Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial.

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 reliability; and validity by convergent and known-groups analyses. RESULTS: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively). CONCLUSIONS: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www. CLINICALTRIALS: gov/ct2/show/NCT03548220 .

Pyruvate kinase (PK) deficiency is a rare genetic blood disorder with a wide range of signs and symptoms that may have a negative impact on patients' quality of life. Patient-reported outcome (PRO) instruments are tools that assess how a disease affects a patient from the patient's perspective. These instruments must go through a validation process to make sure they truly capture the patient's experience with their condition or its treatment. This study aimed to validate two new PRO instruments in adult patients enrolled in the ACTIVATE clinical trial (NCT03548220), where patients with PK deficiency received the drug mitapivat or a placebo. These two new PRO instruments are the first to be developed specifically for PK deficiency: the PK Deficiency Diary (PKDD), a daily diary that asks 7 questions to measure the core signs and symptoms of PK deficiency, and the PK Deficiency Impact Assessment (PKDIA), a weekly questionnaire with 12 questions to assess the impact of PK deficiency on a patient's life. The results of this study showed that the PKDD and PKDIA properly and reliably measured the signs, symptoms, and impacts of PK deficiency that they aimed to capture. These findings indicate that the PKDD and PKDIA are the first validated PROs specifically for PK deficiency and can help improve the understanding of the impact of PK deficiency on patients' quality of life.

Comparison of raw and regression approaches to capturing change on patient-reported outcome measures.

PURPOSE: 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. METHODS: Both simulated and PROMIS® pain interference items were used to calculate change employing three methods: raw change scores and regression estimators proposed by Lord and Novick (LN) and Cronbach and Furby (CF). In the simulated data, estimators' ability to recover true change was compared. Standard errors of measurement (SEM) and estimation (SEE) with associated 95% confidence limits were also used to identify criteria for significant improvement. These methods were then applied to real-world data from the PROMIS® study. RESULTS: In the simulation, both regression estimators reduced variability compared to raw change scores by almost half. Compared to CF, the LN regression better recovered true simulated differences. Analysis of the PROMIS® data showed similar themes, and change score distributions from the regression estimators showed less dispersion. Using distribution-based approaches to calculate thresholds for significant within-patient change, smaller changes could be detected using both regression estimators. CONCLUSIONS: These results suggest that calculating change using regression estimates may result in more increased measurement sensitivity. Using these scores in lieu of raw differences can help better identify individuals who experience real underlying change in PROs in the course of a trial, and enhance the established methods for identifying thresholds for meaningful within-patient change in PROs.

Psychometric evaluation of the Urgency NRS as a new patient-reported outcome measure for patients with ulcerative colitis.

BACKGROUND: The Urgency Numeric Rating Scale (NRS) was developed as a content-valid single-item patient-reported outcome measure to assess severity of bowel urgency. Here, we evaluated the psychometric properties of the Urgency NRS. METHODS: Data were from a multicenter, randomized, placebo-controlled phase 3 trial in adults with moderately to severely active ulcerative colitis (NCT03518086). Patients completed the Urgency NRS using a daily electronic diary, from which weekly average Urgency NRS scores were calculated. Test-retest reliability, known-groups validity, construct validity, responsiveness, and score interpretation were assessed using the modified Mayo score, Inflammatory Bowel Disease Questionnaire (IBDQ), Patient Global Rating of Severity (PGRS), Patient Global Rating of Change (PGRC), and Geboes score. RESULTS: The study sample comprised 1,162 participants (40.2% female). Mean Urgency NRS score was higher (worse) at baseline than at week 12 (6.2 vs. 3.7). Test-retest reliability was strong, with intra-class correlation coefficients of 0.76-0.89. Baseline least-square mean Urgency NRS score was higher for participants with a PGRS score greater than the median (worse symptoms) than for those with a PGRS score less than or equal to the median (7.5 vs. 5.4; p < 0.0001), indicating good known-groups validity. Urgency NRS score was moderately correlated with IBDQ total and domain scores, PGRS, PGRC, and modified Mayo stool frequency, establishing its convergent validity. Correlations were weak for Geboes score and weak to moderate for modified Mayo endoscopic subscore and modified Mayo rectal bleeding, indicating that the Urgency NRS also had discriminant validity. Patients achieving clinical remission, clinical response, IBDQ remission, and PGRS score improvement showed significantly greater improvement on the Urgency NRS (p < 0.0001 for all), demonstrating responsiveness to change. A ≥ 3-point improvement in Urgency NRS score represented a meaningful improvement in bowel urgency and an Urgency NRS score of ≤ 1 point represented a bowel urgency remission threshold that was closely associated with clinical, endoscopic, and histologic remission. CONCLUSIONS: The Urgency NRS is a valid and reliable patient-reported outcome measure that is suitable for evaluating treatment benefits in clinical trials in patients with moderately to severely active ulcerative colitis.

Absolute and Functional Iron Deficiency in Colon Cancer: A Cohort Study.

Background and Objectives: Iron is an essential micronutrient for many biological functions and has been found to be intimately linked to cancer biology. Although the effects of increased dietary iron consumption in the development of CRC have been previously investigated in several cohort studies, the available evidence on the involvement of iron deficiency in this process is relatively scarce. Previously published papers did not analyze specific outcomes, such as the presence of biologically aggressive histopathological characteristics, that are associated with the subtypes of iron deficiency. The purpose of this study was to investigate the connection between the development of colorectal cancer and the presence of functional iron deficiency (FID), which is defined as insufficient biological availability of iron in the presence of adequate storage reserves, or absolute iron deficiency (AID), which is defined as severely depleted iron storage levels. Materials and Methods: Our paper represents a single center registry-based cohort study. Iron levels were routinely evaluated upon diagnosis of CRC and the collected data were coupled with patient- and tumor-specific data (2018-2022). Spearman's correlation coefficient and the chi-squared test were used to analyze the association. Results: Out of 129 patients, 75 (58.13%) were anemic. AID was identified in 26.35% of cases and FID was encountered in 51.16% of cases. A statistically significant association between FID and lymphatic invasion was encountered. An analysis of the correlation demonstrated a significant association between anemia and right-sided tumor location. Conclusions: Functional iron deficiency seems to be independently associated with lymphatic invasion. Although a statistically significant correlation with the T or N stage was not demonstrated, the analysis suggested a potential positive relationship between the presence of FID and more aggressive tumor characteristics.

The Measurement Performance of the Parkinson's Disease Activities of Daily Living, Interference, and Dependence Instrument.

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.

Memory-Assisted Global Impression of Change (MAGIC).

BACKGROUND: The United States Food and Drug Administration is developing a series of patient-focused drug development guidance documents regarding the collection of patient experience data, including methods for understanding treatment benefit from the patient perspective. The goal of this research was to investigate the concern that the global impression of change scale is subject to recall error and thus not optimal for use as an anchor for estimating meaningful within-person change thresholds. We explored whether memory assistance for recalling baseline status would make a difference in how study participants diagnosed with Parkinson's disease (PD) responded to a patient global impression of change (PGIC) and patient global impression static (PGIS) item. METHODS: The research was completed as a secondary objective of a non-interventional 28-day (± 4 days) study among persons with Parkinson's disease and associated motor fluctuations. At baseline, participants completed the PGIS and then recorded a voice message to their future self in which they spoke about how their PD had affected their "day-to-day" activities over the preceding few days. At the final visit, the PGIC and PGIS were completed, after which participants listened to their memory assistance voice recording, and then completed both items for a second time to calculate a memory-assisted global impression static and change scores (MAGIS and MAGIC, respectively). Spearman correlations (ρ) were examined for the pre- and post- memory assistance evaluations. The degree of agreement pre- and post-memory assistance was quantified using the Shrout & Fleiss intraclass correlation coefficient (ICC [2,1]). An ICC(2,1) ≥ 0.7 served as the pre-specified criterion of acceptability for both the ρ and ICC(2,1) values. RESULTS: Participants in the analytic sample were mean age 68.7 and mostly white (91.7%) and male (69.4%). The average length of time since PD diagnosis was 6.5 years. Correlations between the PGIS and MAGIS were ρ = 0.88; correlations between PGIC and MAGIC were ρ = 0.86. The estimated ICC(2,1) for both the PGIS/MAGIS and PGIC/MAGIC exceeded target success criterion of ICC(2,1) ≥ 0.70. CONCLUSION: Our results show that the MAGIS/MAGIC methodology is feasible and that memory assistance did not substantially alter the PGIS/PGIC scores at the final visit.

Development of the Near Vision Presbyopia Task-based Questionnaire for use in evaluating the impact of presbyopia.

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.clinicaltrials.gov/ct2/show/NCT02780115?term=NCT02780115&draw=2&rank=1.

Development of the Presbyopia Impact and Coping Questionnaire.

INTRODUCTION: Presbyopia is a progressive, age-related 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, anchor-based 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 of correlations and effect sizes generally meeting a priori expectations. The corresponding GRS effect sizes for the PICQ Coping scores were -1.23 (i.e., large) for Patient Global Impression of Change (PGIC) and -0.72 (i.e., medium) for uncorrected near visual acuity (UNVA). The GRS effect sizes for the PICQ Impact scores were -0.60 (i.e., medium) for PGIC and -0.35 (i.e., small) for UNVA. Across three sets of anchor-based analyses for interpreting individual-level change, a responder threshold of -1.00 was identified for both PICQ Coping and PICQ Impact scores. CONCLUSIONS: The totality of evidence from the qualitative and quantitative research establishes that the PICQ scores produced are valid and reliable measures of presbyopia impacts and coping behaviors that are important and relevant for assessing presbyopia treatment outcomes. CLINICALTRIALS. GOV IDENTIFIER: NCT02780115; date of registration May 19, 2016.

Validation of the Overactive Bladder-Bladder Assessment Tool (OAB-BAT): A Potential Alternative to the Standard Bladder Diary for Monitoring OAB Outcomes.

BACKGROUND: An advisory board concluded that a new, comprehensive overactive bladder (OAB) patient-reported outcome (PRO) measure should be developed in accordance with regulatory guidelines. The OAB-Bladder Assessment Tool (OAB-BAT) was developed with qualitative input from OAB patients and experts to measure symptoms, bother, impacts, and satisfaction with treatment. OBJECTIVE: Psychometric evaluation of the OAB-BAT assessing PRO OAB symptoms, bother, and impacts during a 7-d recall period. DESIGN, SETTING, AND PARTICIPANTS: Psychometric testing was conducted for a 28-d observational study of 170 OAB patients. Eligibility criteria included clinician-confirmed OAB diagnosis with at least eight micturitions per day. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Assessments included the OAB-BAT, a 7-d bladder diary, and co-validating OAB PROs. Analysis included classical and modern test theories. A scoring algorithm was developed and psychometric properties were assessed. RESULTS AND LIMITATIONS: The majority of participants were women (72.4%) with moderate OAB symptom severity (53.5%). More than one-third of participants (34.1%) were incontinent. Responses were well balanced across bother and impact items, while symptom frequency items showed sparse responses. Analysis supported an eight-item unidimensional model based on bother and impacts. No items performed differently by gender or continence status. The OAB-BAT showed internal consistency (ω=0.918), retest reliability (two-way random intraclass correlation coefficient=0.81), and convergent validity with the OAB-q (r>0.4). Known groups showed the expected trend. Comparisons between OAB-BAT scores and components of the bladder diary showed a moderate effect size (r>0.4). CONCLUSIONS: The eight-item OAB-BAT with 7-d recall is valid and reliable as an OAB PRO measure. Structural modeling, balanced with content validity considerations, produced robust scores. The OAB-BAT is a useful addition to the clinical assessment of patients, designed to complement the use of bladder diaries for monitoring OAB outcomes, in clinical trial and clinical practice environments. Future studies will need to assess the treatment satisfaction items in a larger sample of patients receiving OAB treatment. PATIENT SUMMARY: We tested a questionnaire designed to assess overactive bladder (OAB) symptoms, bother, satisfaction, and impacts by asking patients to complete it on a weekly basis. We found that the questionnaire accurately captures the symptoms and impacts that are most important to patients with OAB. We conclude that the questionnaire could be a useful instrument and, after further assessment in clinical practice and research, a possible alternative to a bladder diary in measuring OAB outcomes.

Development and Initial Validation Analyses of the Living with Idiopathic Pulmonary Fibrosis Questionnaire.

