Efficacy and Safety Trial of Elobixibat in Patients With Chronic Idiopathic Constipation

A Double-blind, Randomised, Placebo-controlled, Phase 3 Trial in Patients With Chronic Idiopathic Constipation to Demonstrate the Efficacy and Safety of Elobixibat 5 mg and 10 mg for 12 Weeks Followed by a 4-week Withdrawal Period

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01833065

Enrollment

314

Registered

2013-04-16

Start date

2013-04-30

Completion date

2014-04-30

Last updated

2015-10-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Idiopathic Constipation

Brief summary

12 Week Efficacy and Safety Trial Followed by a 4 Week Withdrawal Period for Patients with Chronic Idiopathic Constipation.

Detailed description

The present trial was designed to determine the efficacy and safety of elobixibat treatment (at both doses of 5 mg and 10 mg/day) compared to placebo treatment for 12-week Treatment Period followed by a 4-week Withdrawal Period in patients with chronic idiopathic constipation. During Withdrawal Period a sub-group of patients in elobixibat 5 mg and 10 mg treatment arms respectively received placebo treatment, while rest of the patients continued with 5 mg and 10 mg treatment in respective groups. In placebo groups, patients received elobixibat 10 mg treatment during Withdrawal Period. Patients were followed-up for 2 weeks after end of the Withdrawal Period. The assessment of primary and key secondary end points was done for patients who completed the first 12 weeks of treatment period. Incidence of Adverse Events (AEs) were reported till 2 weeks after end of the Withdrawal Period. The trial was early terminated due to a distribution issue with the trial medication.

Interventions

DRUGElobixibat 10 mg/day

Elobixibat 10 mg/day

DRUGElobixibat 5 mg/day

Elobixibat 5 mg/day

DRUGPlacebo

Placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Body mass index (BMI) ≥18.5 but \<35.0 kg/m\^2 * Male or female ≥18 years of age * Reports \<3 spontaneous Bowel Movements (BM) per week and reports one or more of the following symptoms for the last 3 months with symptom onset at least 6 months before the Screening Visit or before starting chronic therapy with any laxative: 1. Straining during at least 25% of defecations 2. Lumpy or hard stools during at least 25% of defecations 3. Sensation of incomplete evacuation during at least 25% of defecations * Is ambulatory and community dwelling * An initial colonoscopy is required if recommended by national guidelines

Exclusion criteria

* Reports loose (mushy) or watery stools in the absence of any laxative intake in the form of a tablet, a suppository or an enema, or prohibited medicine for \>25% of BMs * The patient reports a BSFS of 6 or 7 during the Pretreatment Period * Has irritable bowel syndrome (IBS) with pain/discomfort as predominant symptoms * Has a structural abnormality of the Gastrointestinal (GI) tract or a disease or condition that can affect GI motility * Has a history of diverticulitis, chronic pancreatitis, active peptic ulcer disease (PUD) not adequately treated, ischaemic colitis, inflammatory bowel disease, laxative abuse, faecal impaction that required hospitalization or emergency treatment, pseudo-obstruction, megacolon, megarectum, bowel obstruction, descending perineum syndrome, ovarian cysts, endometriosis, solitary rectal ulcer syndrome, systemic sclerosis, pre-malignant colonic disease (e.g., familial adenomatous polyposis or hereditary non-polyposis colorectal cancer) or other forms of familial colorectal cancer * Has unexplained and clinically significant GI alarm signals (e.g., lower GI bleeding or heme-positive stool in the absence of known internal or external haemorrhoids, iron-deficiency anaemia, unexplained weight loss) or systemic signs of infection or colitis * Has a potential central nervous system (CNS) cause of constipation (e.g., Parkinson's disease, spinal cord injury, multiple sclerosis) * Has intestinal/rectal prolapse or other known pelvic floor dysfunction * Commonly uses digital maneuvers (perianal pressure or digital disimpaction) or vaginal splinting to facilitate the passage of a bowel movement * Has a history of diabetic neuropathy * Has a history of bariatric surgery for treatment of obesity; surgery to remove a segment of the GI tract; or surgery of the abdomen, pelvic or retroperitoneal area during the 6 months prior to Screening; or appendectomy or cholecystectomy 3 months prior to screening; or other major surgery 1 month prior to Screening * Has a history of cancer with last date of proven disease activity/presence of malignancy within 5 years, except for adequately treated basal cell carcinoma of the skin, cervical dysplasia, or carcinoma in situ of the skin or the cervix * Known human immunodeficiency virus (HIV) or Hepatitis B/C (HBV/HCV) infection * Has a history of hospitalization for any psychiatric disorder, or any suicide attempt in the 2 years prior to Screening * Is actively abusing alcohol or drugs or has a history of alcohol or drug abuse during the 6 months prior to Screening * Is being treated for hypothyroidism, but the dose of medication has not been stable for at least 3 months at the time of Screening * Is a pregnant, breast-feeding, or lactating woman

