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Objectives:Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-μg dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-μg dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-μg linaclotide dose in CIC patients.Methods:This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72 μg or 145 μg, or placebo for 12 weeks. The primary endpoint, 12-week complete spontaneous bowel movement (CSBM) overall responder, required patients to have ≥3 CSBMs and an increase of ≥1 CSBM per week from baseline in the same week for ≥9 of 12 weeks of the treatment period. Secondary endpoints included 12-week change from baseline in bowel (SBM and CSBM frequency, stool consistency, straining) and abdominal (bloating, discomfort) symptoms, monthly CSBM responders, and 12-week CSBM responders among patients who averaged >1 SBM/week at baseline. Sustained response (12-week CSBM overall responders who met weekly criteria for 3 of the 4 final weeks (weeks 9-12) of treatment) was evaluated as an additional endpoint. Adverse events (AEs) were monitored.Results:The intent-to-treat population included 1,223 patients (mean age=46 years, female=77%, white=71%). The primary endpoint was met by 13.4% of linaclotide 72-μg patients vs. 4.7% of placebo patients (P<0.0001, odds ratio=3.0; statistically significant controlling for multiplicity). Sustained response was achieved by 12.4% of linaclotide 72-μg patients vs. 4.2% of placebo patients (nominal P<0.0001). Linaclotide 72-μg patients met 9-of-10 secondary endpoints vs. placebo (P<0.05; abdominal discomfort, P=0.1028). Patients treated with linaclotide 145 μg also improved CIC symptoms for the primary (12.4%) and sustained responder endpoint parameters (11.4%) and for all 10 of the secondary endpoint parameters including abdominal discomfort (P<0.05). Diarrhea, the most common AE, was mild in most instances and resulted in discontinuation of 0, 2.4%, and 3.2% of patients in the placebo, linaclotide 72-μg, and linaclotide 145-μg groups, respectively.Conclusions:Once-daily linaclotide 72 μg significantly improved CIC symptoms in both men and women with a low rate of discontinuation due to diarrhea over 12 weeks of treatment.

Immediate-release (IR) formulation of linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.

Objectives:The Functional Dyspepsia Symptom Diary (FDSD) was developed to address the lack of symptom-focused, patient-reported outcome (PRO) measures designed for use in functional dyspepsia (FD) patients and meeting Food and Drug Administration recommendations for PRO instrument development.Methods:Concept elicitation interviews were conducted with FD participants to identify symptoms important and relevant to FD patients. A preliminary version of the FDSD was constructed, then completed by FD participants on an electronic device in cognitive interviews to evaluate the readability, comprehensibility, relevance, and comprehensiveness of the FDSD, and to preliminarily evaluate its measurement properties.Results:During concept elicitation interviews, 45 participants spontaneously reported 19 symptom concepts. Of those, seven symptoms were selected for assessment by the eight-item FDSD. Cognitive interviews with 57 participants confirmed that participants were able to comprehend and provide meaningful responses to the FDSD, and that the handheld electronic FDSD format was suitable for use in the target population. Scores of the FDSD were well-distributed among response options, item discrimination indices suggested that the FDSD items differentiate among patients with varying degrees of FD severity, and inter-item correlations suggested that no items of the FDSD were capturing redundant information. Internal consistency estimates (0.87) and construct-related validity estimates using known-groups methods were within acceptable ranges.Conclusions:The FDSD is a content-valid PRO measure, with preliminary psychometric evidence providing support for the FDSD's items and total score. Further psychometric evaluations are recommended to more fully test the FDSD's score performance and other measurement properties in the target patient population.

Background There is interest in participants using their own smartphones or tablets (“bring your own device”; BYOD) to complete patient-reported outcome (PRO) measures in clinical studies. Our study aimed to qualitatively evaluate participants’ experience using a provisioned device (PD) versus their own smartphone (BYOD) for this purpose. Methods Participants with chronic obstructive pulmonary disease (COPD) were recruited for this observational, cross-over study and completed PRO measures daily on one device type for 15 days, then switched to the other device type to complete the same measures for another 15 days. After each 15-day period, semi-structured interviews were conducted about their experience with the device. Results Of 64 participants enrolled, the final qualitative analysis populations comprised those who participated in an interview without protocol violations. Thus, the qualitative longitudinal population (LP) included n = 57 (89%), while the qualitative cross-sectional population (CSP) included n = 60 (94%). CSP participants found both device types easy to use. Twenty CSP participants (33%) reported missing data entry on at least one day when using PD, and 24 (40%) reported missing at least one day when using BYOD. In the LP, preference for one of the device types was somewhat evenly split; 45.6% (n = 26) preferred PD and 50.9% (n = 29) preferred BYOD. The most common reason for preferring PD was that it was “dedicated” to the study; the “convenience” of carrying a single device was the main reason for preferring BYOD. Conclusion The findings from the interviews demonstrated few differences in participants’ experience completing PRO measures on a PD versus BYOD. Our study supports the use of BYOD as a potential addition to PD for collecting PRO data and contributes evidence that BYOD may be employed to collect PRO data in demographically diverse patient populations.

