STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.

BACKGROUND: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD. METHODS: Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale. RESULTS: In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth. CONCLUSIONS: STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.

Validation and Update of the Lémann Index to Measure Cumulative Structural Bowel Damage in Crohn's Disease.

BACKGROUND & AIMS: The Lémann Index is a tool measuring cumulative structural bowel damage in Crohn's disease (CD). We reported on its validation and updating. METHODS: This was an international, multicenter, prospective, cross-sectional observational study. At each center, 10 inclusions, stratified by CD duration and location, were planned. For each patient, the digestive tract was divided into 4 organs, upper tract, small bowel, colon/rectum, anus, and subsequently into segments, explored systematically by magnetic resonance imaging and by endoscopies in relation to disease location. For each segment, investigators retrieved information on previous surgical procedures, identified predefined strictures and penetrating lesions of maximal severity (grades 1-3) at each organ investigational method (gastroenterologist and radiologist for magnetic resonance imaging), provided segmental damage evaluation ranging from 0.0 to 10.0 (complete resection). Organ resection-free cumulative damage evaluation was then calculated from the sum of segmental damages. Then investigators provided a 0-10 global damage evaluation from the 4-organ standardized cumulative damage evaluations. Simple linear regressions of investigator damage evaluations on their corresponding Lémann Index were studied, as well as calibration plots. Finally, updated Lémann Index was derived through multiple linear mixed models applied to combined development and validation samples. RESULTS: In 15 centers, 134 patients were included. Correlation coefficients between investigator damage evaluations and Lémann Indexes were >0.80. When analyzing data in 272 patients from both samples and 27 centers, the unbiased correlation estimates were 0.89, 0,97, 0,94, 0.81, and 0.91 for the 4 organs and globally, and stable when applied to one sample or the other. CONCLUSIONS: The updated Lémann Index is a well-established index to assess cumulative bowel damage in CD that can be used in epidemiological studies and disease modification trials.

Evolution of Endoscopic Lesions in Steroid-Refractory Acute Severe Ulcerative Colitis Responding to Infliximab or Cyclosporine.

BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS ≥6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p = .004 and p=.04), for bleeding and ulceration/erosion than for vascular pattern at day 42 [63% and 65% vs. 33% (n=54); p<.001 for both] and at day 98 [78% and 92% vs. 56% (n = 50); p = .007 and p < .001]. Global endoscopic remission rates at day 98 were higher in patients treated with infliximab than with cyclosporine [73% vs. 25% (n = 26 and 24); p < .001]. CONCLUSION: In steroid-refractory ASUC patients responding to a second-line medical therapy, endoscopic remission process started with bleeding remission and was not achieved in half the patients at day 98 for vascular pattern. Infliximab provided a higher endoscopic remission rate than cyclosporine at day 98.

Approaches to Integrating Biomarkers Into Clinical Trials and Care Pathways as Targets for the Treatment of Inflammatory Bowel Diseases.

BACKGROUND & AIMS: There is no consensus on the best way to integrate biomarkers into inflammatory bowel disease (IBD) research and clinical practice. The International Organization for the Study of Inflammatory Bowel Disease aimed to outline biomarker definitions, categories, and operating properties required for their use in registration trials and clinical practice. Using fecal calprotectin as an example, we provide a framework for biomarker development and validation in patients with IBD. METHODS: We reviewed international society guidelines, regulatory agency guidance documents, and standardized reporting guidelines for biomarkers, in combination with publications on fecal calprotectin levels in patients with IBD. We assessed the validity of fecal calprotectin to serve as a surrogate biomarker of IBD activity and outlined a framework for further validation and development of biomarkers. RESULTS: No endpoints have been fully validated as surrogates of risk of disease complications; mucosal healing is the most valid endpoint used to determine risk of disease complications. Fecal level of calprotectin has not been validated as a biomarker for IBD activity because of lack of technical and clinical reliability, assessment of performance when used as a replacement for endoscopy, and assessment of responsiveness to changes in disease states. The level of fecal calprotectin can be used only as a prognostic factor for disease recurrence in patients in remission after medical or surgical treatment. CONCLUSIONS: We reviewed guidelines, regulatory documents, and publications to identify properties required for the development of biomarkers of IBD activity and areas in need of clarification from regulatory agencies and societies. We propose a path forward for research of biomarkers for IBD.

Impact of Counseling Methods on HIV Retesting Uptake in At-Risk Individuals: A Randomized Controlled Study.

Systematic face-to-face pre-HIV test counseling is costly and may discourage clients to present for regular testing. In a randomized, controlled, non-inferiority trial conducted in four facilities providing free-of-charge anonymous HIV testing in Thailand, participants received either: standard counseling according to national guidelines (reference); computer-assisted counseling: interactive counseling on a tablet computer followed by an invitation to ask questions to the counselor; or on-demand counseling: invitation to ask questions to the counselor. Primary endpoint was a HIV retest within 7 months after enrolment visit. Following the planned interim analysis, on-demand counseling was discontinued for futility. In the final analysis in 1036 HIV-uninfected at-risk participants, computer-assisted counseling was non-inferior to standard counseling and had similar acceptability and improvements in HIV knowledge and sexual risk behaviors; however, it significantly reduced the time spent by counselors on counseling. Implementation of pre-HIV test computer-assisted counseling may ease the burden on staff involved in HIV testing.

Efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study.

OBJECTIVE: The efficacy of anti-tumour necrosis factors (anti-TNFs) in patients with Crohn's disease (CD) and symptomatic small bowel stricture (SSBS) is controversial. The aim of this study was to estimate the efficacy of adalimumab in these patients and to identify the factors predicting success. DESIGN: We performed a multicentre, prospective, observational cohort study in patients with CD and SSBS. The included patients underwent magnetic resonance enterography at baseline and subsequently received adalimumab. The primary endpoint was success at week 24, defined as adalimumab continuation without prohibited treatment (corticosteroids after the eight week following inclusion, other anti-TNFs), endoscopic dilation or bowel resection. The baseline factors independently associated with success were identified using a logistic regression model, leading to a simple prognostic score. Secondary endpoints were prolonged success after week 24 (still on adalimumab, without dilation nor surgery) and time to bowel resection in the whole cohort. RESULTS: From January 2010 to December 2011, 105 patients were screened and 97 were included. At week 24, 62/97 (64%) patients had achieved success. The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes. After a median follow-up time of 3.8 years, 45.7%±6.6% (proportion±SE) of patients who were in success at week 24 (ie, 29% of the whole cohort) were still in prolonged success at 4 years. Among the whole cohort, 50.7%±5.3% of patients did not undergo bowel resection 4 years after inclusion. CONCLUSIONS: A successful response to adalimumab was observed in about two-thirds of CD patients with SSBS and was prolonged in nearly half of them till the end of follow-up. More than half of the patients were free of surgery 4 years after treatment initiation. CLINICAL TRIAL REGISTRATION NUMBER: NCT01183403; Results.

Rabies Postexposure Prophylaxis Noncompletion After Dog Bites: Estimating the Unseen to Meet the Needs of the Underserved.

Postexposure prophylaxis (PEP) prevents human rabies and is accessible in Cambodia principally in Phnom Penh, the capital. Timely, affordable access to PEP is a challenge for the mainly rural population. We aimed to identify districts independently associated with PEP noncompletion to position frontline vaccination centers. We analyzed the 2009-2013 database at the Rabies Prevention Center at the Institut Pasteur du Cambodge, Phnom Penh. Logistic regressions identified nongeographic determinants of PEP noncompletion as well as the districts that were independently associated with noncompletion after adjustment for these determinants. The influence of distance by road was estimated using a boosted regression-trees model. We computed a population attributable fraction (rabies index (RI)) for each district and developed a map of this RI distribution. A cartographic analysis based on the statistic developed by Getis and Ord identified clusters of high-RI districts. Factors independently associated with noncompletion were patients' district of residence, male sex, age 15-49 years, initial visit during rice harvest, the dog's status (culled or disappeared), and a prescribed PEP protocol requiring more than 3 PEP sessions (4 or 5). Four clusters of high-RI districts were identified using this analytical strategy, which is applicable to many vaccination or other health services. Positioning frontline PEP centers in these districts could significantly widen access to timely and adequate PEP.

Outcomes 7 Years After Infliximab Withdrawal for Patients With Crohn's Disease in Sustained Remission.

BACKGROUND & AIMS: Little is known about long-term outcomes of patients with Crohn's disease (CD) after infliximab withdrawal. We aimed to describe the long-term outcomes of patients with CD in clinical remission after infliximab treatment was withdrawn. METHODS: We performed a retrospective analysis of data from the 115 patients included in the infliximab discontinuation in patients with CD in stable remission on combined therapy with antimetabolites (STORI) study, performed at 20 centers in France and Belgium from March 2006 through December 2009. The STORI cohort was a prospective analysis of risk and factors associated with relapse following withdrawal of maintenance therapy with infliximab, maintained on antimetabolites, while in clinical remission. We collected data from the end of the study until the last available follow-up examination on patient surgeries, new complex perianal lesions (indicating major complications), and need for and outcomes of restarting therapy with infliximab or another biologic agent. The de-escalation strategy was considered to have failed when a major complication or infliximab restart failure occurred. RESULTS: Of the 115 patients initially included, data from 102 patients (from 19 of the 20 study centers) were included in the final analysis. The median follow-up time was 7 years. Twenty-one percent of the patients did not restart treatment with infliximab or another biologic agent and did not have a major complication 7 years after infliximab withdrawal (95% CI, 13.1-30.3). Among patients who restarted infliximab, treatment failed for 30.1% 6 years after restarting (95% CI, 18.5-42.5). Overall, at 7 years after stopping infliximab therapy, major complications occurred in 18.5% of patients (95% CI, 10.2-26.8) whereas 70.2% of patients had no failure of the de-escalation strategy (95% CI, 60.2-80.1). Factors independently associated with major complications were upper-gastrointestinal location of disease, white blood cell count ≥ 5.0 × 109/L, and hemoglobin level ≤12.5 g/dL at the time of infliximab withdrawal. Patients with at least 2 of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal. CONCLUSIONS: In a long-term follow-up of the STORI cohort (7 years) one fifth of the patients did not restart infliximab or another biologic agent and did not develop major complications. Seventy percent of patients had no failure of the de-escalation strategy (no major complication and no failure of infliximab restart).

Incidence and clinical outcomes of diabetes mellitus in HIV-infected adults in Thailand: a retrospective cohort study.

BACKGROUND: Since 2005, Thailand has scaled up one of the largest antiretroviral treatment (ART) programs in South East Asia. Although diabetes mellitus (DM) incidence is increasing in low and middle-income countries, its burden and contributing factors in the HIV infected population are not well known. METHODS: Using the Thai National AIDS Program data over a period of 8-years, we identified patients diagnosed with DM based on the following records: 1) fasting plasma glucose equal to or greater than 126 mg/dl following the 2013 American Diabetes Association criteria or 2) diagnosis codes E11-E14 of the 2010 WHO International Classification of Diseases, or 3) anti-diabetic drugs. Incidence was the number of new cases divided by that of person-years of follow-up (PYFU). Competing risks survival regression, treating death without DM as a competing event, was used to identify factors associated with DM. The risk of death in patients diagnosed with DM was estimated using Cox regression models. RESULTS: Data of 763,666 PYFU from 199,707 patients (54.2% male; median age 36.2 years at registration with the program) were available and 8383 cases were diagnosed with DM, resulting in an incidence rate of 11.0 per 1000 PYFU. New DM diagnosis was more likely in men (adjusted sub-distribution hazard ratio 1.2), older patients (compared to patients 18 to 34 years old: 1.8 for 35 to 44; 3.0 for 45 to 59; 3.8 for ≥60), and if ART was initiated (1.3). In 2014, 1313 (16.6%) of 7905 diabetic patients had DM complications (11.5% microvascular complications and 6.9% macrovascular complications). Patients diagnosed with DM were at higher risk of death compared to the others. CONCLUSIONS: DM incidence was higher in this Thailand cohort of HIV infected adults than in the general population. Risk factors were similar to those in the general population, in addition to starting ART.

Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma.

This phase 1/2 dose-escalation study investigated the combination of carfilzomib with melphalan and prednisone (CMP) in patients aged >65 years with newly diagnosed multiple myeloma (MM). Melphalan and prednisone were administered orally on days 1 to 4; carfilzomib was IV administered on days 1, 2, 8, 9, 22, 23, 29, and 30 of a 42-day cycle. Patients received up to 9 cycles of CMP. In the phase 1 dose-escalation portion, the primary objectives were to determine the incidence of dose-limiting toxicities during the first cycle of CMP treatment to define the maximal tolerated dose (MTD) of carfilzomib. In the phase 2 portion, the primary objective was to evaluate the overall response rate (ORR) of CMP. In the phase 1 portion of the study, 24 patients received CMP at carfilzomib dosing levels of 20 mg/m(2), 27 mg/m(2), 36 mg/m(2), and 45 mg/m(2). The MTD was established as 36 mg/m(2). In the phase 2 portion of the study, 44 patients were enrolled at the MTD. Among 50 efficacy-evaluable patients treated at the MTD, the ORR was 90%. The projected 3-year overall survival rate was 80%. The combination of CMP was observed to be effective in elderly patients with newly diagnosed MM. This trial was registered at www.clinicaltrials.gov as #NCT01279694 (Eudract identifier 2010-019462-92).

Development of the Lémann index to assess digestive tract damage in patients with Crohn's disease.

BACKGROUND & AIMS: There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, for measuring disease progression. We developed the Lémann Index and assessed its ability to measure cumulative structural bowel damage in patients with Crohn's disease (CD). METHODS: We performed a prospective, multicenter, international, cross-sectional study of patients with CD evaluated at 24 centers in 15 countries. Inclusions were stratified based on CD location and duration. All patients underwent clinical examination and abdominal magnetic resonance imaging analyses. Upper endoscopy, colonoscopy, and pelvic magnetic resonance imaging analyses were performed according to suspected disease locations. The digestive tract was divided into 4 organs and subsequently into segments. For each segment, investigators collected information on previous operations, predefined strictures, and/or penetrating lesions of maximal severity (grades 1-3), and then provided damage evaluations ranging from 0.0 (no lesion) to 10.0 (complete resection). Overall level of organ damage was calculated from the average of segmental damage. Investigators provided a global damage evaluation (from 0.0 to 10.0) using calculated organ damage evaluations. Predicted organ indexes and Lémann Index were constructed using a multiple linear mixed model, showing the best fit with investigator organ and global damage evaluations, respectively. An internal cross-validation was performed using bootstrap methods. RESULTS: Data from 138 patients (24, 115, 92, and 59 with upper tract, small bowel, colon/rectum, and anus CD location, respectively) were analyzed. According to validation, the unbiased correlation coefficients between predicted indexes and investigator damage evaluations were 0.85, 0.98, 0.90, 0.82 for upper tract, small bowel, colon/rectum, anus, respectively, and 0.84 overall. CONCLUSIONS: In a cross-sectional study, we assessed the ability of the Lémann Index to measure cumulative structural bowel damage in patients with CD. Provided further successful validation and good sensitivity to change, the index should be used to evaluate progression of CD and efficacy of treatment.

Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study.

Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (>2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1-10]) as compared to the historical cohort (27% [20-34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution.

Early administration of azathioprine vs conventional management of Crohn's Disease: a randomized controlled trial.

BACKGROUND & AIMS: Immunomodulator therapy is effective for patients with Crohn's disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease. METHODS: We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg ∙ kg(-1) ∙ day(-1), n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti-tumor necrosis factor (TNF)-free remission during the first 3 years after inclusion. RESULTS: During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%-85%) compared with 56% in the conventional management group (interquartile range, 29%-73%) (P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups. CONCLUSIONS: Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov, Number NCT00546546.

Reliability and initial validation of the ulcerative colitis endoscopic index of severity.

BACKGROUND & AIMS: We studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators. METHODS: We created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors ("vascular pattern", "bleeding", and "erosions and ulcers") comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores. RESULTS: There was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details. CONCLUSIONS: The UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details.

Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.

OBJECTIVE: To evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD). METHODS: This phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in ≥2 intestinal segments with a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≥8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score <6), complete remission (CDEIS score <3) and mucosal healing (no ulcer) at weeks 10 and 54. RESULTS: In the intention-to-treat population (n=89) the mean±SD CDEIS score was 14.5±5.3 at baseline; the mean decrease in CDEIS score at week 10 was 5.7 (95% CI 4.6 to 6.8, p<0.0001). Rates of endoscopic response, endoscopic remission, complete endoscopic remission and mucosal healing at week 10 were 54%, 37%, 10% and 4%, respectively. At week 54 the corresponding rates were 49%, 27%, 14% and 8%, respectively. The safety profile was consistent with that of previous CZP trials. CONCLUSIONS: Following CZP treatment in patients with active CD, endoscopic lesions were improved as shown by the decrease in mean CDEIS score and by endoscopic response and remission rates. These benefits were achieved as early as week 10 and were generally maintained through week 54. CLINICAL TRIAL REGISTRATION NUMBER: NCT00297648.

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.

BACKGROUND: Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS: In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS: 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION: Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING: Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

Challenges to the design, execution, and analysis of randomized controlled trials for inflammatory bowel disease.

Treatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody-based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials.

Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.

BACKGROUND & AIMS: It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohn's disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS: We performed a prospective study of 115 patients with Crohn's disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS: After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10(9)/L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 µg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS: Approximately 50% of patients with Crohn's disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials.

The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.