Primary Bile Acid Malabsorption, Secondary Bile Acid Malabsorption, Chronic Diarrhoea
Conditions
Keywords
Primary bile acid malabsorption, Secondary bile acid malabsorption, Chronic diarrhoea, Obeticholic acid, SeHCAT, FXR, FGF19
Brief summary
The investigators propose to develop studies of obeticholic acid (OCA) in patients with bile acid diarrhoea. OCA is a semisynthetic bile acid, also known as 6αethylchenodeoxycholic acid or INT747,and is a potent farnesoid X receptor (FXR) agonist. Preliminary data suggests that patients with bile acid diarrhoea have impaired production of the ileal hormone Fibroblast Growth Factor 19 (FGF19). FGF19 is stimulated by FXR agonists, and regulates bile acid synthesis. This study is a pilot, proof-of-concept, open-label study to investigate whether OCA can stimulate FGF19 in bile acid diarrhoea patients to provide a safe and effective treatment.
Detailed description
Bile acid diarrhoea (BAD) is an under-recognised but common condition of chronic watery diarrhoea. BAD may be secondary to ileal disease affecting the reabsorption and the enterohepatic circulation of bile acids (bile acid malabsorption) or can be an idiopathic, primary BAD (PBAD). In work published in 2009, we described a new mechanism to explain this syndrome of primary BAD. Blood levels of the hormone fibroblast growth factor 19 (FGF19) are reduced in primary and secondary BAD, producing impaired feedback inhibition of bile acid synthesis, leading to excess faecal bile acids, which then produce diarrhoea by stimulating colonic secretion. FGF19 is synthesised in the ileum and we have shown transcription is markedly induced by farnesoid X receptor(FXR) agonists such as chenodeoxycholic acid, an abundant natural bile acid. More potent FXR agonists are logical diagnostic and therapeutic agents for this condition, and obeticholic acid (OCA), which is 100x more potent than chenodeoxycholic acid, has recently been developed. It has been used in phase II studies in primary biliary cirrhosis and in non-alcoholic steatohepatitis where a relatively common side-effect was constipation. We aim to investigate the effects of OCA in patients with primary and secondary BAD to determine whether FGF19 is able to be stimulated in these conditions. We will compare these responses to those in control patients with chronic diarrhoea but without evidence of BAD. It is possible in BAD that the defect in FGF19 levels is due to an inability to respond to FXR stimulation (particularly likely in secondary BAD after ileal resection). Patients with primary BAD may be able to respond and benefit from an increase in FGF19 levels. This study aims to obtain pilot data on the effects of OCA on FGF19, other markers of bile acid metabolism and patient symptoms including diarrhoea. These are early phase II, proof of concept studies.
Interventions
DRUGObeticholic acid
Day -14 to Day 0 subjects will stop their usual diarrhoeal medication. Day 1 to Day 15 Obeticholic acid 25mg tablet will be administered to subjects once daily in the morning. Day 16 to day 28 normal diarrhoeal medication may be re-commenced.
Sponsors
Imperial College Healthcare NHS Trust
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Patients aged 18 - 80 who present at routine Gastrointestinal Outpatient Clinics at Hammersmith and Charing Cross Hospitals with chronic diarrhoea, defined as an average stool frequency of at least three per day, of Bristol Stool Type 6 or 7, for at least 3 months. Previous routine SeHCAT testing to establish the presence or absence of bile acid diarrhoea (BAD) unless there is evidence of TI disease/ resection. BAD will be defined as SeHCAT 7-day retention of less than 15% or diarrhoea in presence of TI disease/ resection. Study subjects will be grouped as having secondary BAD, due to ileal resection or Crohn's disease, or primary BAD, with no obvious cause. The third, control group having chronic diarrhoea but with normal SeHCAT retention (greater than 15%). Female patients must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and for 15 days after the last dose of OCA. Male subjects with female partners of childbearing potential must use ≥ 1 effective method of contraception. Effective methods of contraception are considered to be: 1. Established use of oral, injected or implanted hormonal methods of contraception. 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 4. Male sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). 5. True abstinence: When this is in line with the preferred and usual lifestyle of the subject.
Exclusion criteria
* Patients with other diagnoses leading to diarrhoea, including colorectal neoplasia, ulcerative colitis, coeliac disease, chronic pancreatitis, drug-induced diarrhoea or active infection. * Patients who have not been investigated by standard clinical assessments to exclude these disorders. * Treatment with bile acid sequestrants (colestyramine, colestipol, colesevelam) for 2 weeks before the first dose of OCA. Loperamide use will be allowed up to 16mg/d in divided doses. * Previous biliary surgery, excluding cholecystectomy. * Abnormal bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase on more than 1 occasion. * Chronic liver disease * Chronic kidney disease * Active, serious medical disease with likely life expectancy less than 5 years * Active substance abuse including inhaled or injection drugs in the year prior to screening * Allergy to obeticholic acid. * Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during the trial, breast feeding. Pregnancy will be assessed with urinary β-hCG pregnancy test. * Participation in an investigational new drug trial in the 30 days before randomisation * Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of the study * Failure to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Fasting FGF19 | Day 0, Day 15 | The primary outcome measure is the change over 2 weeks in fasting serum fibroblast growth factor (FGF19) in 3 groups of patients: primary bile acid diarrhoea, secondary bile acid diarrhoea, and a control population of patients with chronic diarrhoea but with normal bile acid retention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Fasting 7α-hydroxy-4-cholesten-3-one | Day 0, Day 15 | Change in fasting 7α-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA. |
| Changes in Serum Total Bile Acids. | Day 0, Day 15 | Dynamic changes of total bile acids over 6 hour period following OCA administration before and after 15 day OCA period. |
| Changes in Non-fasting Response of FGF19 to OCA | Day 0, Day 15 | Change in dynamic response of FGF19 in 6 hours following OCA administration; at start and end of 15 day OCA test period. |
| Changes in Mean Stool Form | Week 2, Week 4 | Change in mean stool form reported per week between week 2 (baseline) and week 4 (week 2 of treatment) using the Bristol Stool Form Scale (range of scores 1 to 7). High scores are a worse outcome (7=liquid stools). |
| Change in Stool Index | Week 2, Week 4 | Change in index calculated on a weekly basis, between week 2 (baseline) and week 4 (week 2 of treatment). Index calculated as (\[weekly stool frequency x mean Bristol Stool Form Scale score\] = Loperamide use \[weekly mg x 3\]). Individual scores ranged from 25 to 1095, with higher scores being worst. |
| Changes in Stool Frequency | Week 2, Week 4 | Change in total number of stool episodes reported per week between week 2 (baseline) and week 4 (week 2 of treatment) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Primary BAD Defined as SeHCAT \<10% without other causes such as Crohn's disease and/or ileal resection | 10 |
| Secondary BAD With Crohn's disease or ileal resection | 10 |
| Idiopathic Diarrhoea Controls Chronic diarrhoea with SeHCAT \>15% and no Crohn's or ileal resection | 8 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 3 | 4 |
Baseline characteristics
| Characteristic | Primary BAD | Secondary BAD | Idiopathic Diarrhoea Controls | Total |
|---|---|---|---|---|
| Age, Continuous | 47 years | 45 years | 39 years | 41 years |
| Region of Enrollment United Kingdom | 10 participants | 10 participants | 8 participants | 28 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 3 Participants | 17 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 0 / 10 | 3 / 10 | 1 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 8 |
Outcome results
Primary
Changes in Fasting FGF19
The primary outcome measure is the change over 2 weeks in fasting serum fibroblast growth factor (FGF19) in 3 groups of patients: primary bile acid diarrhoea, secondary bile acid diarrhoea, and a control population of patients with chronic diarrhoea but with normal bile acid retention.
Time frame: Day 0, Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary BAD | Changes in Fasting FGF19 | 71 percentage increase of baseline |
| Secondary BAD | Changes in Fasting FGF19 | 25 percentage increase of baseline |
| Idiopathic Diarrhoea Controls | Changes in Fasting FGF19 | 130 percentage increase of baseline |
Comparison: Paired comparison of fasting FGF19 at baseline on day 0 and on day 14 of OCA treatmentp-value: 0.007Wilcoxon (Mann-Whitney)
Comparison: Paired comparison of fasting FGF19 at baseline on day 0 and on day 14 of OCA treatmentp-value: 0.11Wilcoxon (Mann-Whitney)
Comparison: Paired comparison of fasting FGF19 at baseline on day 0 and on day 14 of OCA treatmentp-value: 0.12Wilcoxon (Mann-Whitney)
Secondary
Change in Stool Index
Change in index calculated on a weekly basis, between week 2 (baseline) and week 4 (week 2 of treatment). Index calculated as (\[weekly stool frequency x mean Bristol Stool Form Scale score\] = Loperamide use \[weekly mg x 3\]). Individual scores ranged from 25 to 1095, with higher scores being worst.
Time frame: Week 2, Week 4
Population: Missing data in Idiopathic diarrhoea controls
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary BAD | Change in Stool Index | -37.5 index score |
| Secondary BAD | Change in Stool Index | -32.5 index score |
| Idiopathic Diarrhoea Controls | Change in Stool Index | -5.5 index score |
Comparison: Paired difference in weekly index scorep-value: 0.005Wilcoxon (Mann-Whitney)
Comparison: Paired difference in weekly index scorep-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: Paired difference in weekly index scorep-value: 0.61Wilcoxon (Mann-Whitney)
Secondary
Changes in Fasting 7α-hydroxy-4-cholesten-3-one
Change in fasting 7α-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA.
Time frame: Day 0, Day 15
Population: Missing data in Primary BAD
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary BAD | Changes in Fasting 7α-hydroxy-4-cholesten-3-one | -11.5 microgram/L |
| Secondary BAD | Changes in Fasting 7α-hydroxy-4-cholesten-3-one | -27.5 microgram/L |
| Idiopathic Diarrhoea Controls | Changes in Fasting 7α-hydroxy-4-cholesten-3-one | -6.5 microgram/L |
Comparison: Change in fasting C4p-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: Change in fasting C4p-value: 0.11Wilcoxon (Mann-Whitney)
Comparison: Change in fasting C4p-value: 0.02Wilcoxon (Mann-Whitney)
Secondary
Changes in Mean Stool Form
Change in mean stool form reported per week between week 2 (baseline) and week 4 (week 2 of treatment) using the Bristol Stool Form Scale (range of scores 1 to 7). High scores are a worse outcome (7=liquid stools).
Time frame: Week 2, Week 4
Population: Missing data in Idiopathic diarrhoea controls
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary BAD | Changes in Mean Stool Form | -0.71 Score on Bristol scale |
| Secondary BAD | Changes in Mean Stool Form | -0.38 Score on Bristol scale |
| Idiopathic Diarrhoea Controls | Changes in Mean Stool Form | -0.46 Score on Bristol scale |
Comparison: Change in median stool formp-value: 0.05Wilcoxon (Mann-Whitney)
Comparison: Change in median stool formp-value: 0.04Wilcoxon (Mann-Whitney)
Comparison: Change in median stool formp-value: 0.74Wilcoxon (Mann-Whitney)
Secondary
Changes in Non-fasting Response of FGF19 to OCA
Change in dynamic response of FGF19 in 6 hours following OCA administration; at start and end of 15 day OCA test period.
Time frame: Day 0, Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary BAD | Changes in Non-fasting Response of FGF19 to OCA | 11.6 percentage change |
| Secondary BAD | Changes in Non-fasting Response of FGF19 to OCA | 14.6 percentage change |
| Idiopathic Diarrhoea Controls | Changes in Non-fasting Response of FGF19 to OCA | 32.4 percentage change |
Comparison: Change in FGF19 AUCp-value: 0.72Wilcoxon (Mann-Whitney)
Comparison: Change in FGF19 AUCp-value: 0.51Wilcoxon (Mann-Whitney)
Comparison: Change in FGF19 AUCp-value: 0.13Wilcoxon (Mann-Whitney)
Secondary
Changes in Serum Total Bile Acids.
Dynamic changes of total bile acids over 6 hour period following OCA administration before and after 15 day OCA period.
Time frame: Day 0, Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary BAD | Changes in Serum Total Bile Acids. | -18.1 micromol/L |
| Secondary BAD | Changes in Serum Total Bile Acids. | -2.0 micromol/L |
| Idiopathic Diarrhoea Controls | Changes in Serum Total Bile Acids. | -15.5 micromol/L |
Comparison: Change in bile acid 6h AUCp-value: 0.02Wilcoxon (Mann-Whitney)
Comparison: Change in bile acid 6h AUCp-value: 0.04Wilcoxon (Mann-Whitney)
Comparison: Change in bile acid 6h AUCp-value: 0.02Wilcoxon (Mann-Whitney)
Secondary
Changes in Stool Frequency
Change in total number of stool episodes reported per week between week 2 (baseline) and week 4 (week 2 of treatment)
Time frame: Week 2, Week 4
Population: Missing data in Idiopathic diarrhoea controls
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Primary BAD | Changes in Stool Frequency | -4.5 stools per week |
| Secondary BAD | Changes in Stool Frequency | -2.5 stools per week |
| Idiopathic Diarrhoea Controls | Changes in Stool Frequency | 3.0 stools per week |
Comparison: Comparison of change in number of stools per weekp-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: Comparison of change in number of stools per weekp-value: 0.17Wilcoxon (Mann-Whitney)
Comparison: Comparison of change in number of stools per weekp-value: 0.31Wilcoxon (Mann-Whitney)