A preliminary study to examine and evaluate the effect of obeticholic acid (INT-747) for the treatment of portal hypertension in patients with alcoholic liver disease

Plain English Summary

Not provided at time of registration

Study website

Type

Scientific

Contact name

Dr Rajeshwar Mookerjee

ORCID ID

Contact details

Department of Hepatology
Royal Free Hospital
Pond Street
Hampstead
London
NW3 2QG
United Kingdom
+44 (0)207 433 2874
r.mookerjee@ucl.ac.uk

EudraCT/CTIS number

2010-023241-29

IRAS number

ClinicalTrials.gov number

Protocol/serial number

747-204

Scientific title

A pilot study to evaluate the safety, tolerability and efficacy of obeticholic acid (INT-747) for the treatment of portal hypertension

Acronym

PESTO

Study hypothesis

1. Obeticholic acid (OCA) is safe and tolerated in patients with cirrhosis and portal hypertension
2. Obeticholic acid (OCA) will reduce the Hepatic Venous Pressure Gradient (HVPG) in patients with portal hypertension

Ethics approval(s)

National Research Ethics Service (NRES) North London REC 3 Committee approval granted on:
10/12/2010 (Final Protocol)
01/03/2011 (Amendment 1)
05/04/2011 (Amendment 2)
02/12/2011 (Amendment 3)

Study design

Pilot open-label single-centre study

Primary study design

Interventional

Secondary study design

Non randomised study

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Portal hypertension in patients with alcoholic cirrhosis of the liver

Intervention

1. Physical examination
2. Vital signs
3. 12-lead electrocardiogram (ECG)
4. Blood sampling and analysis – peripheral and hepatic blood samples
5. Urine collection and analysis
6. Hepatic vein catheterisation to measure HVPG and other hepatic haemodynamic measures (efficacy cohort only)

Intervention type

Drug

Pharmaceutical study type(s)

Phase

Not Applicable

Drug/device/biological/vaccine name(s)

Obeticholic acid (OCA)

Primary outcome measure

1. Safety and tolerability as measured and assessed throughout the study by monitoring adverse experiences, clinical laboratory values in blood and measures of blood pressure and heart rate, all at baseline, Day 4, Day 7 and at follow up after 2-4 weeks and ECG at baseline and Day 7
2. Portal hypertension measured at baseline and Day 7 by HPVG. Outcome measure of a reduction of ≥15% at Day 7 compared to baseline or a reduction to <12 mmHg

Secondary outcome measures

1. Hepatic haemodynamics including hepatic blood flow (measured from the concentration of indocynanine green in the hepatic venous blood vs peripheral venous blood using the Fick Principle) and intrahepatic resistance (fluoroscopic examination after catheterisation of the right hepatic vein following injection of contrast medium)
2. Liver function: measured by gamma glutamyl transpeptidase (GGT), alanine transaminase (ALT), alkaline phosphatase (ALP), albumin, prothrombin time and bilirubin (total and unconjugated)
3. Pharmacokinetics: measured by plasma drug and metabolite concentrations
4. Inflammation: measured by C-reactive protein

Overall study start date

01/07/2011

Overall study end date

31/12/2012

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Male or female age 18-70 years
2. History of alcoholic cirrhosis with clinical or radiological and biochemical evidence of cirrhosis
3. Evidence of early decompensated cirrhosis (Child-Pugh score ≥7 to ≤12)
4. Patients recruited into the cohort evaluation of efficacy must have significant portal hypertension defined as an HVPG ≥ 12 mmHg
5. Patients with large or grade 3 oesophageal varices as identified by endoscopy within 6 months of screening should be in an endoscopic band ligation program at the time of study entry
6. Female patients must be postmenopausal, surgically sterile, or if premenopausal, must be prepared to use at least one effective (≤1% failure rate) method of contraception during the course of the study and for 14 days after the end of dosing. Male patients with female partners of child bearing potential must be prepared to use at least one effective method of contraception with all sexual partners unless they have had a prior vasectomy. Effective methods of contraception are considered to be:
6.1. Condom (male or female)
6.2. Diaphragm, with spermicide
6.3. Hormonal (e.g. contraceptive pill, patch, intramuscular implant or injection)
6.4. Intrauterine device (IUD)
6.5. Vasectomy (partner)
7. Must be willing and able to give written informed consent and agree to comply with the study protocol

