Determining an optimal clinical dose of elobixibat, a novel inhibitor of the ileal bile acid transporter, in Japanese patients with chronic constipation: a phase II, multicenter, double-blind, placebo-controlled randomized clinical trial

Chronic constipation is one of the most common chronic gastrointestinal conditions, generally characterized by decreased frequency and irregular intervals of bowel movements, changes in stool consistency, straining during bowel movements, and the sensation of incomplete evacuation. Chronic constipation is most often defined according to the Rome III diagnostic criteria of functional constipation published in 2006 [1]. (In the Rome IV diagnostic criteria released in 2016, there were no changes to the diagnostic criteria for functional constipation [2]). Chronic constipation reportedly affects 14–17% of the population [3, 4], occurring more frequently in females and the elderly [5]; it adversely affects both physical and psychological quality of life [6], while simultaneously impairing economic productivity [7]. In a survey of 557 patients with chronic constipation in the United States, about half of respondents were not satisfied with their treatment regimen due to concerns regarding efficacy and safety [8]. According to an online survey of 5155 Japanese subjects, 28.4% of respondents considered themselves to be constipated, revealing that chronic constipation is a ubiquitous problem in Japan [9]. Because chronic constipation arises from multiple causes, no single or combined treatment has been shown to be effective for all chronic constipation patients; thus, there is an unmet need for new, effective treatment options [10, 11].

Elobixibat is a novel ileal bile acid transporter inhibitor that is expressed in the terminal ileum for treatment of chronic constipation [12]. By inhibiting bile acid reabsorption, elobixibat increases the amount of bile acid reaching the large intestine, which subsequently enhances colonic motility and secretion [13]. Elobixibat acts locally in the gut, resulting in minimal systemic exposure [14]. It is well known that bile acids induce diarrhea, and when the enterohepatic circulation of bile acids is broken due to ileal disease or resection, excessive quantities of bile acids may enter the colon, thereby resulting in diarrhea [15, 16]. By exploiting this function of bile acids, elobixibat provides a potential new treatment for chronic constipation.

In the United States, a clinical study was conducted in patients with functional constipation to evaluate the effects of elobixibat on small intestinal and colonic transit. At a dose of 15 or 20 mg once daily for 14 days, elobixibat accelerated overall colonic transit with no effect on small intestinal transit [17]. A phase IIb study, also conducted in the United States, examined the therapeutic effect of elobixibat in patients with chronic idiopathic constipation (CIC). There was a clinically and statistically significant dose–response relationship observed for once-daily doses of elobixibat at 5, 10, or 15 mg. Elobixibat increased stool frequency and improved constipation-related symptoms, e.g., straining and distention. Effects were maintained over 8 weeks of treatment [18].

This article reports the results of a phase IIb dose–response clinical study and determination of the optimal clinical dose of elobixibat in Japanese patients with chronic constipation.

We planned to enroll a total of 176 patients, and assuming a drop-out rate of 20%, we received informed consent from a total of 226 patients. However, the drop-out rate was higher than originally estimated and, as a result, only 163 patients were enrolled. More importantly, only five patients discontinued in less than 5 days after treatment initiation, and these patients were excluded from the primary analysis. Therefore, we concluded that we could ensure sufficient statistical power of 80% or higher for primary endpoint achievement, and the patient enrollment was completed at 163 patients. Patients were randomized to placebo (40 patients), elobixibat 5-mg (43 patients), 10-mg (39 patients), and 15-mg (41 patients) groups. Treatment was completed in 39 patients each in the placebo and 5-mg groups, and in 38 patients each in the 10-mg and 15-mg groups. Reasons for treatment discontinuation were adverse events (7 patients), lack of efficacy (1 patient), and patient convenience (1 patient) (Fig. 1). Among 163 patients in the full analysis set, data for the frequency of SBMs at Week 1 of treatment were missing in 5 patients who discontinued the study drug before Day 5 (2 patients in the 5-mg group, 1 in the 10-mg group, and 2 in the 15-mg group).

There were no considerable differences in the demographics and baseline characteristics of patients with respect to sex, age, BMI, or the presence of IBS-C among the four groups. At baseline, the mean frequency of SBMs was 1.6–1.8 times per week in all groups (Table 1).

The frequency of SBMs at Week 1 (primary endpoint) significantly increased in the 10- and 15-mg elobixibat groups compared with the placebo group (P = 0.0005 and P = 0.0001, respectively; analysis of covariance). These results demonstrated a dose-dependent increase in SBMs from the 5- to 10-mg dose, but similar SBM values between the 10- and 15-mg doses (Fig. 2a). Results from Week 2 showed significant increases in the frequency of SBMs in all elobixibat groups compared with the placebo group (data not shown). A subgroup analysis examined the change from baseline in the primary endpoint in patients with or without IBS-C. Frequency of SBMs significantly increased in the 10- and 15-mg groups without IBS-C and in the 15-mg group with IBS-C, compared with the placebo group (Fig. 2b). The percentages of patients who experienced the first SBM within 24 or 48 h after treatment initiation were significantly higher in the 10- and 15-mg groups compared with the placebo group (Fig. 2c). The mean time to first SBM for each group was as follows (median time to first SBM): placebo, 36.2 h (24.3 h); 5-mg elobixibat group, 19.9 h (5.8 h); 10-mg group, 8.2 h (4.8 h); and 15-mg group, 8.5 h (3.5 h). These results showed dose-dependent increases up to the 10-mg dose, with similar values between the 10- and 15-mg groups.

Our results show significantly larger changes in the frequency of CSBMs in the 10- and 15-mg elobixibat groups compared with the placebo group throughout the study period (Week 1 of treatment: 10-mg group, P = 0.0032, and 15-mg group, P = 0.0002; Week 2 of treatment: 10-mg group, P = 0.0004, and 15-mg group, P = 0.0007) (Fig. 3).

BSFS was close to the ideal stool consistency of “4” in the 10-mg group (Fig. 4). Weekly constipation severity scores were significantly improved in the 10- and 15-mg groups at Week 1 of treatment (P = 0.0224, P = 0.0018), as well as the 15-mg group at Week 2 of treatment (P = 0.0172), compared with the placebo group (Fig. 5).

Bile acids promote colonic secretion through the physiological mechanisms of intracellular activation of adenylate cyclase, increased mucosal permeability, and inhibition of apical Cl⁻/OH⁻ exchange [19‐22]. Bile acids also induce propulsive contractions in the mammalian and human colon [23]. Moreover, bile acids activate colonic motility and secretion in humans [24, 25]. Based on this evidence, elobixibat, with a novel mechanism of action that inhibits reabsorption of bile acids, is anticipated as a new candidate for the treatment of constipation.

In this study of 163 Japanese patients with chronic constipation, elobixibat, at doses of 10 and 15 mg, was associated with a significant change from baseline in the frequency of SBMs at Week 1 of treatment (primary endpoint) compared with placebo. Elobixibat also significantly outperformed placebo in terms of most secondary endpoints, such as the frequency of CSBMs and stool consistency by BSFS. These results show that elobixibat, in once-daily oral doses of 10 and 15 mg, benefits patients with chronic constipation. Stool consistency and constipation severity scores were improved to a greater extent in the 15-mg group compared with the 10-mg group, but there was not a significant difference between the two groups. Although elobixibat also showed benefits at a dose of 5 mg, these effects were inferior to those associated with the 10- and 15-mg doses. Based on these findings, the recommended once-daily oral dose of elobixibat was 10 mg.

Elobixibat was well tolerated in patients with chronic constipation at once-daily oral doses up to 15 mg. The most common adverse events were gastrointestinal disorders such as abdominal pain and diarrhea. Most of these symptoms were mild with very few cases of moderate symptoms. With regards to abdominal pain specifically, it has been reported that certain bile acids are prokinetic in the colon, stimulating propagated contractions [13, 24]. Compared with healthy controls, patients with constipation showed fewer pressure waves and a lower incidence of propagated contractions [26]. As these propagated contractions can be painful, the abdominal pain associated with elobixibat observed in our study was likely related to these propagated contractions stimulated by increased bile acids in colon [27].

A subgroup analysis of primary endpoint data based on the absence or presence of IBS-C showed similar results regardless of IBS-C status. Furthermore, subgroup analysis of patients stratified by IBS-C status showed that there was no significant difference in the frequency of adverse events between patients with IBS-C and patients without IBS-C (Table 3). These data suggest that elobixibat is effective for patients with or without IBS-C. To our knowledge, this is the first report of the effectiveness of elobixibat in improving SBMs in Japanese patients with IBS-C; however, further research is necessary, as IBS symptom relief was not addressed in our current study.

The efficacy and safety of elobixibat were previously examined in a phase IIb clinical study in patients with CIC in the United States [18]. The study showed similar dose–response relationships with regard to the primary endpoint, while our present study showed a slightly higher change from baseline in SBMs in the placebo group and 10-mg group. The incidence of study-related gastrointestinal adverse events was essentially similar between the two studies. In both studies, abdominal pain was the most common adverse event, followed by diarrhea and abdominal distention. These findings suggest that there are no substantial ethnic differences in the efficacy or safety of elobixibat.

It has been previously reported that constipation is a risk factor for cardiovascular disease events [28]. In this trial, elobixibat elicited a decrease in LDL cholesterol levels with no effect on HDL cholesterol as a result of its mechanism of action; these findings were similar to those of the US study [17]. This beneficial effect on the lipid profile is a unique feature of elobixibat; improvement in LDL cholesterol levels might provide incremental benefits to a subset of chronic constipation patients also affected by dyslipidemia [29].

In conclusion, the results of this phase IIb study in Japanese patients with chronic constipation demonstrated that elobixibat significantly improved stool frequency and consistency, and was well tolerated up to 15 mg. Our study results suggest that 10 mg is a clinically optimal dose of elobixibat for Japanese patients with chronic constipation.