E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bile acid diarrhoea (also known as bile acid malabsorption) |
|
E.1.1.1 | Medical condition in easily understood language |
Diarrhoea due to an over production or inadequate reabsorption of bile acids |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080051 |
E.1.2 | Term | Bile acid diarrhoea |
E.1.2 | System Organ Class | 100000004856 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to see if there is any difference in the change in bowel function (measured by a index composed of the number of stools, their type, and use of any rescue medication, taken over 7 days) between the baseline and on week 6 of treatment. We will compare patients on Obeticholic acid, either 10mg or 25mg once daily, or an identical placebo. Patients, and their research team, will not know which medication they have been randomly assigned to take. |
|
E.2.2 | Secondary objectives of the trial |
• Comparison of the effects on bowel function index with 10mg and 25mg doses of OCA, at 2, 4 and 6 weeks • Comparison of the changes in bowel function index with OCA 25mg after 6 and 12 weeks treatment • Comparison of the changes in bowel function index with OCA 10mg for 6 weeks, followed by 25mg for 6 weeks, after 12 weeks total treatment • Changes in need for rescue medication • Changes in individual symptoms of stool frequency, stool type, faecal urgency, incontinence, abdominal pain, and bloating at 2, 4, 6 and 12 weeks • Changes in overall quality of life at 2, 4, 6 and 12 weeks • Proportion of subjects in each group meeting the FDA definition of a weekly responder: a decrease at least 50% in the number of days per week with at least one stool that has a consistency of Type 6 or 7, compared with baseline. • Relationship of response to severity of BAD (i.e. SeHCAT <5% vs. 5-10%) • Changes in specific biomarkers (serum FGF19, C4, total bile acids, faecal calprotectin). • Tolerabil |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male and female subjects aged between 18 and 80 years old. • Previously diagnosed with Primary Bile Acid Diarrhoea in the moderate or severe range, with a SeHCAT test 7d retention ≤ 10%. • Presence of ≥ 14 stools/week, with ≥ 25% of stools being Bristol Stool Form Scale (BSFS) Type 6 or 7. These criteria need to be confirmed by daily symptom diary during screening. • Subjects must be willing and able to give written informed consent and agree to comply with the study protocol.
|
|
E.4 | Principal exclusion criteria |
• Presence of another medical condition known to cause chronic diarrhoea (such as coeliac disease, colorectal neoplasia, inflammatory bowel disease, microscopic colitis, chronic pancreatitis, drug-induced diarrhea, active gastrointestinal infection) or insufficient investigations to exclude these. • Resection of small or large intestine >10cm. • Cholecystectomy, unless diarrhoeal symptoms were present for at least 1 year before the surgery. • Biliary surgery or gastric bypass. • Treatment with bile acid sequestrants (BAS) including Colestyramine, Colestipol or Colesevelam within 4 weeks of randomisation. • Use of opiate medications. Loperamide use is permitted in divided doses up to 16 mg/day. • Acute or chronic kidney disease with serum creatinine ≥ 180 µmol/L at screening. • Concomitant liver disease, except mild NAFLD. • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase > 2x upper limit of normal (ULN) at screening. • Total bilirubin >1x ULN at screening; except that patients with Gilbert’s syndrome with elevated total bilirubin may be enrolled, provided that direct (conjugated) bilirubin levels are within normal limits. • Confirmed abnormal platelet levels of <150,000 or > 450,000 platelets/mL. • Known or suspected use of illicit drugs or drugs of abuse within 1 year. • Pregnancy, planned pregnancy, potential for pregnancy (such as unwillingness to use effective birth control during the study), or breast feeding. • Use of an investigational new drug within 30 days (or 5 elimination half-lives) prior to screening. • History of allergy to any of the ingredients in the investigational medications. • Any other medical condition or social circumstance, which in the opinion of the investigator would impede compliance with or hinder completion of the study • Inability to comply with the protocol or give informed consent.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• The difference in change in bowel function, measured by a composite index of stool frequency, stool type and rescue medication over 7 days, between baseline and week 6 of treatment with OCA, either 10mg or 25mg od, compared with placebo. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Comparison of the changes in bowel function index with OCA 10mg after 6 and 12 weeks treatment • Comparison of the effects on bowel function index with 10mg and 25mg doses of OCA, at 2, 4 and 6 weeks • Changes in need for rescue medication (loperamide) • Changes in individual symptoms of stool frequency, stool type, faecal urgency, incontinence, abdominal pain, and bloating at 2, 4, 6 and 12 weeks • Changes in overall quality of life at 2, 4, 6 and 12 weeks • Proportion of subjects in each group meeting the FDA definition of a weekly responder: a decrease at least 50% in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline. • Relationship of response to severity of BAD (i.e. SeHCAT <5% vs. 5-10%) • Changes in specific biomarkers (serum FGF19, C4, total bile acids, faecal calprotectin). • Tolerability and frequency of side-effects over the duration of the trial.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Data entry and analysis completion |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 30 |