Efficacy and Safety of Elobixibat in Parkinson's Disease with Chronic Constipation: CONST-PD Study

Abstract

Background: Chronic constipation is a common digestive complication of Parkinson's disease (PD).

Objectives: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD.

Methods: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed.

Results: The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported.

Conclusions: Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation.

Trial registration information: Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).

Keywords: Parkinson's disease; autonomic; clinical neurology; constipation; movement disorders; randomized trials.

Figure 1

Flow chart of patient selection. Of the 135 patients who provided informed consent, 35 were excluded because they did not meet the inclusion criteria, etc., and the remaining 100 were temporarily registered. Twenty‐three patients were further excluded, leaving 77 for final registration at baseline (Week 0). Seventy‐four patients (37 each) completed the study. Elo, Elobixibat group; Pbo, Placebo group.

Figure 2

Primary endpoint: from‐baseline changes at Week 4 in the frequency of spontaneous bowel movement. Based on the BMD records of each patient, mean SBM frequency per week was calculated at baseline (Week 0) and Week 4 in the Elo and Pbo groups. ANCOVA analysis was performed for the comparison of SBM changes between the two groups, and paired t‐test was used to assess Week 4 versus baseline changes within each group. A significant difference is observed only for the Week 4 versus baseline change in the Elo group (**P = 0.0079). ANCOVA, analysis of covariance; BMD, bowel movement diary; Elo, elobixibat; Pbo, placebo; SBM, spontaneous bowel movement.

Figure 3

Weekly assessment of stool form. Stool forms were assessed for each patient as the weekly median BSFS (type 1–7). Patients subgrouped according to their baseline stool forms of type 1/2 and 3–5 were followed up in later weeks. The percentage of patients is shown with different colors corresponding to the weekly assessed median BSFS. 0 week is the baseline. Left panel: Elobixibat group; Right panel: Placebo group. BSFS, Bristol stool form scale.