OBJECTIVE: Linaclotide is an investigational minimally absorbed guanylate cyclase-C receptor agonist (GCCA). Psychometric analyses using data from one Phase 2b study and two Phase 3 trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patientreported outcome (PRO) measures assessing changes in the severity of symptoms.
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 2b doseranging study (n = 307 ITT) and to two doses of linaclotide taken once daily for 12 weeks in the Phase 3 trials (n = 1,271 ITT). Seven PRO measures addressing abdominal symptoms (pain, discomfort, bloating) and bowel function (spontaneous bowel movement [SBM]/complete SBM [CSBM] frequency, stool consistency, straining) were assessed daily using interactive voice response system technology. Patients completed the Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) at the Randomization and End-of-treatment Visits. Intra-class correlation coefficients (ICCs), Pearson correlations, F-tests, and effect sizes were computed to evaluate the reliability, construct validity, discriminating ability, and responsiveness of the PRO measures in a clinical trial context.
RESULTS: The CC PRO measures showed satisfactory test-retest reliability; ICCs ranged from 0.68 for straining in Phase 2b to 0.91 for abdominal pain in Phase 3. Convergent and divergent validity correlations between the CC PRO measures and PAC-QOL provided evidence of the validity of the PRO measures (see Table). Known-groups F-tests were statistically significant and in the expected direction, substantiating the discriminating ability of the CC PRO items. Responsiveness statistics for bowel symptom PRO measures were large (0.86-3.29 in Phase 2b and 0.79-2.68 in Phase 3), and for abdominal symptom PRO measures, moderate to large (0.54-1.03 in Phase 2b and 1.02-1.21 in Phase 3). Results were consistent across the Phase 2b and 3 studies.
CONCLUSION: In large Phase 2b and Phase 3 studies of CC patients, linaclotide significantly improved PRO measures of abdominal and bowel symptoms. The psychometric analyses strongly support the reliability, validity, discriminating ability, responsiveness, and usefulness of the PRO measures assessing CC symptom severity and change evaluated in these clinical studies.
