A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation

Abstract

Objectives: A3309 is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor. We conducted an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, phase IIb study, which evaluated A3309 in patients with chronic idiopathic constipation (CIC).

Methods: Patients with CIC (modified Rome III criteria and <3 complete (CSBM) spontaneous bowel movements (SBMs)/week during the 2-week baseline) were randomized to 5, 10, or 15 mg A3309 or placebo once daily. The primary end point was change in SBM number during week 1 compared with baseline. Other bowel and abdominal symptoms were assessed as secondary end points. Serum 7αC4 and lipids were evaluated as biomarkers of BA synthesis/loss.

Results: In all, 190 patients (mean 48 years, 90% female) were randomized. Mean increase (95% confidence interval) in SBM for week 1 were 1.7 (0.7-2.8) for placebo vs. 2.5 (1.5-3.5), 4.0 (2.9-5.0), and 5.4 (4.4-6.4) for 5 mg, 10 mg (P<0.002), and 15 mg (P<0.001) A3309, respectively. Increased stool frequency was maintained over 8 weeks. Time to first SBM and CSBM were significantly reduced in the 10- and 15-mg A3309 groups compared with placebo. Straining and bloating decreased with A3309 compared with placebo (P<0.05). Increased 7αC4 and reduced low-density lipoprotein cholesterol with A3309 suggested increased BA synthesis and BA loss. The most common adverse events (AEs) were abdominal pain and diarrhea, which occurred most commonly in the 15-mg A3309 group. No drug-related serious AEs were observed.

Conclusions: A3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 weeks of treatment.

Figure 1

Patient flow diagram. Completer PP (per protocol) population=all intention to treat (ITT) patients who completed the study and were at least 80% compliant with study medication and patient reports during the treatment period. AE, adverse event.

Figure 2

Change from baseline in weekly spontaneous bowel movement (SBM) frequency for treatment week 1. ITT, intention to treat.

Figure 3

Effect of A3309 and placebo on weekly stool frequency. Mean weekly SBM (a) and CSBM (b) frequency. Significance values shown are for the overall change from baseline between A3309 and placebo. ***P<0.001, *P<0.05. CSBM, complete spontaneous bowel movement; ITT, intention to treat; SBM, spontaneous bowel movement.

Figure 4

Effect of A3309 and placebo on weekly stool consistency, straining, and bloating. Changes in stool consistency (a), straining (b), and bloating (c) over the treatment period. Significance values shown are for the overall change from baseline between A3309 and placebo. ***P<0.001, *P<0.05. BSFS, Bristol Stool Form Scale (7-graded scale, see text for explanations); ITT, intention to treat.