E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Portal Hypertension in Patients with Cirrhosis |
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E.1.1.1 | Medical condition in easily understood language |
Portal Hypertension in Patients with Cirrhosis |
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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 |
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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. 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.
The primary research questions are:
What is the effect of OCA, at up to 3 dose levels (10 mg, 25 mg and if appropriate a third dose ≤50 mg), when used in patients with cirrhosis on their portal blood pressure?
How safe is OCA, at up to 3 dose levels (10 mg, 25 mg and if appropriate a third dose ≤50 mg), when used in patients with alcoholic cirrhosis?
Doses or cohorts may be repeated for confirmation of the data |
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E.2.2 | Secondary objectives of the trial |
What is the effect of OCA, at up to 3 dose levels (10 mg, 25 mg and if appropriate a third dose ≤50 mg), when used in patients with cirrhosis, on their liver haemodynamics including liver blood flow?
What is the effect of OCA, at up to 3 dose levels (10 mg, 25 mg and if appropriate a third dose ≤50 mg), when used in patients with cirrhosis, on their liver and renal function?
What is the effect of OCA, at up to 3 dose levels (10 mg, 25 mg and if appropriate a third dose ≤50 mg), when used in patients with cirrhosis, on their kidney function?
Evaluate how OCA, studied at up to 3 dose levels (10 mg, 25 mg and if appropriate a third dose ≤50 mg), is managed by the body, (pharmacokinetics) in patients with cirrhosis and portal hypertension?
Doses or cohorts may be repeated for confirmation of the data |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 a feature of portal hypertension (endoscopic, radiological or other).
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. 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; orHormonal (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. |
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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 with a 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, including:
• 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is an improvement in portal pressure as assessed by a reduction of ≥ 15% in HVPG or have a HVPG < 12 mmHg, compared to baseline after approximately 7 days of treatment. The statistical analyses and descriptive statistics to be used will be specified in the statistical analysis plan. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 7 compared to baseline |
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E.5.2 | Secondary end point(s) |
Secondary
Descriptive statistics and statistical analyses, if appropriate for secondary endpoints will be specified in the statistical analysis plan and will be conducted for the following parameters
Hepatic haemodynamics
• Hepatic blood flow and intrahepatic resistance
Liver and renal function
• Gamma-glutamyl transferase (GGT), alanine transferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin, prothrombin time, International Normalised Ratio (INR), bilirubin (total, unconjugated, conjugated), creatinine clearance, fractionated sodium (FENa).
Pharmacokinetics
• Plasma drug and metabolite concentrations
Inflammation
• C-reactive protein (CRP) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 7 compared to baseline |
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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 | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 | 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
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LVLS: The end of the trial is defined as the last follow up visit of the last participant undergoing the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |