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Multicenter, Placebo-Controlled, Randomized, Double-Blind, Parallel-Group Study Investigating the Efficacy and Safety of Elobixibat in Patients with Parkinson's Disease Complicating Chronic Constipation. (CONST-PD)

Effects of Elobixibat administration in patients with Parkinson's syndrome complicated with chronic constipation

100

The sex ratio of the study subjects was 47.4% male and 52.6% female in the Elobixibat group (E-group) and 48.7% male and 51.3% female in the placebo group (P-group). The median (min-max) age in the E-group was 69.5 (47-85) years, and 64.0 (43-83) years in the P-group. The mean+-SD of height and weight was 158.80+-10.63 cm and 58.94+-11.48 kg in E-group and 161.42+-9.18 cm and 59.59+-11.35 kg in P-group. There was no significant bias among the study subjects in terms of gender, height and weight.

There were 100 study subjects provisionally enrolled in the study. Of these, 23 dropped out because they were found to be ineligible, and 77 were randomized, 38 to E-group and 39 to P-group. All randomized study subjects were administered the study drug, and 74 subjects (37 subjects in each group) completed the administration period, except for 3 subjects (1 in E-group and 2 in P-group) who discontinued the study at the subject's request or for other reasons after administration of the study drug. All 38 randomized patients in E-group and all 39 patients in P-group were adopted into the FAS, PPS, and safety analysis population as assigned, so the composition of each analysis population was the same.

The incidence and number of cases of adverse events that occurred during administration of study drugs were 55.3%(21/38) in E-group and 10.3%(4/39) in P-group, all of which were considered to have an undeniable causal relationship with study drugs. There were no serious illnesses or illnesses that required discontinuation of the study drug in this study.

1. Primary endpoint (1)The comparison of weekly frequency* of spontaneous bowel movements (SBM) between screening period and treatment period week 4. * Frequency of bowel movement without suppositories, enema or dismipaction during each 7 days The mean frequency of SBM in E-group in FAS was 4.2 times/week at the start of treatment and 5.9 times/week at treatment period week 4, and the changes (mean+ -SD) in the frequency of SBM from start of treatment to treatment period week 4 was 1.7+ -3.7 times/week (p=0.0079). Similarly, the mean frequency of SBM in P-group was 4.5 times/week at baseline and 5.3 times/week at treatment period week 4, and the changes in SBM frequency from baseline to treatment period week 4 was 0.8+ -2.8 times/week (p=0.0889). There was a significant increase in SBM frequency in E-group, while there was no statistically significant difference in P-group, for the hypothesis that the changes in SBM frequency from baseline to treatment period week 4 would be zero. The difference (point estimate and 95% CI) between E-group and P-group in the changes in SBM frequency from baseline and at treatment period week 4 adjusted for gender was 0.8 (-0.57 to 2.09) times/week (p=0.2601) and there was no significant difference between groups. 2.Secondary endpoint (1)Changes in the frequency and transition of SBM per week from the screening period In response to the hypothesis that the changes in SBM frequency at each period from the start of treatment was zero, significant increases in SBM frequency was observed at all periods in E-group. In P-group, a significant increase in the amount of changes at treatment period week 2 was observed, but not at other treatment periods. (2)Changes and transition in complete spontaneous bowel movements (CSBM*) from screening period to treatment period week 4 *SBM without sensation of incomplete evacuation In response to the hypothesis that the changes in CSBM frequency at each period from the start of treatment was zero, a significant increase in CSBM frequency was observed in E-group at all treatment periods. In P-group, a significant increase in the amount of changes at treatment period week 4 was noted, but not at other treatment periods. CSBM frequency in E-group showed a significant difference only at treatment week 1 and 2, and not at other treatment periods. (3)Changes in Bristol Stool Form Scale (BSFS) from screening period to treatment period week 4 The BSFS (median mean+ -SD at each assessment period) for E-group and P-group in FAS were 2.5+ -1.3 and 2.7+ -1.4 (p=0.5692), 3.9+ -1.6 and 2.8+ -1.6 (p=0.0057), 4.0+ -1.4 and 3.0+ -1.4 (p=0.0119), 3.5+ -1.2 and 3.2+ -1.4 (p=0.4461), and 3.8+ -1.6 and 3.1+ -1.5 (p=0.1035). The BSFS was significantly larger in E-group than in P-group up to treatment period week 2, but there were no significant differences between groups after treatment period week 3. (4)Usage of the rescue medication The percentage of patients who used the rescue medication before treatment in FAS was 28.9%(11/38) in E-group and 20.5%(8/39) in P-group, and 28.9%(11/38) in E-group and 28.2%(11/38) in P-group after treatment. (5)Japanese Version of Patient Assessment of Constipation Quality of Life (JPAC-QOL) The total JPAC-QOL scores (mean+ -SD) of E-group and P-group in FAS were 1.2+ -0.5 and 1.3+ -0.6 (p=0.8456), 1.0+ -0.5 and 1.2+ -0.5 (p=0.1359), 1.0+ -0.5 and 1.2+ -0.5 (p=0.1359), and 1.9+ -0.0 (p=0.0843), in the order at the start of treatment, treatment period week 4 and discontinuation, respectively, but there was no significant difference between groups at any treatment periods. Among the summary scores of the JPAC-QOL, physical discomfort score at discontinuation [E-group: 2.0 (no SD due to only one example), P-group: 1.8+ -0.0; p<0.0001] and satisfaction score at treatment period week 4 (E-group: 2.2+ -1.0, P-group: 2.9+ -0.9; p=0.0022) significant differences were observed between E-group and P-group. For other summary scores, no significant difference was observed between groups (p=0.0546 to 1.0000). (6)Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) In the MDS-UPDRS Part I-IV total scores, there were no summary scores and treatment periods with significant differences between groups (p=0.0622 to 0.9206). There were no significant differences between the Elobixibat and placebo groups in the MDS-UPDRS Part I-IV total scores, summary scores, or treatment periods (p=0.0622 to 0.9206). (7)Parkinson's Disease Questionnaire-39 (PDQ-39) The PDQ-39 summary score and treatment period at which there was a significant difference between groups were stigma at discontinuation [E-group: 5.0 (no SD due to only one case), P-group: 2.0+ -0.0; p<0.0001]. There were no significant differences between groups in other summary scores and treatment periods (p=0.0663 to 1.0000). The PDQ-39 summary score and treatment periods at which there was a significant difference between the Elobixibat and placebo groups were stigma at discontinuation [E-group: 5.0 (no SD due to only one case), P-group: 2.0+-0.0; p<0.0001]. There were no significant differences between groups in other summary scores and treatment periods (p=0.0663 to 1.0000). (8)Euro-Qol 5 dimensions (EQ-5D) The EQ-5D efficacy values (mean+ -SD) of E-group and P-group in FAS were 0.7+ -0.2 and 0.7+ -0.2 (p=0.6481), 0.7+ -0.2 and 0.7+ -0.2 (p=0.8628), and 0.1 (no SD due to only one case) and 0.8+ -0.0 (p=0.0247), in the order of the start of treatment, treatment period week 4 and discontinuation. There were significant differences at only discontinuation, but no significant differences were observed between groups at the start of treatment and treatment period week 4. (9)Usage of dopamine antagonists L-dopa doses remained generally constant throughout the study participation period in each group. P-group tended to have a higher median L-dopa dose overall, but there was no clear difference between groups.

The frequency of SBM increased in 4 weeks of Elobixibat administration. The frequency of SBM and CSBM at treatment period week 1 and CSBM at treatment period week 2 were significantly higher in E-group. The BSFS were significantly larger in E-group at treatment period week 1 and 2. Satisfaction score in the JPAC-QOL at treatment week 4 was significantly higher in P-group. Adverse events and their frequency observed in this study were predictable.

Jan. 24, 2024

Jan. 24, 2024

https://doi.org/10.1002/mdc3.13972

No

None

https://jrct.niph.go.jp/latest-detail/jRCTs031200172

Hatano Taku

Juntendo University Hospital

3-1-3 Hongou, Bunkyo-ku, Tokyo

thatano@juntendo.ac.jp

Hatano Taku

Juntendo University Hospital

2-1-1 Hongou, Bunkyo-ku,Tokyo

+81-3-3813-3111

thatano@juntendo.ac.jp

Complete

Oct. 26, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

<At the time of temporary registration>
1) Patients with Parkinson's disease in stages 1 to 4 on the Hoehn & Yahr scale
2) Patients with two or more of the following symptoms related to spontaneous bowel movement from at least 6 months before Informed Consent
i)Fewer than 3 spontaneous bowel movements per week
ii)Straining during more than 25% of defecations
iii)Lumpy or hard stools more than 25% of defecations
iv)Sensation of incomplete evacuation more than 25% of defecations
3)Patients aged >=20 years at the time of Informed Consent
4)Outpatient
5)Patients who can provide written Informed Consent

<At the time of temporary registration/registration>
1)Patients who have or are suspected to have organic constipation
2)Patients who have or are suspected to have dyschezia
3)Patients who are unable to use the rescue medication (Bisacodyl suppositories 10 mg)
4)Female patients who are pregnant, breastfeeding, or hope to raise children
5)Patients with current medical history of serious dysfunction related to the kidney (creatinine>=2.00 mg/dL) or the liver (total bilirubin >=3.0 mg/dL or AST or ALT >=100 U/L) or serious heart disease
6)Patients with malignant tumors
7)Patients with a history of hypersensitivity to Elobixibat
8)Patients who are taking bile acid preparations ( ursodeoxycholic acid, chenodeoxycholic acid), aluminum-containing preparations (sucralfatehydr ate, aldioxa, etc.), cholestyramine, colestimide or midazolam
9)Patients whose score of MMSE is 26 or less
10)Patients who were considered as ineligible by the investigator for safety or poor protocol compliance
<At the time of registration>
11)Patients who used the rescue medication (Bisacodyl suppositories 10 mg) at least five times during the 2-week screening period
12)Patients who used the rescue medication less than 72 hours after bowel movement during the 2-week screening period
13)Patients with mushy stool or watery stools (BSFS type 6 or 7) in spontaneous bowel movement during the 2-week screening period
14)Patients who used prohibited medications/therapies during the 2-week screening period

Both

Parkinson's disease, chronic constipation

Take 10mg of Elobixibat or placebo once a day before meal. After the 2-week screening period, the study drug will be started on the day of enrollment.

Parkinson's syndrome,chronic constipation,Symptomatic constipation

Comparison of weekly frequency* of spontaneous bowel movement between screening period and treatment period week 4
*Frequency of bowel movement without suppositories, enema or disimpaction during each 7 days

-Changes in the frequency and transition of spontaneous bowel movement from screening period
-Changes and transitions in complete spontaneous bowel movement* from screening period to treatment period week 4
-Changes in Bristol Stool Form Scale from screening period to treatment period week 4
-Usage of the rescue medication
-JPAC-QOL
-MDS-UPDRS
-PDQ-39
-EQ-5D
-Usage of dopamine antagonists
-Subgroup analysis on the basis of background factors and dose of study drug
*Spontaneous bowel movement without sensation of incomplete evacuation

+81-3-5802-1584

Oct. 06, 2020

none