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Papers by David Andrae

Quality of Life Research, Sep 22, 2022

Patient-reported outcome (PRO) analyses often involve calculating raw change scores, but limitati... more Patient-reported outcome (PRO) analyses often involve calculating raw change scores, but limitations of this approach are well documented. Regression estimators can incorporate information about measurement error and potential covariates, potentially improving change estimates. Yet, adoption of these regression-based change estimators is rare in clinical PRO research.

Journal of Patient-Reported Outcomes

Background Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic... more Background Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). Methods All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test–retest...

Journal of Patient-Reported Outcomes, Dec 1, 2021

Background: Presbyopia is a progressive condition that reduces the eye's ability to focus on near... more Background: Presbyopia is a progressive condition that reduces the eye's ability to focus on near objects with increasing age. After a systematic literature review identified no existing presbyopia-specific patient-reported outcome (PRO) instruments meeting regulatory guidance, a new PRO instrument, the Near Vision Presbyopia Task-based Questionnaire (NVPTQ), was developed. Results: To explore the patient experience with presbyopia, concept elicitation interviews were conducted with 20 presbyopic participants. The most frequently reported impacts were difficulty with reading menus/books/newspapers/magazines, reading on a cell phone/caller ID, and reading small print. Based on these results, a task-based PRO instrument (the NVPTQ) was developed instructing participants to complete four near-vision, paper-based reading tasks (book, newspaper, nutrition label, menu) under standardized settings, and subsequently assess their vision-related reading ability and associated satisfaction. The draft NVPTQ was cognitively debriefed with a sample of 20 presbyopes, which demonstrated that most participants interpreted the items as intended and endorsed the relevance of the concepts being assessed. After the qualitative research, the draft instrument was psychometrically tested using data from a Phase 2 study. Based on item-level analyses, all items in the NVPTQ demonstrated expected response option patterns and lacked substantial floor or ceiling effects. The reliability, validity, and responsiveness of the NVPTQ Performance and Satisfaction domain scores were assessed. All domains scores had large Cronbach's coefficient α values and good test-retest statistics, indicating that the scores are internally consistent and produce stable values over time. The pattern of correlations with a concurrent measure of visual functioning (National Eye Institute Visual Function Questionnaire 25) demonstrated that the NVPTQ domain scores were related to an alternative assessment of near-vision activities. The NVPTQ domain scores were able to distinguish between groups that were known to differ on the clinical outcome of uncorrected near visual acuity, supporting the construct validity of these scores. The NVPTQ domain scores showed evidence of responsiveness to change by being able to distinguish between groups defined as improved and not improved based on patient-reported and clinical outcomes. Conclusions: This research has resulted in a content-valid and psychometrically sound instrument designed to evaluate vision-related reading ability and satisfaction with vision-related reading ability. Trial registration: ClinicalTrials.gov NCT02780115. Registered 23 May 2016, https:// www. clini caltr ials. gov/ ct2/ show/ NCT02 780115? term= NCT02 78011 5& draw= 2& rank=1.

Ophthalmology and therapy, Oct 13, 2021

Introduction: Presbyopia is a progressive, agerelated visual condition that is characterized by r... more Introduction: Presbyopia is a progressive, agerelated visual condition that is characterized by reduced ability to focus on near/close objects, causing impacts on individuals' daily function and health-related quality of life. The Presbyopia Impact and Coping Questionnaire (PICQ) is a new patient-reported outcome (PRO) instrument that assesses presbyopia impact and use of coping behaviors among presbyopic individuals. Methods: To document the impacts of presbyopia and associated coping behaviors, concept elicitation (CE) interviews were conducted with 20 presbyopic participants. Results from the CE interviews were used to develop draft items for additional testing. Following item generation, the draft PICQ was cognitively debriefed with 20 participants. Data from a phase 2 controlled clinical trial were used for psychometric analyses of the PICQ. The PICQ was administered at site visits throughout a 28-day treatment period. Confirmatory factor analysis (CFA) methods were used to guide the development of the scoring algorithm. The reliability (internal consistency, test-retest), construct validity (convergent and discriminant validity, known-groups methods), and responsiveness (Guyatt's responsiveness statistic [GRS]) of the PICQ scores were evaluated. Finally, anchorbased and distribution-based methods were used to inform thresholds for interpreting meaningful within-patient change. Results: CE interviews identified the important and relevant presbyopia-related impacts and coping behaviors and 22 items were drafted and cognitively debriefed. Following minor revisions and item addition/deletion, a version of the PICQ including 23 items was subjected to psychometric testing. The analysis sample included 151 participants. The CFA established two PICQ domain scores, Coping and Impact, on 0-to-4 scales that demonstrate good model fit (root mean square error of approximation = 0.06, comparative fit index = 0.98, Tucker-Lewis index = 0.98, standardized root mean square = 0.07). Cronbach's alphas for the Coping and Impact scores were 0.89 and 0.84, respectively. Test-retest intraclass correlation coefficients were 0.77 for Coping and 0.67 for Impact. The pattern of results assessing construct validity was acceptable for the PICQ Coping and Impact scores, with the magnitude