Rationale: Several new drugs for idiopathic pulmonary fibrosis (IPF) are in development. Tools are needed to assess whether these drugs benefit patients on outcomes that matter most to them. Health-related quality of life (HRQL) is one such outcome. It is influenced by many factors, but symptoms and their impacts are two strong drivers.Objectives: To develop a questionnaire to assess symptoms, disease impacts, and HRQL specifically for patients with IPF.Methods: Working with the U.S. Food and Drug Administration through the Drug Development Tool Qualification process, focus groups, concept elicitation, and cognitive debriefing interviews were conducted to inform the development of a 44-item pilot questionnaire. The pilot paper-and-pen questionnaire was migrated to an equivalent electronic version and field-tested in a 14-day study. Response data were subjected to psychometric testing, including exploratory factor analysis, item calibration using item response theory models, test-retest reliability, and validity testing.Measurements and Main Results: A total of 125 patients with IPF (62.4% men) completed the longitudinal study. The mean ± SD age of the cohort was 69 ± 7.60 years, and the mean FVC% predicted was 71 ± 20.0. After factor and item analyses, 35 items were retained, and these comprise the two modules (symptoms and impacts) of the Living with IPF (L-IPF) questionnaire. The L-IPF yields five scales demonstrating good psychometric properties, including correlation with concurrently collected FVC% predicted and the ability to discriminate between patients with differing levels of IPF severity.Conclusions: The L-IPF is a new questionnaire that assesses symptoms, disease impacts, and HRQL in patients with IPF.

Evaluation and Validation of the Modified Reflux Symptom Questionnaire-Electronic Diary in Patients With Persistent Gastroesophageal Reflux Disease.

OBJECTIVES: 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 = 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 ω = 0.95). Retest reliability and convergent validity were strong for a heartburn weekly severity score, regurgitation weekly severity score, and total GERD severity score. DISCUSSION: The final 8-item mRESQ-eD is a reliable and valid instrument with good psychometric properties for use in clinical trials in patients with persistent GERD. The mRESQ-eD may be considered for inclusion in clinical trials for persistent GERD and potentially positioned, in consultation with Food and Drug Administration, as endpoints to characterize treatment benefit.

Effects of treatment with eluxadoline on abdominal pain in patients with IBS-D: Additional post hoc analyses of Phase 3 trials.

BACKGROUND: Recurring abdominal pain is a characteristic and often unpredictable and debilitating symptom of irritable bowel syndrome with diarrhea (IBS-D). Measuring the effects of IBS-D treatments on abdominal pain remains a significant challenge in clinical trials. Here, we aimed to examine the effect of eluxadoline through various post hoc analyses. METHODS: Data from two eluxadoline Phase 3 trials were pooled over 26 weeks, comparing eluxadoline 100 mg twice daily to placebo. Worst abdominal pain (WAP) was measured daily on a 0-10 scale. WAP responder criteria were prospectively defined as a ≥30% improvement in daily WAP score on ≥50% of days. Pairwise, two-sided Cochran-Mantel-Haenszel tests assessed treatment effects. Cumulative distribution functions were used to plot WAP response rates using variations on the response criteria. KEY RESULTS: Of 1615 patients with IBS-D (66% female, mean age 46 years), 806 received eluxadoline and 809 received placebo; 48.3% and 44.0% were WAP responders (≥30% improvement), respectively (P value not significant). When the response threshold was increased to 50% daily WAP improvement from baseline, a significantly greater percentage of eluxadoline-treated patients versus placebo-treated patients were WAP responders (38.7% vs 32.5%, respectively; P = .009). At Week 26, average WAP changes from baseline were -3.4 and -3.0 points, respectively (P = .002). CONCLUSIONS AND INFERENCES: Despite small effect sizes, eluxadoline demonstrated consistent and sustained improvement in WAP compared to placebo across a range of prospective and post hoc analyses. Assessing WAP response across a range of measures is important for fully understanding a treatment's efficacy.

The impact of treatment with eluxadoline on health-related quality of life among adult patients with irritable bowel syndrome with diarrhea.

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.

Economic Burden of Irritable Bowel Syndrome with Diarrhea: Retrospective Analysis of a U.S. Commercially Insured Population.

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. RESULTS: Of 39,306 patients (n = 19,653 each for IBS-D and matched controls) included, mean (± SD) age was 47 (± 17) years and 76.5% were female. Compared with controls, IBS-D patients had a significantly higher mean annual number of hospitalizations, ED visits, office visits, and monthly (30-day) prescription fills. Mean annual all-cause health care costs for IBS-D patients were $13,038, with over half (58.4%) attributable to office visits and other outpatient services (e.g., diagnostic tests and laboratory or radiology services), and remaining costs attributable to prescriptions (19.5%), inpatient admissions (13.6%), and ED visits (8.5%). GI-related ($3,817) and symptom-related ($1,693) costs were also primarily driven by other outpatient service costs. After adjusting for demographics and comorbidities, incremental annual all-cause costs associated with IBS-D were $2,268 ($9,436 for IBS-D patients vs. $7,169 for matched controls; P < 0.001) per patient/year, of which 78% were from medical costs and 22% were from prescription costs. CONCLUSIONS: IBS-D was associated with a substantial burden in direct costs in this population. Compared with matched controls, IBS-D patients had greater medical service use and incurred significantly more annual all-cause health care costs, even after controlling for demographics and comorbidities. Incremental costs associated with IBS-D were primarily attributable to increased use of medical services rather than pharmacy costs. DISCLOSURES: This study was funded by Allergan. The authors received no compensation related to the development of the manuscript. Buono and Andrae are employees of Allergan. Mathur is an employee of Axtria. Averitt was an employee of Axtria at the time this study was conducted. Data from this manuscript have previously been presented in poster format by Buono at the American College of Gastroenterology Annual Scientific Meeting; Honolulu, Hawaii; October 16-21, 2015. Mathur and Averitt were involved in conducting the study analyses. All authors were involved in the study design, interpretation of the data, and preparation of the manuscript. The authors take full responsibility for the scope, direction, and content of the manuscript and have approved the submitted manuscript.

Economic burden of inadequate symptom control among US commercially insured patients with irritable bowel syndrome with diarrhea.

AIMS: To assess healthcare resource use and costs among irritable bowel syndrome (IBS) with diarrhea (IBS-D) patients with and without evidence of inadequate symptom control on current prescription therapies and estimate incremental all-cause costs associated with inadequate symptom control. METHODS: IBS-D patients aged ≥18 years with ≥1 medical claim for IBS (ICD-9-CM 564.1x) and either ≥2 claims for diarrhea (ICD-9-CM 787.91, 564.5x), ≥1 claim for diarrhea plus ≥1 claim for abdominal pain (ICD-9-CM 789.0x), or ≥1 claim for diarrhea plus ≥1 pharmacy claim for a symptom-related prescription within 1 year of an IBS diagnosis were identified from the Truven Health MarketScan database. Inadequate symptom control, resource use, and costs were assessed up to 1 year following the index date. Inadequate symptom control included any of the following: (1) switch or (2) addition of new symptom-related therapy; (3) IBS-D-related inpatient or emergency room (ER) admission; (4) IBS-D-related medical procedure; (5) diagnosis of condition indicating treatment failure; or (6) use of a more aggressive prescription. Generalized linear models assessed incremental costs of inadequate symptom control. RESULTS: Of 20,624 IBS-D patients (mean age = 48.5 years; 77.8% female), 66.4% had evidence of inadequate symptom control. Compared to those without inadequate symptom control, patients with evidence of inadequate symptom control had significantly more hospitalizations (12.0% vs 6.0%), ER visits (37.1% vs 22.6%), use of outpatient services (73.0% vs 60.7%), physician office visits (mean 11.0 vs 8.1), and prescription fills (mean 40.0 vs 26.7) annually (all p < .01). Incremental costs associated with inadequate symptom control were $3,065 (2013 US dollars), and were driven by medical service costs ($2,391; 78%). LIMITATIONS: Study included US commercially insured patients only and inferred IBS-D status and inadequate symptom control from claims. CONCLUSIONS: Inadequate symptom control associated with available IBS-D therapies represents a significant economic burden for both payers and IBS-D patients.

Eluxadoline for Irritable Bowel Syndrome with Diarrhea.

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.).

