Cost Effectiveness of Ribociclib in Combination with Fulvestrant for the Treatment of Postmenopausal Women with HR+/HER2- Advanced Breast Cancer Who Have Received No or Only One Prior Line of Endocrine Therapy: A Canadian Healthcare Perspective.

BACKGROUND: The MONALEESA-3 trial demonstrated the efficacy and safety of ribociclib plus fulvestrant versus placebo plus fulvestrant for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). This analysis evaluated the cost effectiveness of ribociclib plus fulvestrant versus fulvestrant in patients with HR+/HER2- ABC from a Canadian healthcare payer perspective. METHODS: The incremental cost-effectiveness ratio (ICER), expressed as incremental costs per quality-adjusted life-year (QALY) gained for ribociclib plus fulvestrant versus fulvestrant, was estimated using a semi-Markov cohort model developed in Microsoft Excel, with states for progression-free, post-progression, and dead. A 15-year time horizon was used. Survival distributions for progression-free survival (PFS), post-progression survival (PPS), and time to discontinuation (TTD) were based on parametric survival distributions fit to data from MONALEESA-3. Health-state utilities were estimated using EQ-5D index values collected in MONALEESA-3. Direct costs of ABC treatment (medication and administration costs, follow-up and monitoring, adverse events, subsequent treatments) were based on Canadian-specific values from published sources. Costs (2019 CAN$) and QALYs were discounted at 1.5% annually. RESULTS: In the base case, ribociclib plus fulvestrant was estimated to result in gains of 1.19 life-years and 0.96 QALYs versus fulvestrant, at an incremental cost of $151,371. The ICER of ribociclib plus fulvestrant versus fulvestrant was $157,343 per QALY gained based on the mean of probabilistic analyses. Results were sensitive to parametric distributions used for projecting long-term TTD, PFS, and PPS. CONCLUSIONS: For patients with HR+/HER2- ABC, ribociclib plus fulvestrant is projected to result in substantial gains in QALYs compared with fulvestrant. At its current list price, ribociclib used in combination with fulvestrant is likely to be cost effective in these patients at a threshold ICER of $157,343. These results may be useful in deliberations regarding reimbursement and access to this treatment.

Cost Effectiveness of Ribociclib Plus a Nonsteroidal Aromatase Inhibitor in Pre-/Perimenopausal, HR+ and HER2- Advanced Breast Cancer: A Canadian Healthcare Perspective.

BACKGROUND AND OBJECTIVES: The MONALEESA-7 trial demonstrated the efficacy and safety of ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) [with goserelin] for pre-/perimenopausal women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer. This analysis evaluated the cost effectiveness of ribociclib plus NSAI vs NSAI monotherapy and tamoxifen monotherapy from the perspective of the Canadian healthcare system. METHODS: The incremental cost-effectiveness ratio expressed as incremental costs per quality-adjusted life-year (QALY) gained for ribociclib plus an NSAI vs an NSAI and vs tamoxifen was estimated using a semi-Markov cohort model developed in Microsoft Excel with a 15-year time horizon and states for progression-free survival, post-progression survival, and dead. Survival distributions for progression-free survival, post-progression survival, and time to discontinuation as well as health-state utilities were estimated using data from MONALEESA-7. Direct costs of advanced breast cancer treatment were based on Canadian-specific values from published sources. Costs ($CAN 2019) and QALYs were discounted at 1.5% annually. RESULTS: Ribociclib plus an NSAI was estimated to yield gains of 1.42 life-years and 1.17 QALYs vs an NSAI, and 2.61 life-years and 2.12 QALYs vs tamoxifen, at incremental costs of $209,701 and $220,836, respectively. In probabilistic analyses, the incremental cost-effectiveness ratio for ribociclib plus an NSAI was estimated to be $178,872 per QALY gained vs an NSAI and $104,400 per QALY gained vs tamoxifen. Results of deterministic analyses were similar (incremental cost-effectiveness ratios of $177,245 and $103,316 vs NSAI and tamoxifen, respectively). Results were sensitive to parametric distributions used for projecting progression-free survival and the time horizon. CONCLUSIONS: At its current list price, ribociclib used in combination with NSAI is likely to be co-effective relative to an NSAI alone or tamoxifen alone if the willingness-to-pay threshold is less than approximately $178,000 per QALY. These results have informed deliberations regarding reimbursement and access to this treatment in Canada and may be useful for decision makers in other settings.

Preferences of Canadian Patients and Physicians for Treatment of HR+/HER2- Advanced Breast Cancer.

(1) Background: Past research suggests that patients with advanced breast cancer prefer treatments with improved clinical outcomes and lower risk of side effects. Evidence on preferences of Canadian patients and physicians for treatments for advanced breast cancer is limited. (2) Methods: Patients' and physicians' preferences for treatments for HR+/HER2-, pre-/peri-menopausal advanced breast cancer were assessed by an online discrete choice experiment (DCE). Treatment alternatives were characterized by seven attributes regarding dosing, efficacy, and toxicities, with levels corresponding to those for ribociclib plus a non-steroidal aromatase inhibitor (NSAI), NSAI, and tamoxifen. For patients, impacts of advanced breast cancer on quality of life (QOL) and ability to work/perform activities of daily living also were assessed. Patients were recruited by a Canadian breast cancer patient advocacy group through email and social media. Physicians were recruited by email. (3) Results: Among 118 patients starting the survey, 23 completed ≥ 1 DCE question (19%). Among 271 physicians who were sent the e-mail invitation, 21 completed ≥ 1 DCE question (8%). For both patients and physicians, the increased probability of remaining alive and without cancer progression over 2 years was the most important attribute. A treatment with attributes consistent with ribociclib plus NSAI was chosen by patients and physicians in 70% and 88% of the time, respectively. A substantial proportion of patients reported worrying about future diagnostic tests and their cancer getting worse; (4) Conclusions: Canadian patients and physicians are generally concordant in preference for advanced breast cancer treatments, preferring ribociclib plus NSAI to other options.

Anxiety, Depression and Quality of Life Improve After One Month and Three Months of Home Parenteral Nutrition: A Pilot Study in a Canadian Population.

BACKGROUND: Patients receiving home parenteral nutrition (HPN) have a reduced quality of life (QoL), but it is unknown if this is associated with psychiatric comorbidities such as anxiety or depression. AIM: The aim of this study was to assess anxiety, depression and QoL in patients transitioning from hospital to HPN. METHODS: We conducted a prospective study in adult patients receiving parenteral nutrition (PN) during transition from hospital to home. We assessed anxiety and depression (Hospital Anxiety and Depression Scale; HADS), health-related quality of life (HRQoL; SF-36) and health status (EQ-5D) before discharge and again later at one and three months after HPN was started. RESULTS: Of the 29 patients, 15 had an underlying malignancy. At baseline, 93% of patients with malignancy had anxiety or depression (HADS A and/or HADS D >7) or both, while of the patients without malignancy, 60% had anxiety, and 40% had depression. Questionnaires were completed by 21 patients at one month and by 15 at three months. Anxiety and depression scores decreased significantly after one month of HPN (mean difference [MD] anxiety: 4.3; 95% CI, 1.2-7.5, P = 0.004; MD depression: 4.0; 95% CI, 1.5-6.5, P = 0.001), and the decrease persisted at three months (MD anxiety: 35; 95% CI, 0.35-6.6, P = 0.02; MD depression: 2.5; 95% CI, 0.06-5.0, P = 0.04). Overall, patients reported an improvement in HRQoL (SF-36) after one month of HPN, and this improvement was maintained at three months in those patients who survived. CONCLUSION: Home parenteral nutrition is associated with improvements in anxiety, depression and HRQoL at one month and three months after discharge from hospital. The improvements in Qol, anxiety and depression seem greater in patients with underlying malignancy.

Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2- metastatic breast cancer.

BACKGROUND: Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2- MBC. METHODS: A systematic literature review of RCTs in HR+, HER2- MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson's product-moment correlation and Spearman's rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). RESULTS: Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5-6 months of incremental PFS/TTP. CONCLUSION: We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2- MBC.

Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2- metastatic breast cancer?

BACKGROUND: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic breast cancer (MBC) accounts for 73% of all MBCs. Endocrine therapy (ET) is the basis of first-line (1L) therapy for patients with HR+/HER2- MBC. Novel therapies have demonstrated improvements in progression-free survival (PFS) compared to ET. The clinical relevance of PFS is being debated, as there is no proven direct correlation with overall survival (OS) benefit to date. We reviewed studies of HR+/HER2- MBC to assess PFS and other factors that influence OS and treatment response, and health-related quality of life (HRQoL). METHODS: The Embase®, Medline®, and Cochrane databases were systematically searched to identify studies in adult women with HR+/HER2- MBC, published between January 2006 and January 2017, and written in English. Phase II and III randomized controlled trials (RCTs), observational, and retrospective studies were included. RESULTS: Seventy-nine RCTs were identified: 58 (73%) in the 1L+ setting and 21 (27%) in second-line or greater settings. PFS hazard ratios (HRs) were reported in 61 (77%) studies; 31 (39%) reported significant PFS improvements. OS was reported in 44 (41%) studies; 12 (15%) reported significant OS improvements. Significant improvements in both PFS and OS were reported in only 6 (8%) studies (1 Phase II; 5 Phase III). Patients with HER2- MBC received, on average, ≥5 lines of therapy, with no consistent treatment pathway. Baseline characteristics, prior therapies, and the type and number of post-progression therapies significantly impacted OS. PFS, response rates, and HRQoL decreased with each line of therapy (EuroQol 5 Dimensions: 0.78 1L vs. 0.70 post-progression). CONCLUSION: Few RCTs in HR+/HER2- MBC have demonstrated significant improvements in OS. Factors other than choice of 1L therapy impact OS, including post-progression therapies, which cannot be controlled in RCTs. This study emphasizes the importance of PFS improvement in 1L treatment of HR+/HER2- MBC.

Cost effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.

OBJECTIVE: To evaluate the cost effectiveness of dabrafenib versus dacarbazine and vemurafenib as first-line treatments in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a Canadian healthcare system perspective. METHODS: A partitioned-survival analysis model with three mutually exclusive health states (pre-progression, post-progression, and dead) was used. The proportion of patients in each state was calculated using survival distributions for progression-free and overall survival derived from pivotal trials of dabrafenib and vemurafenib. For each treatment, expected progression-free, post-progression, overall, and quality-adjusted life-years (QALYs), and costs were calculated. Costs were based on list prices, a clinician survey, and published sources. A 5-year time horizon was used in the base case. Costs (in 2012 Canadian dollars [CA$]) and QALYs were discounted at 5% annually. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Dabrafenib was estimated to yield 0.2055 more QALYs at higher cost than dacarbazine. The incremental cost-effectiveness ratio was CA$363,136/QALY. In probabilistic sensitivity analyses, at a threshold of CA$200,000/QALY, there was an 8.2% probability that dabrafenib is cost effective versus dacarbazine. In deterministic sensitivity analyses, cost effectiveness was sensitive to survival distributions, utilities, and time horizon, with the hazard ratio for overall survival for dabrafenib versus dacarbazine being the most sensitive parameter. Assuming a class effect for efficacy of BRAF inhibitors, dabrafenib was dominant versus vemurafenib (less costly, equally effective), reflecting its assumed lower daily cost. Assuming no class effect, dabrafenib yielded 0.0486 more QALYs than vemurafenib. CONCLUSIONS: At a threshold of CA$200,000/QALY, dabrafenib is unlikely to be cost effective compared with dacarbazine. It is not possible to make reliable conclusions regarding the relative cost effectiveness of dabrafenib versus vemurafenib based on available information.

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how.

BACKGROUND: Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations--such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers--on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials. DISCUSSION: In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials. SUMMARY: When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.

BACKGROUND: 5-Aminosalicylic acid (5-ASA) is a first-line therapy for inducing and maintaining remission of mild and moderately active ulcerative colitis (UC). When the proximal margin of inflammation is distal to the splenic flexure, 5-ASA therapy can be delivered as a rectal suppository, foam or liquid enema. OBJECTIVES: The primary objective was to assess the efficacy and safety of rectal 5-ASA for maintaining remission of distal UC. SEARCH METHODS: We searched MEDLINE (1966 to August 2012), the Cochrane Library (August 2012), abstracts from major gastroenterology meetings (1997-2011) and bibliographies of relevant publications to identify relevant studies. SELECTION CRITERIA: Eligible studies were randomized controlled trials comparing rectal 5-ASA to placebo or another active treatment for a minimum duration of six months. Symptom scores needed to be assessed in at least one study outcome. Patients had to be at least 12 years of age with disease extent less than 60 cm from the anal verge or distal to the splenic flexure, as determined by barium enema, colonoscopy or sigmoidoscopy. Patients were expected to be in remission prior to the treatment trial. DATA COLLECTION AND ANALYSIS: Study eligibility was independently assessed by three authors. Data were extracted using standardized forms by two independent reviewers, with inter-rater agreement assessed using Cohen's Kappa and disagreements resolved by consensus. In cases where clarification of study results or methodology was needed, corresponding authors were contacted. The methodological quality of each trial was assessed by the Cochrane risk of bias tool and by a 30-point scale developed and used previously by the authors. Pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) for continued clinical, endoscopic and histologic remission were estimated for comparisons between rectal 5-ASA and placebo or oral 5-ASA, and for comparisons among 5-ASA doses. Heterogeneity was assessed using the Chi(2) test and visual inspection of forest plots. If no significant heterogeneity was identified (P > 0.10 for Chi(2)) a fixed-effect model (Mantel-Haenstzel) was used. If heterogeneity was significant, a random-effects model was used. MAIN RESULTS: Nine studies (484 patients) met the pre-specified inclusion criteria (Kappa 1.00). Six studies were rated as low risk of bias. Three studies were rated as high risk of bias due to blinding (two open label and one single-blind). The total daily dose of rectal 5-ASA ranged from 0.5 g to 4 g, and dose frequency ranged from once to three times daily. 5-ASA was delivered as liquid enema in five studies or as a suppository in four studies. Follow-up ranged from 6 to 24 months. Rectal 5-ASA was significantly superior to placebo for maintenance of symptomatic remission over a period of 12 months.Sixty-two per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 30% of patients in the placebo group (4 studies; 301 patients; RR 2.22, 95% CI 1.26 to 3.90; I(2) = 67%; P < 0.01). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 144 events) and inconsistency (i.e. unexplained heterogeneity). Rectal 5-ASA was significantly superior to placebo for maintenance of endoscopic remission over a 12 month period. Seventy-five per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 15% of patients in the placebo group (1 study; 25 patients; RR 4.88, 95% CI 1.31 to 18.18; P < 0.05). There was no statistically significant difference in the proportion of patients who experienced at least one adverse event. Sixteen per cent of patients in the rectal 5-ASA group experienced at least one adverse compared to 12% of placebo patients (2 studies; 160 patients; RR 1.35, 95% CI 0.63 to 2.89; I(2) = 0%; P = 0.44). The most commonly reported adverse events were anal irritation and abdominal pain. No statistically significant differences between rectal and oral 5-ASA were identified for either symptomatic or endoscopic remission over a period of six months. Eighty per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 65% of patients in the oral 5-ASA group (2 studies; 69 patients; RR 1.24, 95% CI 0.92 to 1.66; I(2) = 0%; P = 0.15). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 50 events) and high risk of bias (i.e. both studies in the pooled analysis were open label). Eighty per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 70% of patients in the oral 5-ASA group (2 studies; 91 patients; RR 1.14, 95% CI 0.90 to 1.45; I(2) = 0%; P = 0.26). In two small trials, one comparing 2 g/day 5-ASA enemas to 4 g/day 5-ASA enemas and the other comparing 0.5 g/day 5-ASA suppositories to 1 g/day 5-ASA suppositories no dose response relationship was observed. AUTHORS' CONCLUSIONS: The limited data available suggest that rectal 5-ASA is effective and safe for maintenance of remission of mild to moderately active distal UC. Well designed randomized trials are needed to establish the optimal dosing regimen for rectal 5-ASA, to compare rectal 5-ASA with rectal corticosteroids and to identify subgroups of patients who are more or less responsive to specific rectal 5-ASA regimens. The combination of oral and rectal 5-ASA appears to be more effective than either oral or rectal monotherapy for induction of remission. The efficacy of combination therapy for maintenance of remission has not been assessed and could be evaluated in future trials.

Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery.

BACKGROUND: Although postinfectious irritable bowel syndrome (PI-IBS) is a well-recognised complication of acute gastroenteritis, its prognosis remains poorly defined. The natural history of PI-IBS was assessed among participants in the Walkerton Health Study (WHS), which has followed the long-term effects of a large outbreak of acute gastroenteritis related to municipal water contamination in May 2000. METHODS: WHS participants were invited to return for annual assessment at a research clinic. Adult residents of Walkerton at the time of the outbreak who enrolled in 2002/2003 and returned for assessment in 2008 were eligible for a PI-IBS study cohort if they had no prior history of IBS or inflammatory bowel disease. A modified Bowel Disease Questionnaire was used to diagnose IBS by Rome I criteria and to identify IBS subtypes. RESULTS: Of 4561 WHS participants, 2451 returned for their 8 year assessment and 1166 were eligible for the PI-IBS study cohort (688 females, mean age 46.2 years). The prevalence of IBS among 742 eligible subjects who suffered acute gastroenteritis during the outbreak declined from 28.3% after 2-3 years to 15.4% after 8 years, but remained significantly increased compared with controls who did not have acute gastroenteritis (OR 3.12; 95% CI 1.99 to 5.04). Independent risk factors for PI-IBS at 8 years included female gender, younger age, prior anxiety/depression, and fever or weight loss during the acute enteric illness. IBS subtypes were not stable over time. CONCLUSIONS: Acute gastroenteritis can trigger IBS symptoms that persist for at least 8 years. Characteristics of the host and the acute enteric illness can predict the long-term risk of PI-IBS.

Prevalence of uninvestigated dyspepsia 8 years after a large waterborne outbreak of bacterial dysentery: a cohort study.

BACKGROUND & AIMS: Symptoms of dyspepsia may occur following an episode of acute gastroenteritis, but data are conflicting. We assessed prevalence of uninvestigated dyspepsia in a cohort of individuals, some of whom were exposed to bacterial dysentery in May 2000, as well as risk factors for dyspepsia in exposed individuals. METHODS: This was a cohort study conducted in the town of Walkerton, Ontario, Canada. Involved individuals were recruited into the Walkerton Health Study between 2002 and 2003 and were attending for annual assessment in 2008. Exposed individuals were subdivided into those with self-reported gastroenteritis, with acute illness unconfirmed by health records, and those with clinically confirmed gastroenteritis, with substantiation of acute illness by health record review. Presence of dyspepsia at 8 years, according to a broad definition (any symptom referable to the upper gastrointestinal tract), and the Rome II criteria, was compared between exposed and nonexposed individuals. RESULTS: Of 2597 subjects eligible, 1088 (41.9%) provided data for analysis, and 706 (64.9%) had reported acute gastroenteritis. Multivariate odd ratios for dyspepsia at 8 years in exposed individuals using a broad definition and the Rome II definition were 2.09 (95% confidence interval: 1.58-2.78) and 2.30 (95% confidence interval: 1.63-3.26), respectively. Prevalence of dyspepsia was higher in females; smokers; those with premorbid irritable bowel syndrome, anxiety, or depression; and those reporting >7 days of diarrhea or abdominal cramps during the acute illness. CONCLUSIONS: Symptoms of dyspepsia 8 years after an outbreak of acute gastroenteritis were significantly more prevalent in exposed compared with nonexposed individuals.

An outbreak of acute bacterial gastroenteritis is associated with an increased incidence of irritable bowel syndrome in children.

OBJECTIVES: Acute bacterial gastroenteritis is associated with subsequent post-infectious irritable bowel syndrome (PI-IBS) in adults. Less is known about this relationship in children. In May 2000, contamination of municipal water by Escherichia coli 0157:H7 and Campylobacter species caused a large outbreak of acute gastroenteritis in Walkerton, Ontario. We assessed this association among a cohort of children enrolled in the Walkerton Health Study (WHS). METHODS: WHS participants who were under age 16 at the time of the outbreak but who reached age 16 during the 8-year study follow-up were eligible for the pediatric PI-IBS study cohort. Eligibility also required no diagnosis of IBS or inflammatory bowel disease before the outbreak and permanent residency in the Walkerton postal code at the time of the outbreak. Validated criteria were used to classify subjects as having had no gastroenteritis (unexposed controls), self-reported gastroenteritis, or clinically suspected gastroenteritis during the outbreak. From 2002 to 2008, standardized biennial interviews used a modified Bowel Disease Questionnaire to diagnose IBS by Rome I criteria. Risk factors for IBS were identified by logistic regression. RESULTS: In all, 467 subjects were eligible for the pediatric PI-IBS study cohort (47.1% female; mean age 11.6+/-2.44 years at the time of the outbreak). Of these, 305 were exposed to GE (130 clinically suspected and 175 self-reported) and 162 were unexposed controls. The cumulative incidence of IBS was significantly increased among exposed subjects vs. controls (10.5% vs. 2.5%; odds ratio 4.6, 95% confidence interval (1.6, 13.3)). In an unadjusted risk factor analysis, IBS was associated with a shorter time interval from exposure to assessment of IBS symptoms, female gender, diarrheal illness lasting more than 7 days, weight loss >10 lb, and antibiotic use during the outbreak. In adjusted analyses, both female gender and time interval to assessment of IBS symptoms remained independent predictors of PI-IBS. CONCLUSIONS: Acute bacterial gastroenteritis is associated with subsequent IBS in children as in adults. Risk factors for PI-IBS in children are similar to those identified among adults. Confirmation of these findings in similar cohorts is needed.

A tutorial on pilot studies: the what, why and how.

Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format.

Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis.

BACKGROUND & AIMS: Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS. METHODS: We screened 79 functional variants of genes with products involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity and performed fine mapping in regions of interest. We compared data from Walkerton residents who developed gastroenteritis and reported PI-IBS 2 to 3 years after the outbreak (n = 228, cases) with data from residents who developed gastroenteritis but did not develop PI-IBS (n = 581, controls). RESULTS: Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = .0059 and rs5743836, -T1237C; P = .0250; r(2) < 0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260, -C160A; P = .0352); and 1 was in IL6, which encodes a cytokine (rs1800795, -G174C; P = .0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861; P = .0069) and 14 associations that could be accounted for by linkage disequilibrium with the 4 original variants. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors. CONCLUSION: This is the first descriptive study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with development of IBS following acute gastroenteritis.

Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.

BACKGROUND: 5-Aminosalicylates (5-ASA) are considered a first-line therapy for inducing and maintaining remission of mild to moderately active ulcerative colitis (UC). When inflammation in UC is limited to the distal colon, 5-ASA can also be administered rectally as a suppository, enema or foam. OBJECTIVES: A systematic review was undertaken to evaluate the efficacy of rectal 5-ASA for treating active distal UC. SEARCH STRATEGY: Electronic searches of the MEDLINE database (1966-2008), the Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD Group Specialized Trials Register were supplemented by manual reviews of reference listings and conference proceedings. SELECTION CRITERIA: Randomized trials comparing rectal 5-ASA to placebo or another active therapy were eligible for inclusion. Eligible trials enrolled patients with a distal disease margin less than 60 cm from the anal verge or distal to the splenic flexure. Trials that enrolled subjects less than 12 years of age were excluded. DATA COLLECTION AND ANALYSIS: Eligibility was assessed by three authors. Data were extracted by two authors using standardized forms. Pooled odds ratios (POR) for inducing improvement and remission by symptomatic, endoscopic and histologic criteria were calculated using an intention to treat principle. Fixed effects models were used unless heterogeneity was encountered within groups (P < 0.10), where random effects models were used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, subgroup analyses were performed for disease extent, total daily 5-ASA dose, 5-ASA formulation (enema,suppository, foam) and the type of control intervention (placebo or another active therapy). MAIN RESULTS: Thirty-eight studies fulfilled the inclusion criteria. Rectal 5-ASA was superior to placebo for inducing symptomatic, endoscopic and histological improvement and remission, with POR for symptomatic improvement 8.87 (8 trials, 95% CI: 5.30 to 14.83; P < 0.00001), endoscopic improvement 11.18 (5 trials, 95% CI 5.99 to 20.88; P < 0.00001), histologic improvement 7.69 (6 trials, 95% CI 3.26 to 18.12; P < 0.00001), symptomatic remission 8.30 (8 trials, 95% CI 4.28 to 16.12; P < 0.00001), endoscopic remission 5.31 (7 trials, 95% CI 3.15 to 8.92; P < 0.00001), and histologic remission 6.28 (5 trials, 95% CI 2.74 to 14.40; P < 0.0001). Rectal 5-ASA was superior to rectal corticosteroids for inducing symptomatic improvement and remission with POR 1.56 (6 trials, 95% CI 1.15 to 2.11; P = 0.004) and 1.65 (6 trials, 95% CI 1.11 to 2.45; P = 0.01), respectively. Rectal 5-ASA was not superior to oral 5-ASA for symptomatic improvement (POR 2.25; 95% CI 0.53 to 19.54; P = 0.27). Neither total daily dose nor 5-ASA formulation affected treatment response. AUTHORS' CONCLUSIONS: Rectal 5-ASA should be considered a first-line therapy for patients with mild to moderately active distal UC. The optimal total daily dose and dose frequency of 5-ASA remain to be determined. Future research should define differences in efficacy among patient subgroups defined by proximal disease margin and disease activity. There is a strong need for consensus standardization of outcome measurements for clinical trials in ulcerative colitis.

Post-infectious irritable bowel syndrome.

Post-infectious irritable bowel syndrome (PI-IBS) is a common disorder wherein symptoms of IBS begin after an episode of acute gastroenteritis. Published studies have reported incidence of PI-IBS to range between 5% and 32%. The mechanisms underlying the development of PI-IBS are not fully understood, but are believed to include persistent sub-clinical inflammation, changes in intestinal permeability and alteration of gut flora. Individual studies have suggested that risk factors for PI-IBS include patients' demographics, psychological disorders and the severity of enteric illness. However, PI-IBS remains a diagnosis of exclusion with no specific disease markers and, to date, no definitive therapy exists. The prognosis of PI-IBS appears favorable with spontaneous and gradual resolution of symptoms in most patients.

Development and validation of a risk score for post-infectious irritable bowel syndrome.

OBJECTIVES: Acute gastroenteritis (GE) is an important risk factor for the development of irritable bowel syndrome (IBS). We used observational data from the Walkerton Health Study (WHS) to develop and validate a risk score for post-infectious (PI) IBS. METHODS: Model derivation and validation were based on a split-sample method from a cohort of patients with exposure to GE (n=1,368). Study participants were randomly assigned to the derivation and validation cohorts in a 1:1 ratio. Within the derivation cohort, univariate and multivariable logistic regression were used to identify risk factors associated with IBS. The risk model was then applied to the validation cohort. Overall model performance was assessed using the area under the receiver operating curve (ROC). The risk score was developed using multivariable regression coefficients obtained from the derivation set and validated in the validation set. Classification and regression tree (CART) modeling was used to determine cutoff values for high, intermediate, and low risk based on the total score. RESULTS: Nine variables were identified as important predictors of IBS (gender, age<60, longer duration of diarrhea, increased stool frequency, abdominal cramping, bloody stools, weight loss, fever, and psychological disorders (anxiety and depression)). The discriminatory power of the risk model based on the area under ROC was 0.70 and was similar in the validation set. The risk score model showed good accuracy in both the derivation and validation sets and was able to distinguish among cohorts at low, intermediate, and high risk for developing PI-IBS. Percentages of patients with PI-IBS in the low, intermediate and high risk were 10, 35, and 60% in the derivation cohort and 17, 36, and 62% in the validation cohort. CONCLUSIONS: A simple risk tool that uses demographics and symptoms of acute GE can predict which patients with acute GE are at risk of developing PI-IBS. This tool may be used clinically to assess risk and to guide treatment.

Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen.

BACKGROUND & AIMS: A large outbreak of acute gastroenteritis at the annual meeting of the Canadian Society of Gastroenterology Nurses and Associates (CSGNA) was attributed to food-borne norovirus. A prospective study was undertaken to determine the incidence and natural history of postinfectious irritable bowel syndrome (PI-IBS). METHODS: Questionnaires addressing demographics, medical history, acute illness, prior bowel function, and current symptoms were mailed to all delegates within 1 month of the outbreak. Follow-up questionnaires were mailed at 3, 6, 12, and 24 months. The prevalence of new Rome I IBS among participants with and without acute enteric illness during the outbreak was calculated for each time point. Risk factors were assessed by multiple logistic regression. RESULTS: Baseline surveys were returned by 139 of 197 delegates (70.6%; mean age, 48 +/- 6 years; 95.0% female), of whom 135 (97.1%), 133 (95.7%), 128 (92.1%), and 116 (83.4%) returned the 3-, 6-, 12-, and 24-month surveys, respectively. One hundred seven respondents (76.9%) reported an acute enteric illness during the outbreak. Eighteen subjects reported premorbid IBS. Among the remainder, 21 of 89 who experienced gastroenteritis (23.6%) reported symptoms consistent with PI-IBS at 3 months versus 1 of 29 (3.4%) who remained well (odds ratio, 6.9; 95% confidence interval, 1.0-48.7; P = .014). At 6, 12, and 24 months, the prevalence of IBS was similar among exposed versus nonexposed individuals. In multiple logistic regression, vomiting during the acute illness independently predicted risk of PI-IBS at 3 months (odds ratio, 10.5; 95% confidence interval, 1.3-85.5; P = .028). CONCLUSIONS: PI-IBS is common after presumptive viral gastroenteritis but might be more transient than after bacterial dysentery.