Neurogastroenterology and Motility, Jan 27, 2020

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Alimentary Pharmacology & Therapeutics, Mar 22, 2017

Background The mixed land j-opioid receptor agonist and d-opioid receptor antagonist, eluxadoline... more Background The mixed land j-opioid receptor agonist and d-opioid receptor antagonist, eluxadoline, is licensed in the USA for the treatment of irritable bowel syndrome with diarrhoea (IBS-D), based on the results of two large Phase 3 clinical trials. Aim To understand the time course of treatment benefits with eluxadoline by comparing responder rates over the first month of treatment with responder rates over longer treatment intervals. Methods In this post hoc analysis of two Phase 3 studies, composite and adequate relief (AR) responder rates were calculated over month 1 and patients were stratified by their responder status. Cumulative counts over subsequent intervals (months 1-3, months 1-6, months 2 through 6) were tallied. Results The studies randomised 2428 patients. Over month 1, 24.6%, 22.8% and 12.5% of patients were composite responders with eluxadoline 100 mg, eluxadoline 75 mg and placebo respectively. For month 1 responders, 77.8% and 81.5% (over months 1-3) and 70.7% and 73.9% (over months 1-6) showed a continuous response with eluxadoline 100 mg and 75 mg respectively. [Correction added on 5 April 2017, after first online publication: The percentage for the responders over months 1-3 was previously wrong and has been corrected.] Of the month 1 nonresponders, <20% showed a response over months 1-3 or months 1-6. Similar results were seen for the analysis of proportions of AR responders over these time intervals. Conclusions Over two-thirds of patients who respond over the first month retain a positive response over 6 months of treatment with eluxadoline, indicating that early clinical response to eluxadoline is associated with sustained benefits for up to 6 months in patients with IBS-D.

Gastroenterology, Aug 1, 2013

BACKGROUND & AIMS: Simultaneous agonism of the m-opioid receptor and antagonism of the d-opioid r... more BACKGROUND & AIMS: Simultaneous agonism of the m-opioid receptor and antagonism of the d-opioid receptor can reduce abdominal pain and diarrhea in patients with irritable bowel syndrome with diarrhea (IBS-D) without constipating side effects. We evaluated the efficacy and safety of a minimally absorbed, m-opioid receptor agonist and d-opioid receptor antagonist (eluxadoline) in a phase 2 study in patients with IBS-D. METHODS: We randomly assigned 807 patients to groups that received oral placebo twice daily or 5, 25, 100, or 200 mg oral eluxadoline for 12 weeks. The primary end point was clinical response at week 4, defined by a mean reduction in daily pain score from baseline of !30%, and of at least 2 points on 0À10 scale, as well as a stool consistency score of 3 or 4 on the Bristol Stool Scale (1-7) for at least 66% of daily diary entries during that week. RESULTS: Significantly more patients receiving 25 mg (12.0%) or 200 mg (13.8%) eluxadoline met the primary end point of clinical response than patients given placebo (5.7%; P < .05). Patients receiving eluxadoline at 100 mg and 200 mg also had greater improvements in bowel movement frequency and urgency, global symptoms, quality of life, and adequate relief assessments (P < .05). Additionally, patients receiving 100 mg (28.0%) or 200 mg (28.5%) eluxadoline were significantly more likely than those receiving placebo (13.8%; P < .005) to meet the US Food and Drug Administration response end point during the full 12 weeks of the study. Eluxadoline was well tolerated with a low incidence of constipation. CONCLUSIONS: In a phase 2 study of the mixed m-opioid receptor agonist/dopioid receptor antagonist eluxadoline vs placebo in patients with IBS-D, patients given eluxadoline were significantly more likely to be clinical responders, based on a composite of improvement in abdominal pain and stool consistency. Further study of eluxadoline is warranted to assess its potential as a treatment for IBS-D. ClinicalTrials.gov number, NCT01130272

