RESUMEN

Background: Symptom severity is the largest factor in determining subjective health in COPD. Symptoms (eg, chronic cough, dyspnea) are associated with decreased health-related quality of life (HRQoL). We evaluated the impact of arformoterol on HRQoL in COPD patients, measured by St George's Respiratory Questionnaire (SGRQ). Post hoc growth mixture model (GMM) analysis examined symptom response profiles. Methods: We examined data from a randomized, double-blind, parallel-group, 12-month safety trial of twice-daily nebulized arformoterol 15 µg (n=420) versus placebo (n=421). COPD severity was assessed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) status. GMM analysis identified previously unknown patient subgroups and examined the heterogeneity in response to SGRQ Symptoms scores. Results: SGRQ Total score improved by 4.24 points with arformoterol and 2.02 points with placebo (P=0.006). Significantly greater improvements occurred for arformoterol versus placebo in SGRQ Symptoms (6.34 vs 4.25, P=0.031) and Impacts (3.91 vs 0.97, P=0.001) scores, but not in Activity score (3.57 vs 1.75, P=0.057). GMM identified responders and nonresponders based on the SGRQ Symptoms score. End-of-study mean difference in SGRQ Symptoms scores between these latent classes was 20.7 points (P<0.001; 95% confidence interval: 17.6-23.9). Compared with nonresponders, responders were more likely current smokers (55.52% vs 44.02%, P=0.0021) and had more severe COPD (forced expiratory volume in 1 second [FEV1]: 1.16 vs 1.23 L, P=0.0419), more exacerbations (0.96 vs 0.69, P=0.0018), and worse mean SGRQ Total (59.81 vs 40.57, P<0.0001), Clinical COPD Questionnaire (3.29 vs 2.05, P<0.0001), and Modified Medical Research Council Dyspnea Scale (3.13 vs 2.75, P<0.0001) scores. Arformoterol-receiving responders exhibited significantly greater improvements in FEV1 (0.09 vs 0.008, P=0.03) and fewer hospitalizations (0.13 vs 0.24, P=0.02) than those receiving placebo. Conclusion: In this study, arformoterol treatment significantly improved HRQoL reflected by SGRQ. For the analysis performed on these data, arformoterol may be particularly effective in improving lung function and reducing hospitalizations among patients who are unable to quit smoking or present with more severe symptoms.

Asunto(s)

RESUMEN

BACKGROUND: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. OBJECTIVE: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. METHODS: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. RESULTS: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48-0.54, 0.32-0.39, and 0.61-0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%-76% and 71%-82% of weeks with agreement, respectively). CONCLUSIONS: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

RESUMEN

BACKGROUND: Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes. AIM: Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures. STUDY METHODS: Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed. RESULTS: The CC Symptom Severity Measures demonstrated satisfactory test-retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change. CONCLUSION: In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.

RESUMEN

IMPORTANCE OF THE FIELD: Irritable bowel syndrome (IBS) represents one of the most common gastrointestinal disorders, with the diarrhea-predominant form (D-IBS) representing an area of high unmet medical need. One difficulty in identifying suitable treatments for IBS is that although there are animal models for the components of IBS, it is not clear whether animals are afflicted by the disease. In a recently completed Phase II study, the kappa-opioid agonist, asimadoline, was shown to be efficacious in a prospectively defined subgroup of D-IBS patients. This study confirmed a good safety profile for asimadoline. AREAS COVERED IN THIS REVIEW: The chemistry, pharmacology, pharmacokinetics, pharmacodynamics and clinical safety and efficacy of asimadoline in relationship to IBS is reviewed. Papers were searched over the past 20 years using the PubMed database and key words 'asimadoline', 'kappa-opioid agonist' and 'irritable bowel syndrome'. Abstracts were reviewed and appropriate full papers were then evaluated. WHAT THE READER WILL GAIN: The reader will gain an appreciation of kappa-opioid agonists as IBS treatments. TAKE HOME MESSAGE: In a prospectively defined, clinically relevant patient subgroup, asimadoline shows efficacy in the treatment of D-IBS.

Asunto(s)

RESUMEN

BACKGROUND: The objective of this study was to develop and validate a daily electronic Endometriosis Pain and Bleeding Diary (EPBD) for assessing treatment-related changes in endometriosis symptoms from the patient's perspective in a clinical trial setting. METHODS: The EPBD items were developed based on clinician input and the results of 5 focus groups (N = 38) and 3 iterative sets of cognitive interviews (N = 22). The psychometric properties were evaluated using data collected in a usual-practice, non-intervention study conducted at 4 sites in the United States. Existing questionnaires were also administered to explore the construct validity of the EPBD. The development and validation processes were consistent with the recommendations in the 2009 FDA Patient Reported Outcomes Guidance to Industry. RESULTS: Focus group participants described 2 distinct types of pain (intermittent and continuous), which they felt were relevant and important to monitor. Participants also indicated that pain and bleeding/spotting associated with intercourse were important symptoms related to endometriosis. Cognitive interviews with additional endometriosis patients served to optimize item content, wording, and response options. Psychometric analyses found the EPBD items to behave as expected, for example, item-level means for subjects with severe endometriosis symptoms were higher (i.e., worse) compared with subjects with mild symptoms. Item-total correlations for the EPBD pain items (range 0.40-0.89) indicated that the items were related but not redundant. EPBD pain ratings correlated highly with the modified Brief Pain Inventory-Short Form Pain Intensity score (range 0.46-0.61). Women with severe endometriosis symptoms reported significantly higher intermittent and continuous dysmenorrhea and intermittent and continuous pelvic pain ratings and greater interference with daily activities compared with women with mild symptoms (all p < 0.01). CONCLUSIONS: The results of this study show that the 17-item EPBD reliably and validly characterizes the types of pain that endometriosis patients identified as being important. As a daily patient-reported assessment, it overcomes the significant potential for intra- and inter-rater variability and rater and recall bias that is inherent in the Biberoglu and Behrman Scale. Additional studies are required to confirm the dimensionality and optimal scoring of the EPBD, to corroborate the present results, and to assess other important measurement properties, such as responsiveness.

Asunto(s)

RESUMEN

OBJECTIVES: Persistently impaired psychosocial functioning has been recognized in many individuals with bipolar disorder. However, existing measures of functional disability have been adapted for use in bipolar disorder based mainly on those developed for use in other conditions. The present study involved the development and validation of a new patient self-report measure specific to bipolar disorder, the Bipolar Functional Status Questionnaire (BFSQ). METHODS: Relevant constructs were identified, evaluated, and refined through an expert advisory panel in conjunction with patient interviews. Questionnaire items were vetted through iterative patient interviews. Psychometric properties were determined based on patient responses from implementation of the proposed 33-item questionnaire in an 11-site study of 596 patients with bipolar disorder across varied phases of illness. RESULTS: Eight constructs were identified as fundamental to functional status in bipolar disorder: cognitive function, sleep, role functioning, emotional functioning, energy/vitality, social functioning, personal management, and sexual functioning. Psychometric validation supported item reduction to a 24-item unidimensional scale, with high internal consistency (coefficient alpha's = 0.93-0.95), high test-retest reliability (intraclass correlation coefficient = 0.86, 95% confidence interval = 0.82-0.89), strong convergent validity with other functional disability measures (r's > 0.70), and highly significant discriminant validity across illness phases, with large effect sizes (Cohen's d > 0.70). CONCLUSIONS: The BFSQ is a psychometrically sound self-report measure that can be used to effectively quantify functional status across different clinical states in patients with bipolar disorder.

Asunto(s)