Introduction: Understanding how patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) treat their disease and what drives treatment satisfaction or discontinuation is important when considering new treatment options. Treatment choice may be difficult, due in part to the heterogeneity and/or severity of these disorders. This analysis of the Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform (CONTOR) study examined treatment patterns and outcomes among participants with IBS-C or CIC. Methods: CONTOR included fully insured US patients with: both medical and pharmacy benefits and >1 medical claim for constipation (ICD-9-CM diagnosis code: 564.0x); or >1 claim for IBS (564.1x) or abdominal pain (789.0x) plus >1 pharmacy claim for a stool softener/laxative; or >1 claim for linaclotide or lubiprostone (October 2014 to November 2016). Over the 12-month study period, participants completed a baseline and quarterly survey, which included the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire and an assessment of overall treatment satisfaction. Monthly surveys collected patient-reported new or discontinued IBS-C/CIC treatments. Association between quality of life and changes in treatment satisfaction was determined by multivariate analyses. Results: Of 2052 CONTOR participants, 93.8% (n=1922) were female; the mean (SD) age was 46.7 (11.9) years. At baseline, the majority of participants reported their IBS-C/CIC treatment included over-thecounter (OTC) medication use (65.4%), while 22.2% reported OTC and prescription treatment (Table 1). The concomitant use of prescription and OTC treatments remained consistent over the study period. The most common reasons for discontinuing any treatment were failure to improve constipation (41.4%), bloating (39.4%), and pain (34.7%); improved symptoms no longer required medication in 28.7% of participants. The odds of becoming satisfied with treatment were higher in participants with improved PACQOL total scores (defined as >0.5 improvement from baseline) compared to those with no improvement (p<0.001) (Table 2). Conclusion: The majority of participants with IBS-C or CIC used a variety of treatments to manage their disease. Improved quality of life was associated with treatment satisfaction.

Introduction: Treatment of patients with chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) may provide symptom improvement, which is associated with increased quality of life (QOL), a key factor impacting patients perception of treatment satisfaction. This analysis assessed patient-reported outcomes before and on/after initiating linaclotide, based on survey data from the Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform (CONTOR). Methods: CONTOR participants included fully insured patients aged >8 years, identified via claims from a large, geographically diverse US health insurer, with: >1 medical claim for constipation (ICD-9-CM diagnosis code: 564.0x); or >1 claim for IBS (564.1x) or abdominal pain (789.0x) plus >1 pharmacy claim for a stool softener/laxative; or >1 claim for linaclotide or lubiprostone. Over the 1-year study period, participants completed self-administered baseline/quarterly surveys, which assessed treatment satisfaction, symptoms (Patient Assessment of Constipation Symptoms [PAC-SYM]), and QOL (PAC-QOL). Participants reporting over-the-counter (OTC) constipation treatment who then reported initiating linaclotide regardless of continued OTC treatment were included; those reporting any concomitant lubiprostone use were excluded. Outcomes were measured before and on/after the initiation of linaclotide and for daily and non-daily linaclotide use. Results: 124 participants reported initiating linaclotide after taking an OTC treatment, with ics similar to 2052 participants in the overall CONTOR population (Table 1). Linaclotide frequency of use at initiation was daily (53.2%), as needed (33.9%), every other day (8.9%), or weekly (4.0%). A greater proportion of participants were satisfied with their treatment on/after initiating linaclotide vs. before (39.2% vs. 30.2%). Mean PAC-SYM and PAC-QOL scores were lower on/after initiating linaclotide vs. before, indicating better QOL and fewer symptoms, respectively (Table 2). Greater changes in outcomes were observed among patients who reported daily linaclotide use. Conclusion: Among CONTOR participants initiating linaclotide after reporting OTC use, overall treatment satisfaction increased on/after initiating linaclotide, with mild improvement in symptoms and QOL. These results warrant further investigation to assess whether outcomes continue to improve with longer linaclotide use.

Objective To quantitatively compare equivalence and compliance of patient-reported outcome (PRO) data collected via provisioned device (PD) versus bring your own device (BYOD). Methods Participants with stable chronic obstructive pulmonary disease (COPD) completed the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT ® ) daily and COPD Assessment Test™ (CAT) and Patient Global Impression of Severity (PGIS) of COPD weekly on either PD or BYOD for 15 days, then switched device types for 15 days. EXACT was scored using the Evaluating Respiratory Symptoms in COPD (E-RS ® : COPD) algorithm and equivalence assessed using intraclass correlation coefficients (ICCs) adjusting for cross-over sequence, period, and time. Two one-sided tests (TOSTs) used ICC adjusted means with 10%, 20%, and 40% of total score tested as equivalence margins. Compliance and comfort with technology were assessed. Equivalence across 3 device screen sizes was assessed following the second completion period. Results Participants (N = 64) reported high comfort with technology, with 79.7% reporting being “quite a bit” or “very” comfortable. Weekly compliance was high (BYOD = 89.7–100%; PD = 76.9–100%). CAT and E-RS: COPD scores correlated well with PGIS ( r  > 0.50) and demonstrated equivalence between PD and BYOD completion (ICC = 0.863–0.908). TOST equivalence was achieved within 10% of the total score ( p  > 0.05). PRO measure scores were equivalent across 3 different screen sizes (ICC = 0.972–0.989). Conclusions Measure completion was high and scores equivalent between PD and BYOD, supporting use of BYOD in addition to PD for collecting PRO data in COPD studies and in demographically diverse patient populations. Highlights Historically, provisioned handheld devices [PD] have been provided to participants to enter patient-reported outcome (PRO) data during a clinical trial. Allowing participants to report data using their own smartphone or other internet-connected device (known as ‘bring your own device’ [BYOD]) is of growing interest. Measure completion was high for both device types when assessing daily and weekly compliance. Scores were found to be equivalent for both the Evaluating Respiratory Symptoms in COPD and COPD Assessment Test™ between PD and BYOD using 2 different methods. This study supports use of BYOD in addition to PD for collecting PRO data in COPD studies and contributes evidence that BYOD may be successfully employed in demographically diverse patient populations.

Objectives The aim was to document, from the perspective of the empirical literature, the primary symptoms of functional dyspepsia (FD), evaluate the extent to which existing questionnaires target those symptoms, and, finally, identify any missing evidence that would impact the questionnaires’ use in regulated clinical trials to assess treatment efficacy claims intended for product labeling. Methods A literature review was conducted to identify the primary symptoms of FD and existing symptom-based FD patient-reported outcome (PRO) instruments. Following a database search, abstracts were screened and articles were retrieved for review. The primary symptoms of FD were organized into a conceptual model and the PRO instruments were evaluated for conceptual coverage as well as compared against evidentiary requirements presented in the FDA’s PRO Guidance for Industry. Results Fifty-six articles and 16 instruments assessing FD symptoms were reviewed. Concepts listed in the Rome III criteria for FD ( n  = 7), those assessed by existing FD instruments ( n  = 34), and symptoms reported by patients in published qualitative research ( n  = 6) were summarized in the FD conceptual model. Except for vomiting, all of the identified symptoms from the published qualitative research reports were also specified in the Rome III criteria. Only three of the 16 instruments, the Dyspepsia Symptom Severity Index (DSSI), Nepean Dyspepsia Index (NDI), and Short-Form Nepean Dyspepsia Index (SF-NDI), measure all seven FD symptoms defined by the Rome III criteria. Among these three, each utilizes a 2-week recall period and 5-point Likert-type scale, and had evidence of patient involvement in development. Despite their coverage, when these instruments were evaluated in light of regulatory expectations, several issues jeopardized their potential qualification for substantiation of a labeling claim. Conclusions No existing PRO instruments that measured all seven symptoms adhered to the regulatory principles necessary to support product labeling. As such, the development of a new FD symptom PRO instrument is supported.

Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide–soluble guanylate cyclase–cyclic guanosine 3′,5′-monophosphate signaling, is being investigated for the treatment of patients with HFpEF. CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency: diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO2 by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire. The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers.