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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Chronic Idiopathic Constipation

Intervention / Treatment
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* Drug: Elobixibat 10 mg/day
* Drug: Elobixibat 5 mg/day
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: Straining during at least 25% of defecations Lumpy or hard stools during at least 25% of defecations 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EBX 10<br>Elobixibat 10 mg/day | Drug: Elobixibat 10 mg/day<br>* Elobixibat 10 mg/day<br>* Other names: A3309;|
| Experimental: EBX 5<br>Elobixibat 5 mg/day | Drug: Elobixibat 5 mg/day<br>* Elobixibat 5 mg/day<br>* Other names: A3309;|
| Placebo Comparator: PLCBO<br>Placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | During the first 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of CSBM Response | 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'). | Within first 24 hours of treatment initiation | 
| Change From Baseline in Weekly Frequency of Spontaneous Bowel Movement (SBMs) | The change from Baseline for the continuous variable was estimated using a repeated measures analysis of covariance (ANCOVA) model. | From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period | 
| Change From Baseline in Weekly Stool Consistency of SBMs | 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. | From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period | 
| Total Patient Assessment of Constipation - Quality of Life (PAC-QOL) Score Responder | 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. | At Week 12 | 
| Change From Baseline in Weekly Degree of Straining of SBMs | 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. | From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period | 
| Change From Baseline in Weekly Abdominal Bloating Score | 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. | From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period | 
| Change From Baseline in Weekly Abdominal Discomfort Score | 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. | From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period |