Factor Analyses of Chronic Constipation Patient-Reported Outcome Measures: Results From Phase 2b and Phase 3 Trials of Linaclotide

Abstract

Purpose: Factor analyses of patient-reported outcome (PRO) data from 1 Phase 2b and 2 Phase 3 clinical trials of linaclotide for the treatment of chronic constipation (CC) were conducted to examine the patterns of correlations among the PRO measures and provide evidence of their construct validity. Methods: 307 patients with CC were analyzed in a Phase 2b multicenter, randomized, double-blind, placebo-controlled, dose-range-finding, parallel-group clinical study comparing placebo and 4 doses of oral linaclotide taken once daily for 4 weeks. Daily PRO measures addressing abdominal symptoms (pain, discomfort, bloating) and bowel symptoms (spontaneous bowel movement [SBM] frequency, complete SBM [CSBM] frequency, stool consistency, straining) and a weekly measure (constipation severity) were administered using interactive voice response system technology. Using these data, principal component analyses (PCA) and exploratory factor analyses (EFA) explored the structure of the CC PRO symptoms. Using confirmatory factor analysis (CFA), the EFA results were evaluated with data (N=1272) collected in 2 Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group 12-week clinical trials (145 or 290 μg oral linaclotide or placebo). Results: The PCA of data averaged over the treatment period indicated 2 dimensions accounting for 70.4% of the total variance. The 2-factor EFA produced 1 factor consisting of abdominal symptoms (pain, discomfort, and bloating) and a second factor consisting of bowel symptoms (SBM frequency, CSBM frequency, stool consistency, straining, and constipation severity). When the 2-factor CFA model was applied to the correlation matrix with select correlated error variances, the fit of the model to the data was very satisfactory, as were the factor loadings (Table).Table: Table. Factor loadings (standard errors) and model goodness of fit statistics for CC PRO measuresConclusion: The factor analyses enhance the construct validity of the PRO measures by establishing the composition of 2 factors that explain the pattern of correlations among the CC PRO items. One factor explained the correlations among the bowel symptoms and a second explained the correlations among the abdominal symptoms. The weekly rating of constipation severity was more strongly related to the bowel symptoms factor than the abdominal symptoms factor. Additionally, the 2 factors, abdominal symptoms and bowel symptoms, were highly related. Disclosure: Lauren Nelson, Valerie Williams, Cheryl Coon, and Sheri Fehnel: employees of RTI-HS, with whom Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc., contract for research; Robyn Carson: employee of Forest Laboratories, Inc., in which she owns stocks and/or stock options; Mollie Baird and Jeffrey Johnston: employees of Ironwood Pharmaceuticals, Inc, in which they own stock and/or stock options. This research was supported by an industry grant from Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc., were involved in the study design; collection, analysis and data interpretation; and decision to submit these data for presentation. Study was sponsored by Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc.