Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint

Background: Alosetron is approved to treat women with severe IBS and diarrhea (IBS-D) who have failed standard therapy. In our study, we aimed to evaluate alosetron efficacy using new US Food and Drug Administration (FDA) endpoints and utilization in clinical practice. Methods: This prospective, open-label, multicenter, observational 12-week study evaluated women with severe IBS-D enrolled in the alosetron prescribing program. The coprimary FDA endpoints were changes from baseline in stool consistency and abdominal pain severity. Responders achieved a 30% decrease compared with baseline in weekly average of the worst abdominal pain in the past 24 h, and a 50% or greater reduction from baseline in the number of days/week with at least one stool of type 6 (mushy) or type 7 (watery) consistency. Secondary endpoints included changes from baseline in stool frequency, fecal urgency and fecal incontinence. Results: Enrolled patients ( n = 192) were primarily White (90.6%), with a mean age of 44.5 years. Patient and physician rating of IBS severity was between moderate and severe (85.9% concordance, Spearman coefficient 0.429, p < 0.0001). Alosetron 0.5 mg twice daily (82.8%) was the most common dosing regimen. A total of 152 alosetron-treated patients completed the study. Of 105 fully evaluable patients, 45% met the FDA composite endpoint responder criteria for ⩾50% of the study period. Improvements in all individual symptoms were statistically significant compared with baseline. There were no serious adverse events, cases of colonic ischemia, or complications of constipation. Conclusion: In a clinical practice setting study, alosetron demonstrated treatment success using a rigorous FDA composite endpoint and also improved multiple other IBS symptoms, including fecal urgency and incontinence in women with severe IBS-D [ ClinicalTrials.gov identifier: NCT01257477]

Biomarkers and Clinical Characteristics Associated with Nonalcoholic Steatohepatitis Fibrosis Progression: Centaur Study

Background: Cenicriviroc (CVC) is an oral C-C chemokine receptor type 2/5 antagonist currently being evaluated for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). In the Phase 2b CENTAUR study, CVC treatment resulted in a significant, durable antifibrotic benefit compared with placebo. The aims of this CENTAUR analysis were to characterize the subpopulation of fibrosis progressors (FPs) initially treated with placebo during Year 1 compared to fibrosis non-progressors (FNs), and to evaluate the effect of CVC in FPs on histology and biomarkers of fibrosis during Year 2. Methods:Adults with histologically confirmed NASH, nonalcoholic fatty liver disease activity score (NAS) ≥4, and liver fibrosis Stages 1–3 (NASH Clinical Research Network) received CVC 150 mg once daily (Arm A) or placebo (Arm C), respectively, for 2 years; Arm B received placebo in Year 1 and crossed over to CVC in Year 2. FPs were defined as subjects who experienced worsening in fibrosis by ≥1 stage from baseline to Year 1 and were identified from the placebo-treated modified intent-to-treat population (N=126) in Year 1 (Arms B and C). Clinical characteristics and serum biomarkers were analyzed at baseline and over time. Histology was assessed by a central pathologist blinded to treatment assignment. The effect of CVC (Arm B) vs. placebo (Arm C) on FPs was assessed during Year 2. Results: Of Year 1 placebo-treated subjects in Arms B and C (N=126), 29% (n=37) were identified as FPs (mean age: 52.1 years; mean body mass index: 34.1 kg/m2 ; NAS ≥5: 89%; type 2 diabetes mellitus: 46%). A greater proportion of FPs compared to FNs at baseline were female (62% vs. 49%), Hispanic/Latino (89% vs. 78%), and had higher disease activity (NAS ≥5: 89% vs. 71%; hepatocellular ballooning grade 2: 65% vs. 51%). Considerably more FPs vs. FNs had fibrosis Stage 1 (65% vs. 20%) and aspartate aminotransferase>30 U/L (89% vs. 74%) at baseline. During Year 1, increases in serum transforming growth factor-beta (TGF-β) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and liver biopsy alpha-smooth muscle actin ( α-SMA) staining were observed for FPs vs. FNs. During Year 2, CVC treatment was associated with increased TIMP-1, as well as reduced α-SMA staining and attenuated serum TGF-β concentrations compared to placebo (Figure). Conclusion: The unique study design of CENTAUR enabled characterization of NASH FPs during Year 1 and evaluation of the antifibrotic effect of CVC in Year 2. Female sex, ethnicity, and inflammatory disease activity are key characteristics of FPs. In those FPs, CVC treatment was associated with a reduction of some biomarkers of fibrosis (TGF-β and α-SMA) vs. placebo in Year 2. These findings warrant further investigation