Value in Health, May 1, 2020

Gastroenterology, May 1, 2012

In early Crohn's disease (CD) patients at risk for disabling disease, two possible treatment stra... more In early Crohn's disease (CD) patients at risk for disabling disease, two possible treatment strategies are considered as potentially highly effective : accelerated step-care (steroids + AZA) or early combined immunosuppression (anti-TNF + AZA). However the accelerated step-care strategy (early AZA) has been poorly explored. The aim of this randomized, openlabel, controlled trial was to compare an early AZA approach with conventional step-care therapy in early CD. Methods: patients with a diagnosis of CD of less than 6mos, naive to immunosuppressors and biologics, with no previous history of surgery and having at least two predictors of disabling disease were randomized to receive AZA 2.5mg/kg at inclusion (e-AZA) or on demand according to guidelines (Controls). Predictors of disabling CD included an age<40 years, active perianal disease within the first 6 mos and need for oral steroids within the first 3 mos1. Patients were included in 24 GETAID centres between 2005, July, and 2010, December. The primary endpoint was the proportion of trimesters spent in steroid-free and anti-TNF-free remission during the first 3 years after inclusion. Data were compared between e-AZA and Control groups using non-parametric tests. Results: 147 patients were randomized to e-AZA or to Controls. Five patients were excluded just after inclusion, leaving 142 patients (71 e-AZA, 71 Controls) with a median (IQR) follow-up of 35 mos (15-36) at the reference date of ongoing follow-up (2011, October 1). They were 71 M and 71 F with median age (IQR) of 27 yrs (22-29) and a median disease duration of 2.5 months (1-3.7). 42 Controls (62%) required immunosuppressors during follow-up after a median time of 5.6 months (3.2-9.6). The proportion of trimesters in remission (median, IQR) was 61% (12-83) in e-AZA patients, vs. 50% (30-72) in Controls (NS). Additionally, 19 e-AZA patients (29%) required anti-TNF vs.18 Controls (26%, NS), 2 (3%) had unplanned surgical perianal procedures vs. 9 Controls (13%, p 0.055), and 7 (11%) had intestinal surgery vs. 14 Controls (21%, p 0.11). Median values of mean CDAI and C-reactive protein did not differ between the 2 groups. Conclusion: in patients at risk for disabling CD, early AZA was not associated with a significantly increased clinical remission rate during the first years of CD. More than one third of control patients had a mild-to-moderate course not requiring immunosuppressors at a 3 year follow-up. These data do not support the widespread use of an accelerated stepcare strategy compared to conventional step-care.

Quality of Life Research, Sep 28, 2018

Purpose Irritable bowel syndrome with diarrhea (IBS-D) significantly impacts health-related quali... more Purpose Irritable bowel syndrome with diarrhea (IBS-D) significantly impacts health-related quality of life (HRQOL). This post hoc analysis of two phase III trials evaluated the effects of eluxadoline treatment on disease-specific HRQOL among patients with IBS-D. Methods Adult patients meeting Rome III criteria for IBS-D were randomized to oral eluxadoline (75 mg or 100 mg) or placebo twice daily in two phase III clinical trials for 52 weeks (IBS-3001) and 26 weeks (IBS-3002). The Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire assessed disease-specific HRQOL throughout the study. Changes from baseline to Week 26 in IBS-QOL total and subscale scores were analyzed using an analysis of covariance model. Percentages of IBS-QOL responders with ≥ 14-and 20-point changes were evaluated for IBS-QOL total and subscale scores. A longitudinal mixed-effects model was fitted to evaluate mean IBS-QOL total scores. A cumulative distribution function for change from baseline to Week 26 in IBS-QOL total score was plotted. Results Mean changes from baseline to Week 26 for the IBS-QOL total and all subscale scores were significantly higher for patients treated with eluxadoline (both doses) compared to placebo. A significantly greater proportion of eluxadoline-treated patients were responders compared to placebo. Mean and mixed-effects model estimated mean IBS-QOL total scores were consistently higher for eluxadoline versus placebo over 52 weeks. Conclusions Compared to placebo, twice-daily eluxadoline treatment significantly improved HRQOL among patients with IBS-D in two phase III trials.

