| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Portal Hypertension in Patients with Cirrhosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| High blood pressure in the portal vein (a blood vessel that conducts blood from the gastrointestinal tract and spleen to the liver) in patients with of chronic liver disease called cirrhosis |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036200 |
| E.1.2 | Term | Portal hypertension |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| 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 |
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 |
|
| E.2.2 | Secondary objectives of the trial |
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?
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
|
|
| E.4 | Principal 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 <8kPa
o Renal: serum creatinine >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 α 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
|
|
| E.5 End points |
| E.5.1 | 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 assessments. The primary endpoint for this study is the effect of OCA on an improvement in portal pressure as assessed by an HVPG of <12 mmHg or a reduction in HVPG of ≥15% compared to the baseline after 7 days of treatment.
Analysis of the change from baseline in both absolute terms (mmHg) and as a percentage change from baseline will be performed.
Safety and tolerability will be evaluated based on adverse events, laboratory findings and physical examination findings in any patient who received at least one dose of study medication. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 7 compared to baseline |
|
| E.5.2 | 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 7 compared to baseline |
|
| 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 | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of the trial is defined as the last follow up visit of the last participant undergoing the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
Print
