Responders vs clinical response: a critical analysis of data from linaclotide phase 3 clinical trials in IBS-C.

BACKGROUND: US Food and Drug Administration (FDA) set a rigorous standard for defining patient responders in irritable bowel syndrome-C (IBS-C; i.e., FDA's Responder Endpoint) for regulatory approval. However, this endpoint's utility for health-care practitioners to assess clinical response has not been determined. We analyzed pooled IBS-C linaclotide trial data to evaluate clinically significant responses in linaclotide-treated patients who did not meet the FDA responder definition. METHODS: Percentages of FDA non-responders reporting improvement in abdominal pain, bowel function and/or global relief measures were determined using pooled data from two linaclotide Phase 3 IBS-C trials. KEY RESULTS: 1602 IBS-C patients enrolled; 34% of linaclotide-treated and 17% of placebo-treated patients met the FDA Responder Endpoint (p < 0.0001). Among FDA non-responders at week 12, 63% of linaclotide-treated patients reported their abdominal pain was at least somewhat relieved, compared with 48% of placebo-treated patients. For stool frequency, 62% of linaclotide-treated patients reported that they were at least somewhat improved at week 12, compared with 46% of placebo-treated patients. For global IBS symptoms, 65% of linaclotide-treated patients reported at least some IBS-symptom relief, 43% reported adequate relief of IBS symptoms, and 57% reported being satisfied with linaclotide treatment, vs placebo rates of 48%, 34%, and 41% respectively. CONCLUSIONS & INFERENCES: Most linaclotide-treated IBS-C patients who were FDA non-responders reported some improvement in abdominal pain and stool frequency, and global relief/satisfaction. In addition to the FDA Responder Endpoint, differing response thresholds and symptom-specific change from baseline should be considered by clinicians for a complete understanding of clinical response to linaclotide and other IBS-C therapies.

An evaluation of the FDA responder endpoint for IBS-C clinical trials: analysis of data from linaclotide Phase 3 clinical trials.

BACKGROUND: Our objective was to evaluate the performance of the Food and Drug Administration (FDA) Responder Endpoint for clinical trials in IBS-C, using data from two large Phase 3 clinical trials of linaclotide. The FDA interim endpoint requires that, for 50% of trial weeks, patients report ≥30% decrease in Abdominal Pain at its worst and (in the same week) an increase in Complete Spontaneous Bowel Movements (CSBMs) of ≥1 from baseline. METHODS: Anchor-based methodology was used to estimate thresholds of clinically meaningful change using symptom-specific patient rating of change questions (PRCQs) and symptom severity questions. The diagnostic accuracy of the FDA Responder Endpoint was assessed using sensitivity/specificity-based methods. KEY RESULTS: Using anchor-based methods, the estimates of the clinically meaningful improvement thresholds for Abdominal Pain ranged from 25.9% to 32.4% and thresholds for increase in weekly CSBM rate ranged from 1.4 to 1.6 CSBMs per week. Compared with the symptom-specific PRCQs for patient rating of relief, the FDA Responder Endpoint has a sensitivity of 60.7%, a specificity of 93.5%, and an accuracy of 82.0%. Changing the number of weeks required to be a responder or the percentage improvement in the Abdominal Pain criteria did not result in notable improvement in the accuracy of the FDA Responder Endpoint. CONCLUSIONS & INFERENCES: The FDA Responder Endpoint for IBS-C clinical trials represents clinically meaningful improvements in IBS-C symptoms for patients with excellent specificity and reasonable sensitivity.

Gender differences in the longitudinal predictors of adolescent dating violence.

BACKGROUND: Adolescent dating violence is a public health problem. The public health approach to prevention is to identify predictors of problem behaviors and develop interventions to eliminate or reduce those predictors with the intention of altering the chain of causation. Longitudinal data are preferred for identifying predictors of behavior but all dating violence studies have used cross-sectional data. We use longitudinal data to examine predictors of adolescent dating violence from several domains guided by an ecological perspective. METHODS: Eighty percent (N = 1,965) of the 8th- and 9th-graders in one county completed baseline questionnaires in school and 90% (N = 1,759) of those adolescents completed questionnaires again 1&1/2 years later. Proportional odds models were used to identify cross-sectional correlates and longitudinal predictors of dating violence perpetration that occurred between baseline and follow-up. RESULTS: Most of the study variables were correlated with dating violence in cross-sectional analyses. Having friends who are victims of dating violence, using alcohol, and being of a race other than white predicted dating violence perpetration by females. Holding attitudes that are accepting of dating violence predicted dating violence perpetration by males. CONCLUSION: The findings suggest that intervention strategies should vary for males and females and that when basing interventions on cross-sectional findings, scarce resources may be stretched to address persons who may not truly be at risk of beginning to perpetrate dating violence.

The Safe Dates program: 1-year follow-up results.

OBJECTIVES: An earlier report described desirable 1-month follow-up effects of the Safe Dates program on psychological, physical, and sexual dating violence. Mediators of the program-behavior relationship also were identified. The present report describes the 1-year follow-up effects of the Safe Dates program. METHODS: Fourteen schools were in the randomized experiment. Data were gathered by questionnaires in schools before program activities and 1 year after the program ended. RESULTS: The short-term behavioral effects had disappeared at 1 year, but effects on mediating variables such as dating violence norms, conflict management skills, and awareness of community services for dating violence were maintained. CONCLUSIONS: The findings are considered in the context of why program effects might have decayed and the possible role of boosters for effect maintenance.