| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary biliary cirrhosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary biliary cirrhosis (PBC) is a rare, chronic, autoimmune liver disease characterized by both liver and biliary tract lesions that progresses to cirrhosis and other complications. |
|
| 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 | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10019805 |
| E.1.2 | Term | Hepatobiliary disorders |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the effects of OCA in patients with PBC on:
-Serum alkaline phosphatase (ALP) and total bilirubin, together as a composite endpoint
-Safety |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effects of OCA in patients with PBC on:
-Hepatocellular injury and liver function, including histology (inflammatory,
structural [portal, parenchymal] and fibrotic assessments)
-Disease specific symptoms
-Biomarkers and noninvasive assessments of liver fibrosis
-Bile acids (BA)
-Other exploratory evaluations |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Genetics Research Study (A Phase 3, Double Blind, Placebo Controlled Trial and Long Term Safety Extension of Obeticholic Acid in Patients with Primary Biliary Cirrhosis)
To study genes that may be involved in the development of Primary Biliary Cirrhosis (PBC) disease (and related conditions). |
|
| E.3 | Principal inclusion criteria |
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL Practice Guidelines; [Lindor 2009; EASL 2009]), as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:
-History of elevated ALP levels for at least 6 months
-Positive AMA titer or PBC specific antibodies
-Liver biopsy consistent with PBC
2. At least 1 of the following qualifying biochemistry values:
- ALP≥1.67x ULN
-Total bilirubin > ULN but < 2x ULN
3. Age ≥18 years
4. Taking UDCA for at least 12 months (stable dose for ≥ 3 months) prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months) prior to Day 0
5. Contraception: Female patients of childbearing potential must use ≥ 1
effective (≤ 1% failure rate) method of contraception during the trial and for 30 days after the End of Treatment (EOT) visit.
6. Must provide written informed consent and agree to comply with the trial protocol. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the trial if they meet any of the following:
1. History or presence of other concomitant liver diseases including:
-Hepatitis C virus (HCV) infection; patients with active hepatitis B (HBV)
infection will be excluded, however, patients who have seroconverted
(HbsAg and Hbe Ag negative) may be included after consultation with the medical monitor.
-Primary sclerosing cholangitis (PSC)
-Alcoholic liver disease
-Definite autoimmune liver disease or overlap hepatitis
-Nonalcoholic steatohepatitis (NASH)
-Gilbert’s Syndrome (exclusion due to interpretability of bilirubin levels)
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
-History of liver transplantation, current placement on a liver transplant list or current MELD score ≥ 15
-Portal hypertention with complications, including: known gastric or
large esophageal varices, poorly controlled or diuretic resistant ascites,
history of variceal bleeds or related therapeutic or prophylactic
interventions (e.g., beta blockers, insertion of variceal bands or
transjugular intrahepatic portosystemic shunt [TIPS]), or hepatic
encephalopathy
-Cirrhosis with complications, including history or presence of: spontaneous
-Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/dL (178 μmol/L) bacterial peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN
3. Patients with severe pruritus or those requiring systemic treatment for pruritus (e.g., with bile acid sequestrants [BAS] or rifampicin) within 2 months of Day 0 will be excluded.
4. Administration of the following medications is prohibited as specified below:
-Prohibited 6 months prior to Day 0 and throughout the trial (i.e., to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate,
mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates;
budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
-Prohibited 12 months prior to Day 0 and throughout the trial (i.e., to last dose and/or EOT): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
5. Patients who have previously participated in a clinical trial of OCA will not be allowed to participate.
6. History or presence of clinically concerning cardiac arrhythmias likely to affect survival during the trial, or prolongation of Screening (pretreatment) QT or QTc interval of > 500 milliseconds (msec).
7. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint (evaluated as a responder analysis):
ALP < 1.67x ULN and total bilirubin within normal limits (WNL), and
ALP decrease of ≥ 15% (to exclude clinically insignificant ALP changes) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Double blind phase : Screening(≤ -1 to-8 Wks), Day 0, W2, M3, M6, M9, M12/LTSE D1, End of Treatment (if applicable), follow-up
Long term safety extension: M3, M6, M9, M12, End of Treatment |
|
| E.5.2 | Secondary end point(s) |
Analyses regarding secondary endpoints will be specified in the SAP and conducted for the following parameters. It is anticipated that additional disease prognostic algorithms will be published during the course of the trial. Where appropriate, secondary analyses will be conducted using such algorithms. At the blinded data review a determination will be made as to which algorithms will be evaluated statistically, as it is likely that there will be small numbers of patients for some algorithms and formal statistical analysis will not therefore be appropriate.
• ALP response rates of 10%, 20% and 40% change
• Disease Prognostic Risk (criteria in relevant patients):
-ALP ≤ 3x ULN and AST ≤ 2x ULN and normal bilirubin
- ALP ≤ 1.5x ULN and AST ≤ 1.5x ULN and bilirubin within normal limits
- ALP ≤ 1.67x ULN and normal bilirubin
- Normal bilirubin and normal albumin
• Clinical laboratory values:
- GGT, ALT, AST, total and conjugated bilirubin
- Albumin, prothrombin time and INR
• Liver biopsy/histology: Inflammatory, structural (portal, parenchymal) and fibrotic assessments
• Disease Specific Symptoms:
- PBC-40
- 5-D Pruritus Questionnaire
- Pruritus VAS
• Biomarkers and non-invasive assessments of liver fibrosis
- Fibrosis biomarkers (ELF)
- TE (at selected trial sites)
- Other analytes: TNF-α, TGF-β, IL-6, CK-18 and lysophosphatidic acid
• Bile acids
- Plasma OCA, other bile acids and conjugate concentrations
- Bile and feces concentrations (at selected trial sites) |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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 | 7 |
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