Journal of Hepatology, Aug 1, 2020

The American Journal of Gastroenterology, Oct 1, 2016

Frontiers in Neurology, Mar 31, 2022

Parkinson's disease is a neurodegenerative disease that can be associated with motor fluctuations... more Parkinson's disease is a neurodegenerative disease that can be associated with motor fluctuations that result in substantial negative impact to an individual's activities of daily living. Understanding the patient's perspective about the impact of Parkinson's disease therapies is an important part of drug development and shared treatment decision-making. The objective of this research was to examine the structure, scoring, internal consistency, test-retest reliability, and concurrent and known groups validity of the Parkinson's Disease Activities of Daily Living, Interference and Dependence © (PD-AID) instrument, a new, patient-reported outcomes instrument, developed to assess the clinical benefit of Parkinson's disease treatment from the patient's perspective. This was a non-interventional study among persons with mild-to-moderate Parkinson's disease currently using and responding to L-Dopa. The structure of the measure was confirmed applying item response theory to data from baseline, supporting 4 candidate scores. Baseline Patient Global Impression of Severity ratings facilitated known-groups analysis. Data from all participants were used to estimate test-retest reliability. Concurrent validity was assessed using correlations with related measures. Participants (n = 94) were mean age 69 years (mean time since diagnosis 6.9 years); 34 experienced L-Dopa-related dyskinesia. Psychometric models supported 4 candidate scoring regimes for the PD-AID. All exhibited adequate reliability and validity characteristics and strong internal consistency. Correlations with reference measures were in the expected direction and range of magnitude. Analyses supported the PD-AID as fit-for-purpose, producing psychometrically sound scores. Further research to confirm the measurement properties of the PD-AID in an expanded sample and to establish thresholds for meaningful score changes is recommended.

Journal of managed care & specialty pharmacy, Apr 1, 2017

BACKGROUND: The economic burden associated with irritable bowel syndrome with diarrhea (IBS-D) is... more BACKGROUND: The economic burden associated with irritable bowel syndrome with diarrhea (IBS-D) is not well understood. OBJECTIVES: To (a) evaluate total annual all-cause, gastrointestinal (GI)related, and symptom-related (i.e., IBS, diarrhea, abdominal pain) health care resource use and costs among IBS-D patients in a U.S. commercially insured population and (b) estimate incremental all-cause health care costs of IBS-D patients versus matched controls. METHODS: Patients aged ≥ 18 years with 12 months of continuous medical and pharmacy benefit eligibility in 2013 were identified from the Truven Health MarketScan research database. The study sample included patients with ≥ 1 medical claim with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code in any position for IBS (ICD-9-CM 564.1x) and either (a) ≥ 2 claims for diarrhea (ICD-9-CM 787.91, 564.5x) on different service dates in 2013, or (b) ≥ 1 claim for diarrhea plus ≥ 1 claim for abdominal pain (ICD-9-CM 789.0x) on different service dates in 2013, or (c) ≥ 1 claim for diarrhea plus ≥ 1 pharmacy claim for a symptom-related prescription on different service dates in 2013. Controls included patients with no claims for IBS, diarrhea, abdominal pain, or symptom-related prescriptions in 2013. Controls were randomly selected and matched with IBS-D patients in a 1:1 ratio based on age (± 4 years), gender, geographic location, and health plan type. All-cause health care resource utilization included medical and pharmacy claims for health care services associated with any condition. Total health care costs were defined as the sum of health plan-paid and patient-paid direct health care costs from prescriptions and medical services, including inpatient, emergency department (ED), and physician office visits, and other outpatient services. A total cost approach was used to assess all-cause, GI-related, and symptom-related health care costs for IBS-D patients. An incremental cost approach via generalized linear models was used to assess the excess all-cause costs attributable to IBS-D after adjusting for demographics and general and GI comorbidities. What this study adds Incremental costs associated with IBS-D were primarily attributable to increased use of medical services rather than pharmacy costs.

The New England Journal of Medicine, Jan 21, 2016

BACKGROUND Effective and safe treatments are needed for patients who have irritable bowel syndrom... more BACKGROUND Effective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy and safety of eluxadoline, a new oral agent with mixed opioid effects (μ-and κ-opioid receptor agonist and δ-opioid receptor antagonist), in patients with IBS with diarrhea. METHODS We randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26. RESULTS For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P = 0.01 and P = 0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P = 0.11 and P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P = 0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666 patients in the safety population (0.3%). CONCLUSIONS Eluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea in men and women, with sustained efficacy over 6 months in patients who received the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and NCT01553747, respectively.

The American Journal of Gastroenterology, Oct 1, 2014

Introduction: Patients with dyspepsia oft en pose a diagnostic challenge given their symptoms are... more Introduction: Patients with dyspepsia oft en pose a diagnostic challenge given their symptoms are nonspecifi c such as bloating, fl atulence, distention, and abdominal pain. Th e symptoms of dyspepsia in small intestinal bacterial overgrowth (SIBO) occur due to an overproliferation of the gut fl ora, which is manifested by maldigestion. Bacteria within the small intestine ferment sugars and release gaseous byproducts which can be measured through breath testing, the current cornerstone of noninvasive diagnosis of SIBO. Th ese bacteria may also produce nutrients, including folate, which can then be absorbed by the host. We hypothesize that elevated folate levels in patients with maldigestive symptoms may indicate SIBO as the contributor to those symptoms, and indicate earlier testing and treatment. Methods: Data was collected on all patients with a xylose breath test performed between January 2005 and December 2013 at Montefi ore Medical Center, an urban hospital. Patients were enrolled in the study if a folate level was available in our electronic medical record within the preceding year of breath testing. Comparisons of folate levels were analyzed with a 2-sample Z test and likelihood ratio calculations. Results: Seventy patients diagnosed with SIBO based on breath testing and 14 patients negative for SIBO were enrolled, each with a folate level in the preceding year. Fift y percent of patients with SIBO and 28% of patients negative for SIBO had an elevated folate level (p value=0.0659). In our study, patients with an elevated folate level were 1.75 times more likely to have SIBO than patients with a normal folate level (95% CI=0.74-4.14). Conclusion: In patients with symptoms of maldigestion, there is a trend towards folate levels being more elevated in those with diagnosed SIBO as compared to those without the disease. In this study of patients who underwent breath testing, those with elevated folate levels were more likely to be diagnosed with SIBO. Based on our results, folate may be useful in suggesting an underlying diagnosis of SIBO in patients with dyspepsia.

The American Journal of Gastroenterology, Oct 1, 2017

Clinical and translational gastroenterology, 2020

This study aimed to examine the validity of the modified Reflux Symptom Questionnaire-electronic ... more This study aimed to examine the validity of the modified Reflux Symptom Questionnaire-electronic Diary (mRESQ-eD) through patient input and psychometric testing of the questionnaire to support use in clinical trials in patients with persistent gastroesophageal reflux disease (GERD) and in accordance with Food and Drug Administration guidance on patient-reported outcome instruments. METHODS: Cognitive interviews were conducted with patients (n 5 30) to evaluate the interpretability and content validity of draft mRESQ-eD items. Patient data from a phase 2b clinical study (ClinicalTrials.gov identifier: NCT02637557) on persistent GERD served to aid in the construction of weekly scores for heartburn severity, regurgitation severity, and total GERD severity. These scores' psychometric properties were also evaluated. RESULTS: Minor modifications were made to the draft mRESQ-eD based on patient feedback to improve interpretability and clarity of the instrument. Psychometric analysis suggested that an 8-item version of the mRESQ-eD was best suited to the clinical data. The internal consistency was found to be high (Coefficient v 5 0.95). Retest reliability and convergent validity were strong for a heartburn weekly severity score, regurgitation weekly severity score, and total GERD severity score.

Gastroenterology, May 1, 2014

Background: Celiac disease (CeD) is a genetic autoimmune condition affecting 1% of the western po... more Background: Celiac disease (CeD) is a genetic autoimmune condition affecting 1% of the western population. Triggered by the ingestion of gluten, CeD is managed by a Gluten-Free diet (GFD), however recurrent symptoms due to inadvertent exposure and non-adherence to GFD are common and found in up to 71.8% of individuals with CeD. Symptoms can significantly impact quality of life and the disease is associated with an increased risk of gastrointestinal (GI) cancers and T-cell lymphoma. Tight junctions (TJ) control paracellular permeability, increased in CeD, caused in part, by an inflammatory immune response subsequent to paracellular transport of gluten peptides into the intestinal lamina propria through epithelial TJs. Larazotide acetate is a first-in-class oral peptide that prevents TJ opening and reduces gluten uptake, inhibiting gluten and cytokine-induced intestinal permeability and inflammation in vivo. The aim of the study was to investigate the efficacy of Larazotide acetate to improve signs and symptoms in individuals with CeD while on a GFD. Methods: In this outpatient, randomized, parallel, double-blind, placebo-controlled, multicenter study, conducted in 74 sites in North America, 342 CeD patients on a GFD for ≥12 months were randomized to receive placebo or Larazotide acetate 0.5, 1, or 2 mg three times daily (TID). The 20-week study had a 4-week placebo run-in, 12-week treatment phase, and 4-week placebo run-out. The primary outcome was the average on-treatment score in the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD GSRS) domains of Diarrhea, Indigestion, and Abdominal pain. Results: The primary endpoint of symptom reduction was met at the 0.5 mg dose of Larazotide acetate compared with placebo in both Modified Intention To Treat (MITT) (ANCOVA p=0.022, MMRM p=0.005) and Per Protocol (PP) analysis (ANCOVA p=0.007, MMRM p=0.001) (Figure 1). The 0.5 mg dose showed favorable outcomes for CeD Patient Reported Outcome (CeD PRO) GI domain, decrease in CeD PRO Symptomatic days (MITT ANCOVA 0.017) (Figure 2), an increase in Symptom-Free days (MITT ANCOVA p=0.034) and a decrease in Non-GI symptoms (MITT ANCOVA p=0.010). No increases in anti-tTG (IgA and IgG) titers were observed at any dose of Larazotide acetate. Safety of Larazotide acetate was comparable to placebo. Conclusion: Larazotide acetate 0.5 mg reduced GI and non-GI symptoms, while reducing the number of Symptomatic days. The safety and tolerability profile of Larazotide acetate was comparable to placebo. This study represents the first large therapeutic trial in CeD to meet its primary endpoint of reducing signs and symptoms and is the first successful trial of a novel class of agents targeting TJ regulation. Larazotide acetate 0.5 mg has the potential to be the first pharmacologic CeD treatment and warrants further investigation in Phase III clinical trials. 929c A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis.

Journal of Antimicrobial Chemotherapy, Jun 7, 2013

Table 2). When the geometric mean MIC values were compared, they varied from 0.97 to 1.28 by BMD ... more Table 2). When the geometric mean MIC values were compared, they varied from 0.97 to 1.28 by BMD and 0.88 to 1.23 by the Etest. The vancomycin MIC values showed fluctuation from year to year. This fluctuation was not statistically significant either by the BMD method (P ¼ 0.225) or the Etest (P¼ 0.136). Although the vancomycin MIC values fluctuated from year to year, we could not detect vancomycin MIC creep with either method. These differences between the years could be due to the large variability among the number of isolates from each year. Similar to the vancomycin susceptibility trend, the daptomycin MICvalues also showed fluctuation over time. This fluctuation was found to be statistically significant (P ¼ 0.005), but no MIC creep was detected between 1999 and 2009. In conclusion, although MIC fluctuation was found in our institution over time, we did not detect a decrease in vancomycin and daptomycin susceptibility among MRSA blood isolates over an 11 year period, either by BMD or the Etest. It is important to monitor the trend in vancomycin and daptomycin MICs, as changes in vancomycin MICs for S. aureus can occur over time within specific institutions.