Chronic Idiopathic Constipation
Conditions
Brief summary
Efficacy and Safety Trial of elobixibat in Patients with Chronic Idiopathic Constipation treated for 26 Weeks.
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 26-week Treatment Period in patients with chronic idiopathic constipation. Patients were followed-up for 2 weeks after end of the Treatment 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 treatment. The trial was early terminated due to a distribution issue with the trial medication.
Interventions
Sponsors
Ferring Pharmaceuticals
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
No
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 GI tract or a disease or condition that can affect Gastrointestinal (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 manoeuvres (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 Movements (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 12 weeks | This outcome measured the percentage of patients who were PAC-QOL score responder at 12-week of 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 the 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 bloating 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
Belgium, Brazil, Canada, Czechia, Germany, Israel, Poland, South Africa, United Kingdom, United States
Participant flow
Pre-assignment details
The trial included a 4-week Screening Period and a 2-week Pretreatment Period prior to patient randomization to a 26-week Treatment Period. A total of 909 patients were screened in the trial and of these 533 patients were excluded due to screening failure.
Participants by arm
| Arm | Count |
|---|---|
| EBX 10 Elobixibat 10 mg/day was administered orally in a tablet form starting from Baseline visit till EoT visit. | 126 |
| EBX 5 Elobixibat 5 mg/day was administered orally in a tablet form starting from Baseline visit till EoT visit. | 126 |
| PLCBO Placebo was administered orally in a tablet form starting from Baseline visit till EoT visit. | 124 |
| Total | 376 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 9 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 | 2 |
| Overall Study | Others | 0 | 1 | 3 |
| Overall Study | Patient's substantial non-compliance | 1 | 1 | 6 |
| Overall Study | Physician Decision | 0 | 2 | 1 |
| Overall Study | Protocol Violation | 2 | 1 | 0 |
| Overall Study | Trial terminated by Sponsor | 47 | 53 | 51 |
| Overall Study | Withdrawal by Subject | 12 | 11 | 11 |
Baseline characteristics
| Characteristic | Total | EBX 10 | EBX 5 | PLCBO |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 41 Participants | 16 Participants | 13 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 335 Participants | 110 Participants | 113 Participants | 112 Participants |
| Age, Continuous | 46.6 Years STANDARD_DEVIATION 14.3 | 48.0 Years STANDARD_DEVIATION 14.3 | 45.8 Years STANDARD_DEVIATION 14.1 | 46.1 Years STANDARD_DEVIATION 14.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 86 Participants | 26 Participants | 32 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 290 Participants | 100 Participants | 94 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 2 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 80 Participants | 28 Participants | 23 Participants | 29 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 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 | 279 Participants | 95 Participants | 97 Participants | 87 Participants |
| Region of Enrollment Belgium | 6 participants | 2 participants | 2 participants | 2 participants |
| Region of Enrollment Canada | 17 participants | 6 participants | 6 participants | 5 participants |
| Region of Enrollment Czech Republic | 6 participants | 2 participants | 2 participants | 2 participants |
| Region of Enrollment Germany | 46 participants | 15 participants | 16 participants | 15 participants |
| Region of Enrollment Poland | 3 participants | 2 participants | 1 participants | 0 participants |
| Region of Enrollment South Africa | 39 participants | 14 participants | 11 participants | 14 participants |
| Region of Enrollment United Kingdom | 31 participants | 12 participants | 10 participants | 9 participants |
| Region of Enrollment United States | 228 participants | 73 participants | 78 participants | 77 participants |
| Sex: Female, Male Female | 314 Participants | 104 Participants | 107 Participants | 103 Participants |
| Sex: Female, Male Male | 62 Participants | 22 Participants | 19 Participants | 21 Participants |
| Weekly number of CSBM | 0.45 CSBM per week STANDARD_DEVIATION 0.75 | 0.36 CSBM per week STANDARD_DEVIATION 0.66 | 0.44 CSBM per week STANDARD_DEVIATION 0.75 | 0.54 CSBM per week STANDARD_DEVIATION 0.82 |
| Weekly number of SBM | 2.21 SBM per week STANDARD_DEVIATION 1.35 | 2.20 SBM per week STANDARD_DEVIATION 1.34 | 2.13 SBM per week STANDARD_DEVIATION 1.27 | 2.31 SBM per week STANDARD_DEVIATION 1.43 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 42 / 125 | 28 / 126 | 23 / 124 |
| serious Total, serious adverse events | 3 / 125 | 3 / 126 | 1 / 124 |
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
Population: Intention-to-treat (ITT) analysis set consisted of all randomized (as planned) patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EBX 10 | Overall Complete Spontaneous Bowel Movement (CSBM) Response | 15.9 Percentage of patients |
| EBX 5 | Overall Complete Spontaneous Bowel Movement (CSBM) Response | 23.0 Percentage of patients |
| PLCBO | Overall Complete Spontaneous Bowel Movement (CSBM) Response | 12.1 Percentage of patients |
Secondary
Change From Baseline in Weekly Abdominal Bloating Score
The abdominal bloating 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.
Time frame: From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period
Population: The ITT analysis set consisted of all randomized (as planned) patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| EBX 10 | Change From Baseline in Weekly Abdominal Bloating Score | -0.49 Units on a scale |
| EBX 5 | Change From Baseline in Weekly Abdominal Bloating Score | -0.52 Units on a scale |
| PLCBO | Change From Baseline in Weekly Abdominal Bloating Score | -0.35 Units on a scale |
Secondary
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.
Time frame: From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period
Population: The ITT analysis set consisted of all randomized (as planned) patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| EBX 10 | Change From Baseline in Weekly Abdominal Discomfort Score | -0.43 Units on a scale |
| EBX 5 | Change From Baseline in Weekly Abdominal Discomfort Score | -0.46 Units on a scale |
| PLCBO | Change From Baseline in Weekly Abdominal Discomfort Score | -0.38 Units on a scale |
Secondary
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.
Time frame: From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period
Population: The ITT analysis set consisted of all randomized (as planned) patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| EBX 10 | Change From Baseline in Weekly Degree of Straining of SBMs | -1.01 Units on a scale |
| EBX 5 | Change From Baseline in Weekly Degree of Straining of SBMs | -1.04 Units on a scale |
| PLCBO | Change From Baseline in Weekly Degree of Straining of SBMs | -0.91 Units on a scale |
Secondary
Change From Baseline in Weekly Frequency of Spontaneous Bowel Movements (SBMs)
The change from Baseline for the continuous variable was estimated using a repeated measures analysis of covariance (ANCOVA) model.
Time frame: From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period
Population: The ITT analysis set consisted of all randomized (as planned) patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| EBX 10 | Change From Baseline in Weekly Frequency of Spontaneous Bowel Movements (SBMs) | 2.04 SBM per week |
| EBX 5 | Change From Baseline in Weekly Frequency of Spontaneous Bowel Movements (SBMs) | 2.44 SBM per week |
| PLCBO | Change From Baseline in Weekly Frequency of Spontaneous Bowel Movements (SBMs) | 1.55 SBM per week |
Secondary
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.
Time frame: From Baseline (2-week Pretreatment Period) to overall first 12-weeks of Treatment Period
Population: The ITT analysis set consisted of all randomized (as planned) patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| EBX 10 | Change From Baseline in Weekly Stool Consistency of SBMs | 1.41 Units on BSFS |
| EBX 5 | Change From Baseline in Weekly Stool Consistency of SBMs | 1.35 Units on BSFS |
| PLCBO | Change From Baseline in Weekly Stool Consistency of SBMs | 0.83 Units on BSFS |
Secondary
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').
Time frame: Within the first 24 hours of treatment initiation
Population: The ITT analysis set consisted of all randomized (as planned) patients was used for assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EBX 10 | Occurrence of CSBM Response | 20.6 Percentage of patients |
| EBX 5 | Occurrence of CSBM Response | 24.6 Percentage of patients |
| PLCBO | Occurrence of CSBM Response | 12.1 Percentage of patients |
Secondary
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 of 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.
Time frame: At 12 weeks
Population: The ITT analysis set consisted of all randomized (as planned) patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EBX 10 | Total Patient Assessment of Constipation - Quality of Life (PAC-QOL) Score Responder | 34.1 Percentage of patients |
| EBX 5 | Total Patient Assessment of Constipation - Quality of Life (PAC-QOL) Score Responder | 33.3 Percentage of patients |
| PLCBO | Total Patient Assessment of Constipation - Quality of Life (PAC-QOL) Score Responder | 25.8 Percentage of patients |