Item-level assessment of the irritable bowel syndrome quality of life questionnaire in patients with diarrheal irritable bowel syndrome.

BACKGROUND: In previous studies, the Irritable Bowel Syndrome Quality of Life (IBS-QOL) instrument has been determined to have good measurement properties for general irritable bowel syndrome (IBS) and the diarrheal IBS (IBS-d) subtype in clinical trials. OBJECTIVE: This article aims to extend the true-score analyses that have been previously conducted to evaluate the IBS-QOL in IBS-d patients. METHODS: Item response theory analysis was conducted by fitting models to responses from 753 patients with severe IBS-d from a recent clinical trial. Three item response theory models, the constrained graded response model (CGRM), the unconstrained GRM (UGRM), and the testlet response model (TRM), were fit to the 34 items of the IBS-QOL questionnaire. Subsequently, differential item functioning (DIF) for patient sex was assessed by fitting nested models by applying likelihood ratio tests. Model latent trait estimates were then compared with the IBS-QOL score and the IBS Symptom Severity Score. RESULTS: Model fits improved with complexity, with the TRM model fitting best compared with the CGRM and UGRM. The DIF evaluation for patient sex flagged 17 items for the CGRM and 9 items for the UGRM; however, these items were not found to have much effect on the overall estimation of the latent trait. Differential testlet functioning was not indicated, and no items exhibited potential DIF under the TRM because likelihood ratio tests were not statistically significant. Comparison of latent trait estimates to the IBS Symptom Severity Score and IBS-QOL questionnaire revealed high Spearman correlations (0.47 and ≥0.99, respectively). CONCLUSION: Previous true-score approach results were supported by the IBS-QOL item-level analysis. Further, the IBS-QOL total score was found to be a valid measure of perceived quality of life for IBS-d patients when compared with more sophisticated model-based estimates of perceived quality of life. ClinicalTrials.gov identifier: NCT01130272.

Evaluation of the Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire in diarrheal-predominant irritable bowel syndrome patients.

BACKGROUND: Diarrhea-predominant irritable bowel syndrome (IBS-d) significantly diminishes the health-related quality of life (HRQOL) of patients. Psychological and social impacts are common with many IBS-d patients reporting comorbid depression, anxiety, decreased intimacy, and lost working days. The Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire is a 34-item instrument developed and validated for measurement of HRQOL in non-subtyped IBS patients. The current paper assesses this previously-validated instrument employing data collected from 754 patients who participated in a randomized clinical trial of a novel treatment, eluxadoline, for IBS-d. METHODS: Psychometric methods common to HRQOL research were employed to evaluate the IBS-QOL. Many of the historical analyses of the IBS-QOL validations were used. Other techniques that extended the original methods were applied where more appropriate for the current dataset. In IBS-d patients, we analyzed the items and substructure of the IBS-QOL via item reduction, factor structure, internal consistency, reproducibility, construct validity, and ability to detect change. RESULTS: This study supports the IBS-QOL as a psychometrically valid measure. Factor analyses suggested that IBS-specific QOL as measured by the IBS-QOL is a unidimensional construct. Construct validity was further buttressed by significant correlations between IBS-QOL total scores and related measures of IBS-d severity including the historically-relevant Irritable Bowel Syndrome Adequate Relief (IBS-AR) item and the FDA's Clinical Responder definition. The IBS-QOL also showed a significant ability to detect change as evidenced by analysis of treatment effects. A minority of the items, unrelated to the IBS-d, performed less well by the standards set by the original authors. CONCLUSIONS: We established that the IBS-QOL total score is a psychometrically valid measure of HRQOL in IBS-d patients enrolled in this study. Our analyses suggest that the IBS-QOL items demonstrate very good construct validity and ability to detect changes due to treatment effects. Furthermore, our analyses suggest that the IBS-QOL items measure a univariate construct and we believe further modeling of the IBS-QOL from an item response theory (IRT) approach under both non-treatment and treatment conditions would greatly further our understanding as item-based methods could be used to develop a short form.

Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study.

BACKGROUND & AIMS: Simultaneous agonism of the µ-opioid receptor and antagonism of the δ-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, µ-opioid receptor agonist and δ-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 0-10 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 µ-opioid receptor agonist/δ-opioid 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.