Participant type(s)

Patient

Age group

Adult

Lower age limit

18 Years

Upper age limit

70 Years

Sex

Both

Target number of participants

Up to 39, depending on number of cohorts studied (3 cohorts up to 39, 2 cohorts up to 26)

Total final enrolment

34

Participant exclusion criteria

1. Patients with co-existing disease including:
1.1. Significant organ failure defined as:
1.2. Respiratory: PaO2 < 8kPa
1.3. Renal: serum creatinine >150 μmol/L
1.4. Cardiovascular: haemodynamic requirement for inotropic support
1.5. Central nervous system (CNS): hepatic encephalopathy West Haven Criteria score >2
1.6. Decompensated cirrhosis with requirement for organ support
1.7. Concomitant hepatobiliary disease (except hepatitis B or C viral disease), e.g., gallstones, primary sclerosing cholangitis, primary biliary cirrhosis
1.8. Known or suspected hepatic or extra hepatic malignancy, unless adequately treated or in complete remission for ≥ 3 years
1.9. Concomitant pancreatitis
2. Use of treatments for hepatitis B or C virus within 12 months of randomisation, or anticipated use during the study
3. Use of the following drugs within 6 months of randomisation: Immuno-modulatory treatment (including azothiaprine, methotrexate, anti-TNF therapies)
4. Use of concomitant vasoactive drugs within 3 months of randomisation:
4.1. Beta blockers
4.2. Nitrates
4.3. Vasopressin or analogues
5. Use of the following drugs within 3 months of randomisation:
5.1. Systemic corticosteroids
5.2. Pentoxifylline
5.3. Potentially hepatotoxic drugs (including  methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin)
5.4. Ursodeoxycholic acid (UDCA)
5.5. Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated)
6. Change in dose or regimen within 3 months of randomisation of:
6.1. Fibrates or statins
6.2. Angiotensin II receptor antagonist or angiotensin converting enzyme (ACE) inhibitor
7. Presence of human immunodeficiency virus (HIV)
8. If female: pregnant, lactating, or positive serum or urine pregnancy test
9. Body mass index (BMI) >40, or >35 with complications
10. Other concomitant disease or condition likely to significantly decrease life expectancy (e.g., moderate to severe congestive heart failure)
11. Any patient who has received any investigational drug or device within 4 months of dosing, or who is scheduled to receive another investigational drug or device during the course of this study

Recruitment start date

01/07/2011

Recruitment end date

31/12/2012

Countries of recruitment

Belgium, England, United Kingdom

Study participating centre

Department of Hepatology, Royal Free Hospital
Pond Street
Hampstead
London
NW3 2QG
United Kingdom

Study participating centre

University Hospital Leuven (Universitat Ziekenhuis Leuven (UZL))
Dept Hepatology and Pancreaticobiliary Disorders
Herestraat 49
Leuven
B - 3000
Belgium

Organisation

Intercept Pharmaceuticals Inc

Sponsor details

18 Desbrosses Street
New York
NY 10013
United States of America
+1 646 747 1000
TBeecherJones@interceptpharma.com

Sponsor type

Industry

Website

http://www.interceptpharma.com

ROR

https://ror.org/01sx6jc36

Funder type

Industry

Funder name

Intercept Pharmaceuticals Inc

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Publication and dissemination plan

Added 23/03/2018:
Results presented at the 49th Annual Meeting of the European Association for the Study of the Liver in April 2014 (http://www.professionalabstracts.com/ilc2014/planner/index.php?go=abstract&action=abstract_show&absno=3124&;)

Intention to publish date

Individual participant data (IPD) sharing plan

IPD sharing plan summary

Not provided at time of registration

Study outputs