome immune dysfunction in the gastrointestinal tract. QBECO has previously shown promising results in a randomized double-blind placebo controlled phase 2 clinical trials in Crohn’s disease (CD; NCT01809275). These findings were followed-up with a phase 2 open-label trial in ulcerative colitis (UC) to assess endoscopic and histological improvement (NCT02426372). An open-label phase 2 trial was conducted with 11 patients with moderate-to-severe UC. QBECO was self-administered subcutaneously every second day throughout the 16 weeks. Endoscopic and histological assessment was measured at screening, week 8 and week 16. QBECO responders were defined as having a decrease in Mayo score (composite of endoscopic healing, rectal bleeding, stool frequency and global physician’s assessment) of 3 or more points. 7 of 11 patients (63.6%) responded to QBECO and 1 patient (9.1%) was in clinical remission by week 16. For the individual Mayo sub scores, at least a one point improvement was seen in 63.4% of patients for stool frequency, 81.8% for rectal bleeding, 60.0% for endoscopic improvement and 54.5% of patients for global physician’s assessment. Histological improvement was seen in 5 of 10 patients (50%) that had week 16 histology samples. In this proof-of-concept study, UC patients experienced clinical, endoscopic and histological improvement after 16 weeks of QBECO treatment. This highlights the potential for this novel microbial-based immunotherapeutic strategy to restore gastrointestinal immune function in patients with UC.

Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis.

Endoscopic assessment of mucosal disease activity is routinely used to determine eligibility and response to therapy in clinical trials of ulcerative colitis. The operating properties of the existing endoscopic scoring indices are unclear. A systematic review was undertaken to evaluate the development and operating characteristics of endoscopic scoring indices for the evaluation of ulcerative colitis. We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2016. We also searched references and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organization). Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated endoscopic indices for evaluation of ulcerative colitis disease activity were considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with ulcerative colitis using conventional clinical, radiologic and endoscopic criteria. Two authors independently reviewed the studies identified from the literature search. These authors also independently extracted and recorded data on the number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as reliability (intra-rater and inter-rater), validity (content, construct, criterion), responsiveness and feasibility. Any disagreements regarding study inclusion or data extraction were resolved by discussion and consensus with a third author. Risk of bias was assessed by determining whether assessors were blinded to clinical information and whether assessors scored the endoscopic index independently. We also assessed the methodological quality of the validation studies using the COSMIN checklist MAIN RESULTS: A total of 23 reports of 20 studies met the pre-defined inclusion criteria and were included in the review. Of the 20 included validation studies, 19 endoscopic scoring indices were assessed, including the Azzolini Classification, Baron Score, Blackstone Endoscopic Interpretation, Chinese Grading System of Ulcerative Colitis, Endoscopic Activty Index, Jeroen Score, Magnifying Colonoscopy Grade, Matts Score, Mayo Clinic Endoscopic Subscore, Modified Baron Score, Modified Mayo Clinic Endoscopic Subscore, Osada Score, Rachmilewtiz Endoscopic Score, St. Mark's Index, Ulcerative Colitis Colonoscopic Index of Serverity (UCCIS), endoscopic component of the Ulcerative Colitis Disease Activity Index (UCDAI), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Witts Sigmoidoscopic Score and Watson Grade. The individuals who performed the endoscopic scoring were blinded to clinical and/or histologic information in ten of the included studies, not blinded to clinical and/or histologic information in one of the included studies, and it was unclear whether blinding occurred in the remaining nine included studies. Independent observation was confirmed in four of the included studies, unclear in five of the included studies, and non-applicable (since inter-rater reliability was not assessed) in the remaining eleven included studies. The methodological quality (COSMIN checklist) of most of the included studies was rated as 'good' or 'excellent'. One study that assessed responsiveness was rated as 'fair'. The inter-rater reliability of nine endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Endoscopic Activity Index, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS, UCEIS, Watson Grade was assessed in seven studies, with estimates of correlation, ƙ, ranging from 0.44 to 0.97. The iIntra-rater reliability of seven endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS and UCEIS was assessed in three studies, with estimates of correlation, ƙ, ranging from 0.41 to 0.86. No studies assessed content validity. Three studies evaluated the criterion validity of three endoscopic scoring indices including the Rachmilewitz Endoscopic Score, Magnifying Colonoscopy Grade and the UCCIS. These indices were correlated with objective markers of disease activity including albumin, blood leukocytes, C-reactive protein, fecal calprotectin, hemoglobin, mucosal interleukin-8 concentration and platelet count. Correlation estimates ranged from r = -0.19 to 0.83. Thirteen endoscopic scoring indices were tested for construct validity in 13 studies. Estimates of correlation between the endoscopic scoring indices and other measures of disease activity ranged from r = 0.27 to 0.93. Two studies explored the responsiveness of four endoscopic scoring indices including the Mayo Endoscopic Subscore, Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS. One study concluded that the Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS had similar responsiveness for detecting disease change in ulcerative colitis. The other included study concluded that the UCEIS may be the most accurate endoscopic scoring tool. None of the included studies formally assessed feasibility. While the UCEIS, UCCIS and Mayo Clinic Endoscopic Subscore have undergone extensive validation, none of these instruments have been fully validated and only two studies assessed responsiveness. Further research on the operating properties of these indices is needed given the lack of a fully-validated endoscopic scoring instrument for the evaluation of disease activity in ulcerative colitis.