Design outcomes

Primary

Measure	Time frame	Description
Overall Complete Spontaneous Bowel Movement (CSBM) Response	During the first 12 weeks	This outcome measured the percentage of patients who were CSBM responders. A CSBM responder was defined as a patient with ≥3 CSBMs per week and an increase of ≥1 CSBM per week from Baseline, for at least 9 of the 12 weeks in the 12-week Treatment Period, including at least 3 weeks during Weeks 9-12.

Secondary

Measure	Time frame	Description
Change From Baseline in Weekly Frequency of Spontaneous Bowel Movement (SBMs)	From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period	The change from Baseline for the continuous variable was estimated using a repeated measures analysis of covariance (ANCOVA) model.
Change From Baseline in Weekly Stool Consistency of SBMs	From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period	The stool consistency is measured using the seven-point ordinal Bristol Stool Form Scale (BSFS) score. The BSFS classifies human stool into seven types and points them accordingly. Type 1: Separate hard lumps, like nuts (hard to pass) Type 2: Sausage-shaped, but lumpy Type 3: Like a sausage but with cracks on its surface Type 4: Like a sausage or snake, smooth and soft Type 5: Soft blobs with clear cut edges (passed easily) Type 6: Fluffy pieces with ragged edges, a mushy stool Type 7: Watery, no solid pieces, entirely liquid Types 1 and 2 indicate constipation, with 3 and 4 represents the ideal stool form (especially the latter), and 5, 6 and 7 tends towards diarrhoea . For a given assessment week, the weekly stool consistency was defined as the sum of non-missing stool consistency score for SBMs during that week divided by the number of non-missing stool consistency score for SBMs during that week. The parameter was analysed using repeated measures ANCOVA model.
Total Patient Assessment of Constipation - Quality of Life (PAC-QOL) Score Responder	At Week 12	This outcome measured the percentage of patients who were PAC-QOL score responder at 12-week Treatment Period. A PAC-QOL score responder was defined as a patient with ≥50% reduction in total PAC-QOL score from Baseline at Week 12. PAC-QOL is a 28-item questionnaire for psychometric assessment of disease-specific quality of life. The questionnaire is based on 5-point Likert scale; ranging from 0 \[none of the time or not at all\] to 4 \[all of the time or extremely\]). A lower score indicates a better Quality of Life. The PAC-QOL questionnaire is developed specifically for patients with constipation. Total PAC-QOL score was averaged from the individual item score.
Occurrence of CSBM Response	Within first 24 hours of treatment initiation	This outcome measured the percentage of patients who had a CSBM within 24 hours after the first dose of treatment. A CSBM was defined as a spontaneous (occurring without laxative within the preceding 24 hours, including no rescue medication within the preceding 24 hours) bowel movement (as interpreted by the patient, with a beginning and an end, including single or multiple stools), accompanied by a patient reported sense of complete evacuation ('complete').
Change From Baseline in Weekly Abdominal Bloating Score	From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period	The abdominal pain score was measured using the five-point ordinal scale (1=None, 2=Mild, 3=Moderate, 4=Severe, and 5=Very severe). For a given assessment week, the weekly abdominal bloating score was defined as the sum of non-missing abdominal bloating score for SBMs during that week divided by the number of non-missing abdominal bloating score for SBMs during that week. The parameter was analysed using repeated measures ANCOVA model.
Change From Baseline in Weekly Abdominal Discomfort Score	From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period	The abdominal discomfort score was measured using the five-point ordinal scale (1=None, 2=Mild, 3=Moderate, 4=Severe, and 5=Very severe). For a given assessment week, the weekly abdominal discomfort score was defined as the sum of non-missing abdominal discomfort score for SBMs during that week divided by the number of non-missing abdominal discomfort score for SBMs during that week. The parameter was analysed using repeated measures ANCOVA model.
Change From Baseline in Weekly Degree of Straining of SBMs	From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period	The degree of straining was measured using the five-point ordinal scale (1=Not at all, 2=A little bit, 3=A moderate amount, 4=A great deal, and 5=An extreme amount). For a given assessment week, the weekly degree of straining was defined as the sum of non-missing straining score for SBMs during that week divided by the number of non-missing straining score for SBMs during that week. The parameter was analysed using repeated measures ANCOVA model.

Countries

Brazil, Canada, Czechia, Germany, Hungary, Mexico, Poland, Slovakia, South Africa, Sweden, United Kingdom, United States

Participant flow

Pre-assignment details

Trial included 4-week Screening and 2-week Pretreatment Period before patient randomization to treatment sequences i.e. EBX 10/EBX 10, EBX 10/PLCBO, EBX 5/EBX 5, EBX 5/PLCBO and PLCBO/EBX 10. The total study duration was of 16 weeks: the efficacy assessments focused on the first 12 weeks, while safety assessments focused on whole 16 weeks

Participants by arm

Arm	Count
EBX 10 Elobixibat 10 mg/day was administered orally in a tablet form.	103
EBX 5 Elobixibat 5 mg/day was administered orally in a tablet form.	100
PLCBO Placebo was administered orally in a tablet form.	111
Total	314

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Adverse Event	6	1	0	2	3
Overall Study	Lost to Follow-up	1	0	0	0	3
Overall Study	Others	2	1	1	1	4
Overall Study	Protocol Violation	1	0	0	0	2
Overall Study	Subject's substantial non-compliance	0	1	0	0	0
Overall Study	Trial terminated by sponsor	8	8	7	3	13
Overall Study	Withdrawal by Subject	6	2	4	3	11

Baseline characteristics

Characteristic	EBX 10	Total	PLCBO	EBX 5
Age, Continuous	49.6 Years STANDARD_DEVIATION 14.3	49.0 Years STANDARD_DEVIATION 14.7	48.0 Years STANDARD_DEVIATION 16.1	49.5 Years STANDARD_DEVIATION 13.5
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants	29 Participants	11 Participants	9 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	94 Participants	285 Participants	100 Participants	91 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	5 Participants	2 Participants	1 Participants
Race (NIH/OMB) Black or African American	16 Participants	45 Participants	16 Participants	13 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	85 Participants	264 Participants	93 Participants	86 Participants
Region of Enrollment Canada	1 participants	4 participants	1 participants	2 participants
Region of Enrollment Czech Republic	2 participants	4 participants	0 participants	2 participants
Region of Enrollment Germany	4 participants	13 participants	5 participants	4 participants
Region of Enrollment Hungary	15 participants	42 participants	14 participants	13 participants
Region of Enrollment Poland	3 participants	10 participants	3 participants	4 participants
Region of Enrollment Slovakia	5 participants	13 participants	5 participants	3 participants
Region of Enrollment South Africa	12 participants	32 participants	13 participants	7 participants
Region of Enrollment Sweden	1 participants	6 participants	3 participants	2 participants
Region of Enrollment United Kingdom	11 participants	32 participants	12 participants	9 participants
Region of Enrollment United States	49 participants	158 participants	55 participants	54 participants
Sex: Female, Male Female	84 Participants	266 Participants	97 Participants	85 Participants
Sex: Female, Male Male	19 Participants	48 Participants	14 Participants	15 Participants
Weekly number of CSBM	0.33 CSBM per week STANDARD_DEVIATION 0.62	0.36 CSBM per week STANDARD_DEVIATION 0.64	0.43 CSBM per week STANDARD_DEVIATION 0.68	0.32 CSBM per week STANDARD_DEVIATION 0.62
Weekly number of SBM	2.31 SBM per week STANDARD_DEVIATION 1.27	2.32 SBM per week STANDARD_DEVIATION 1.26	2.45 SBM per week STANDARD_DEVIATION 1.35	2.19 SBM per week STANDARD_DEVIATION 1.13

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	25 / 65	11 / 53	13 / 35	20 / 50	24 / 110
serious Total, serious adverse events	0 / 65	0 / 53	0 / 35	1 / 50	3 / 110

Outcome results

Primary

Overall Complete Spontaneous Bowel Movement (CSBM) Response

This outcome measured the percentage of patients who were CSBM responders. A CSBM responder was defined as a patient with ≥3 CSBMs per week and an increase of ≥1 CSBM per week from Baseline, for at least 9 of the 12 weeks in the 12-week Treatment Period, including at least 3 weeks during Weeks 9-12.

Time frame: During the first 12 weeks