Portal Hypertension in Patients with Cirrhosis MedDRA version: 14.1 Level: PT Classification code 10036200 Term: Portal hypertension System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: Obeticholic acid (OCA)
Product Code: INT-747
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Obeticholic acid
CAS Number: 459789-99-2
Current Sponsor code: OCA, 6-ECDCA or INT-74
Sponsors
Intercept Pharmaceuticals Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patients of age 18-70 years. 2. Patients must have a history of alcoholic cirrhosis with confirmed evidence of cirrhosis 3. Evidence of a feature of portal hypertension (endoscopic, radiological or other). 4. Patients recruited into the cohort for evaluation of effects on portal hypertension must have significant portal hypertension defined as a hepatic venous pressure gradient (HVPG) =12 mmHg. 5. Patients with large or grade 3 oesophageal varices as identified by endoscopy within six months of screening should be in an endoscopic band ligation program at the time of study entry. 6. Patients will be understood to be either abstaining from alcohol for at least 6 weeks, or have a stable low alcohol intake (= 4 units per day) for at least 6 weeks, and commit to stay abstinent or to consume = 4 units per day for the duration of the study. 7. Female patients must be postmenopausal, surgically sterile, or if premenopausal, must be prepared to use at least 1 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 1 effective method of contraception with all sexual partners unless they have had a prior vasectomy. Effective methods of contraception are considered to be: • Barrier method, i.e., (a) condom (male or female) or (b) diaphragm, with spermicide; or • Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection); or • Intrauterine device (IUD); or • Vasectomy (partner) 8. Must be willing and able to give written informed consent and agree to comply with the study protocol. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 60 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 18
Exclusion criteria
Exclusion criteria: Patients will be excluded from the study if they meet any of the following: 1. Patients with co-existing disease including: • Significant organ failure defined as: o Respiratory: PaO2 150 µmol/L o Cardiovascular: haemodynamic requirement for inotropic support o CNS: hepatic encephalopathy West Haven Criteria score >2 • Decompensated cirrhosis with a Child-Pugh score >12 or requirement for organ support • Concomitant hepatobiliary disease (except hepatitis B or C viral disease), e.g., primary sclerosing cholangitis, primary biliary cirrhosis • Known or suspected hepatic or extra hepatic malignancy, unless adequately treated or in complete remission for = 3 years • Concomitant acute pancreatitis • Acute alcoholic hepatitis with sepsis, within 3 months 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 4-6 weeks (as specified below) of randomisation: • Beta blockers (= 6 weeks prior to randomisation or, following one-off short term treatment of up to a maximum of 6 days = 3 weeks prior to randomisation) • Nitrates (= 6 weeks prior to randomisation) • Vasopressin or analogues (= 6 weeks prior to randomisation) • Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil or other drugs for erectile dysfunction) = 4 weeks prior to randomisation) 5. Use of the following drugs within 3 months of randomisation: • Systemic corticosteroids • Pentoxifylline • Potentially hepatotoxic drugs (including a methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin), unless well tolerated, and approved by the medical monitor • Ursodeoxycholic acid (UDCA) • 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: • Fibrates or statins • 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. 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. 12. Known iodine allergy or sensitivity to contrast media
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: This study intends to examine the effect of a new drug, obeticholic acid (OCA), on portal hypertension in patients with cirrhosis of the liver. Portal hypertension is a raised blood pressure in a vein in the liver, the portal vein. This liver disease, cirrhosis, increases the pressure inside it and it's branches. This condition is called portal hypertension and it is associated with several complications, some being life-threatening such as damage to and dysfucntion of the kidneys and brain. Lowering the blood pressure level in the portal vein is expected to prevent the development of these complications. Thus, the primary research questions in this study are: What is the effect of OCA, at 3 dose levels (10 mg, 25 mg and 50 mg), when used in patients with cirrhosis on their portal blood pressure (blood pressure in the veins in the liver)? How safe is OCA, at up to 3 dose levels (10 mg, 25 mg and 50 mg), when used in patients with alcoholic cirrhosis? What side effects do ;Secondary Objective: What is the effect of OCA, at 3 dose levels (10 mg, 25 mg and 50 mg), when used in patients with cirrhosis, on their liver haemodynamics including liver blood flow? What is the effect of OCA, at 3 dose levels (10 mg, 25 mg and 50 mg), when used in patients with cirrhosis, on their liver and renal function? What is the effect of OCA, at 3 dose levels (10 mg, 25 mg and 50 mg), when used in patients with cirrhosis, on their kidney function? Evaluate how OCA, studies at 3 dose levels (10 mg, 25 mg and 50 mg), is managed by the body, (pharmacokinetics) in patients with cirrhosis and portal hypertension? ;Primary end point(s): The primary efficacy measure for this study is an improvement in portal pressure as assessed by HVPG after 7 days of treatment. Analysis will be performed for the Efficacy Analysis Set (EFF) population, defined as all patients who receive at least 6 days of study medication and who have both baseline and on-treatment HPVG assessment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints: • Hepatic haemodynamics: hepatic blood flow and intrahepatic resistance • Liver and renal function: GGT, ALT, ALP, albumin, prothrombin time, INR, bilirubin (total, unconjugated, conjugated), and creatinine clearance, FENa, if enough data are available; otherwise data will be listed and summarized. • PK • Inflammation;Timepoint(s) of evaluation of this end point: Day 7 compared to baseline | — |
Countries
Austria, United Kingdom
Outcome results
None listed