P047 HISTOLOGICAL AND ENDOSCOPIC HEALING AFTER QBECO TREATMENT IN AN OPEN-LABEL PHASE 2 STUDY IN PATIENTS WITH ULCERATIVE COLITIS

Current therapies for inflammatory bowel disease (IBD) are aimed at immune suppression. These have not prevented disease progression for the majority of IBD patients and come with consequent risk. There is a recognized need for new, safe and effective treatment for IBD. QBECO is a novel microbial-based immunotherapy designed to stimulate the immune response to overcome immune dysfunction in the gastrointestinal tract. QBECO has previously shown promising results in a randomized double-blind placebo controlled phase 2 clinical trials in Crohn’s disease (CD; NCT01809275). These findings were followed-up with a phase 2 open-label trial in ulcerative colitis (UC) to assess endoscopic and histological improvement (NCT02426372). An open-label phase 2 trial was conducted with 11 patients with moderate-to-severe UC. QBECO was self-administered subcutaneously every second day throughout the 16 weeks. Endoscopic and histological assessment was measured at screening, week 8 and week 16. QBECO responders were defined as having a decrease in Mayo score (composite of endoscopic healing, rectal bleeding, stool frequency and global physician’s assessment) of 3 or more points. 7 of 11 patients (63.6%) responded to QBECO and 1 patient (9.1%) was in clinical remission by week 16. For the individual Mayo sub scores, at least a one point improvement was seen in 63.4% of patients for stool frequency, 81.8% for rectal bleeding, 60.0% for endoscopic improvement and 54.5% of patients for global physician’s assessment. Histological improvement was seen in 5 of 10 patients (50%) that had week 16 histology samples. In this proof-of-concept study, UC patients experienced clinical, endoscopic and histological improvement after 16 weeks of QBECO treatment. This highlights the potential for this novel microbial-based immunotherapeutic strategy to restore gastrointestinal immune function in patients with UC.

Evolving Therapeutic Strategies in the Inflammatory Bowel Disease

It is important to have effective therapeutic strategies and goals in clinical practice and research of inflammatory bowel disease. Conventional end points for clinical trials in Crohn's disease and ulcerative colitis have been based on composite indices, such as the Crohn's Disease Activity Index and the Mayo Clinic Score. Although these indices have been shown to reduce the intestinal injury to some extent, satisfactory results have not been obtained in improving the quality of life of patients. Recently, alternative measures of outcome and definitions of response are being developed beyond symptoms. Mucosal healing as a clinical response and treatment goal has showed better long-term outcomes. Patient-reported outcomes (PROs) are emerging instrument directly created by patient to quantify symptoms. Coprimary realistic treatment 'target', comprising mucosal healing and PROs, can offer a clinically valid endpoint and can be readily applied in practice compare to existing composite indices. 'Treat-to-target' algorithm based on mucosal healing and PROs, in which therapy is progressively intensified until a specific personal treatment goal is reached, could improve quality of life of patient by reducing disease-related disability. Furthermore, histologic remission is an area of increased research focus and has the potential to guide treatment decisions in the future.

Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis.

Adalimumab is used to treat moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) when conventional therapies fail. To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years (PYs). Treatment-emergent adverse events (AEs; first dose to 70days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (MedDRA-v18.1). Rates were assessed as events/100 (E/100 PYs). The database (16 trials; CD, N=3606; UC, N=1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs (CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs (CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies (CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent MedDRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population (CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon (CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals.

The Current Landscape and Lessons from Fecal Microbiota Transplantation for Inflammatory Bowel Disease: Past, Present, and Future.

Fecal microbiota transplantation (FMT) has changed the standard of care for Clostridium difficile infection. However, there is limited data focusing on efficacy and safety profile of FMT in patients with C. difficile infection with underlying inflammatory bowel disease (IBD), including the risk of IBD flare. Recently, there is also emerging evidence supporting the role of FMT to treat IBD including promising randomized trials in ulcerative colitis. However, with heterogeneity across these studies, the clinical application of this emerging therapy has yet to be fully elucidated. Here, we aim to review the current landscape of this rapidly developing field, mapping the efficacy and safety of FMT (1) to treat C. difficile infection in patients with IBD, (2) to treat underlying IBD, and (3) outline ongoing clinical trials and the future of the microbiome space.

Ustekinumab Does Not Increase Risk of Serious Adverse Events: A Meta-Analysis of Randomized Controlled Trials

Introduction: Inflammatory bowel disease (IBD) therapy is continuously evolving with novel drugs targeting various inflammatory pathways. Ustekinumab (USK), a monoclonal antibody inhibiting the IL-12/23 pathway, was approved in September 2016 to treat moderate-to-severe Crohn's disease (CD). While safety data in IBD is limited, USK has been used to treat other autoimmune diseases with favorable safety profiles. We aimed to establish rates of adverse events (AE) and demonstrate non-inferiority of AE of USK compared to placebo and other biologics. Methods: MEDLINE, PubMed and Embase databases were searched in May 2017 using terms “ustekinumab” and “clinical trials.” Two authors independently performed quality assessment and dual extraction. Randomized control trials comparing USK to placebo or other biologics regardless of disease were included. The primary outcome was the odds ratio (OR) of AE of USK vs placebo, expressed as pooled OR and 95% confidence interval (CI). Secondary outcomes included OR of mild/moderate and serious AE (SAE) in USK vs placebo, USK vs biologics, and low vs high-dose USK, respectively (Table 2). A sub-analysis of outcomes in CD trials was performed. Random effects meta-analysis was performed for all outcomes.Table: Table. Odds ratio for Adverse Events in USK groupResults: 16 papers with 6756 subjects (44% female) were included (Fig 1). Infections were the most common AE (Table 1). The OR of serious AE in USK vs placebo was 0.76 (95% CI 0.56-1.03, Fig 2). The OR of mild-to-moderate AE in the USK vs placebo was 1.12 (95% CI 1.01-1.24), suggesting increased risk of mild/moderate AE with USK (Fig 3). However, this was no longer significant after sub-analysis of the three CD trials. Analysis of 5 trials comparing low vs high-dose USK revealed an OR of 0.96 (95% CI 0.46-2.04) for SAE and 1.17 (95% CI 0.98-1.39) for mild-to-moderate AE. Use of USK was not associated with increased AE compared to other biologics, with OR of 0.91 (95% CI 0.61-1.35) for SAE and 0.98 (95% CI 0.85-1.13) for mild/moderate AE. Heterogeneity was low for all calculations.Figure: Prisma diagram for study identification and inclusion.Figure: Forest Plot of Serious Adverse Events, Ustekinumab vs Placebo.Figure: Forest Plot of Mild/Moderate Adverse Events, Ustekinumab vs Placebo.Table: Table. Rates of Adverse EventsConclusion: USK has a comparable safety profile to placebo and other biologics in the treatment of various diseases, although we did find a mildly elevated risk of mild/moderate AE with USK; however, this was not seen in CD trials. The favorable safety profile of USK is of clinical importance with the advent of USK in CD and ongoing clinical trials for ulcerative colitis. More data on long-term safety data in the IBD population is needed.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

Cost-effectiveness of golimumab for the treatment of patients with moderate-to-severe ulcerative colitis in Quebec using a patient level state transition microsimulation

Objective: To conduct cost-effectiveness analyses comparing the addition of golimumab to the standard of care (SoC) for treatment of patients with moderate-to-severe ulcerative colitis (UC) who are refractory to conventional therapies in Quebec (Canada).Methods: An individual patient state transition microsimulation model was developed to project health outcomes and costs over 10 years, using a payer perspective. The incremental benefit estimates for golimumab were driven by induction response and risk of a flare. Flare risks post-induction were derived for golimumab from the PURSUIT maintenance trial and extension study, while those for SoC were derived from the placebo arms of the Active Ulcerative Colitis Trials (ACT) 1 and 2. Other inputs were derived from multiple sources, including retrospective claims analyses and literature. Costs are reported in 2014 Canadian dollars. A 5% annual discount rate was applied to costs and quality-adjusted life-years (QALYs).Results: Compared with SoC, golimumab was projected to increase the time spent in mild disease or remission states, decrease flare rates, and increase QALYs. These gains were achieved with higher direct medical costs. The incremental cost-effectiveness ratio for golimumab vs SoC was $63,487 per QALY.Limitations: The long-term flare projections for SoC were based on the data available from the ACT 1 and 2 placebo arms, as data were not available from the PURSUIT maintenance or extension trial. Additionally, the study was limited to only SoC and golimumab, due to the availability of individual patient data to analyze.Conclusion: This economic analysis concluded that treatment with golimumab is likely more cost-effective vs SoC when considering cost-effectiveness acceptability thresholds from $50,000–$100,000 per QALY.

European Union regulatory and quality requirements for botanical drugs and their implications for Chinese herbal medicinal products development

This paper introduces regulatory pathways and characteristic quality requirements for marketing authorization of herbal medicinal products in the European Union（EU）, and the legal status and applications of "European Union list of herbal substances, preparations and combinations" and "European Union herbal monographs". Also introduced are Chinese herbs that have been granted the EU list entry, those with EU herbal monographs, and registered EU traditional herbal medicinal products with Chinese herbs as active ingredients. Special attention is paid to the technical details of three authorized EU herbal medicinal products (Veregen, Sativex and Episalvan) in comparison with Andrographis paniculata extract HMPL-004 that failed the phase Ⅲ clinical trial for ulcerative colitis. The paper further emphasizes the importance of enriching active fractions of herbal extracts and taking regulatory and quality considerations into account in early stage of botanical drug development.