| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Biliary Cholangitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary Biliary Cholangitis is a rare, chronic autoimmune liver disease characterized by both liver and biliary tract lesions that progress 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036680 |
| E.1.2 | Term | Primary biliary cirrhosis |
| E.1.2 | System Organ Class | 100000004871 |
|
| 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 |
1. To assess the effect of OCA compared to placebo, in conjunction with established local standard of care, on clinical outcomes in subjects with PBC as measured by time to first occurrence of any of the following adjudicated events, derived as a composite event endpoint:
a. Death (all-cause)
b. Liver transplant
c. Model of end stage liver disease (MELD) score ≥15
d. Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of:
i. Variceal bleed
ii. Hepatic Encephalopathy (as defined by a West Haven score of ≥2)
iii. Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
e.Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at least twice in a month)
|
|
| E.2.2 | Secondary objectives of the trial |
To assess the effect of OCA compared to placebo on time to first occurrence of each individual component of the primary endpoint as listed above
To assess the effect of OCA compared to placebo on time to occurrence of liver related death.
To assess the effect of OCA compared to placebo on progression to cirhosis
To assess the effect of OCA compared to placebo on time to occurrence of HCC
To assess the effect of OCA compared to placebo on disease progression via the following:
a. Liver biochemistry
b. Markers of inflammation and fibrosis
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes.
To characterize the PK of OCA and its conjugates in a subset of subjects.
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource utilization, and quality of life measures in subjects treated with OCA compared to placebo.
To assess the safety and tolerability in subjects treated with OCA compared to placebo. |
|
| 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 |
Genetic Substudy and Biopsy Substudy are included
Genetic Substudy.
The following title is mentioned in the Patient Informed Consent but not on the protocol where a description of the genetic s study is contained:
"Optional Genetics Research Study: A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cirrhosis"
A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples. Genetics samples will be collected at Day 0 and every other year beginning at Month 12.
A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved in PBC will be conducted for subjects and at study sites willing to provide samples at Day 0, Month 12, and every other year at the yearly visits thereafter. RNA expression resulting from treatment with OCA will be assessed at indicated timepoints during the study. Subjects will be permitted to decline to provide a blood sample for the genetics study, without affecting their involvement in the study. IRB/IEC review and approval will be required and willing subjects must specifically consent to participate in this evaluation. The samples will be stored for up to 1 year after the end of the study and destroyed after 1 year if not analyzed.
Biopsy Substudy
The purpose of this sub-study is to assess the effect of OCA versus placebo on the histological severity of disease (fibrosis/cirrhosis) in subjects with PBC. in addition, this sub-study will generate data on the relationship between histological changes and clinical, laboratory and non-invasive measures indicative of progression to cirrhosis in patients with PBC. |
|
| E.3 | Principal inclusion criteria |
1. Definite or probable PBC diagnosis (consistent with American
Association for the Study of Liver Diseases [AASLD] and the European
Association for the Study of the Liver [EASL] practice guidelines; Lindor
2009; EASL 2009), as demonstrated by the presence of ≥2 of the
following 3 diagnostic factors:
a. History of elevated ALP levels for at least 6 months
b. Positive antimitochondrial antibody (AMA) titer or if AMA
negative or in low titer (<1:80) PBC-specific antibodies (anti-GP210
and/or anti-SP100 and/or antibodies against the major M2 components
[PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
c. Liver biopsy consistent with PBC
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN
3. Age ≥18 years
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or
has been taking UDCA for at least 12 months with a stable dose for ≥3
months prior to Day 0
5. Contraception: Female subjects must be postmenopausal, surgically
sterile, or, if premenopausal (and not surgically sterile), be prepared to
use ≥1 highly effective method of contraception during the study and for
30 days after the end of treatment. Highly effective methods of
contraception per the CTFG guidelines are those that alone or in
combination results in a failure rate of less than 1% per year when used
consistently and correctly. Highly effective methods of contraception are
as follows:
• Intrauterine device
− Intrauterine device (IUD)
− Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomy (partner)
• Combined (estrogen and progestogen containing) hormonal
contraception (eg, oral, intravaginal or transdermal) associated with
inhibition of ovulation. If oral contraceptives are used, they must be
used in combination with a male or female condom. Female subjects
should have been on the hormone contraception for at least 8 days prior
to Day 1.
• Progestogen-only hormonal contraception (eg oral, injectable or
implantable) associated with inhibition of ovulation. If oral
contraceptives are used, they must be used in combination with a male
or female condom. Female subjects should have been on the hormone
contraception for at
least 8 days prior to Day 1.
• Sexual abstinence, if in line with the preferred and usual lifestyle of
the subject (where abstinence is defined as refraining from heterosexual
intercourse during the entire period of risk associated with study
treatments).
6. Must provide written informed consent and agree to comply with the
study protocol |
|
| E.4 | Principal exclusion criteria |
1. History or presence of other concomitant liver diseases including:
a. Hepatitis C virus infection
b. Active hepatitis B infection; however, subjects who have
seroconverted (hepatitis B surface antigen and hepatitis B e antigen
negative) may be included in this study after consultation with the
medical monitor
c. Primary sclerosing cholangitis
d. Alcoholic liver disease
e. Definite autoimmune liver disease or overlap hepatitis
f. Nonalcoholic steatohepatitis
g. Gilbert's Syndrome
2. Presence of clinical complications of PBC or clinically significant
hepatic decompensation, including:
a. History of liver transplant, current placement on a liver transplant
list, or current MELD score >12. Subjects who are placed on a transplant
list despite a relatively early disease stage (for example per regional
guidelines) may be eligible as long as they do not meet any of the other
exclusion criteria
b. Cirrhosis with complications, including history (within the past 12
months) or presence of:
i. Variceal bleeding
ii. Uncontrolled ascites
iii. Encephalopathy
iv. Spontaneous bacterial peritonitis
c. Known or suspected hepatocellular carcinoma
d. Prior transjugular intrahepatic portosystemic shunt procedure
e. Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2)
serum creatinine >2 mg/dL (178 μmol/L)
3. Mean total bilirubin >5× ULN
4. Subjects who have undergone gastric bypass procedures (gastric lap
band is acceptable) or ileal resection or plan to undergo either of these
procedures
5. Other medical conditions that may diminish life expectancy, including
known cancers (except carcinomas in situ or other stable)
6. If female: plans to become pregnant, known pregnancy or a positive
urine pregnancy test (confirmed by a positive serum pregnancy test), or
lactating
7. Known history of human immunodeficiency virus infection
8. Medical conditions that may cause nonhepatic increases in ALP (eg,
Paget's disease or fractures within 3 months prior do Day 0)
9. Other clinically significant medical conditions that are not well
controlled or for which medication needs are anticipated to change
during the study
10. History of alcohol abuse or other substance abuse within 1 year prior
to Day 0
11. Participation in another investigational product, biologic, or medical
device study within 30 days prior to Screening. Participation in a
previous study of OCA is allowed with 3 months washout prior to
enrollment in this study
12. Mental instability or incompetence, such that the validity of informed
consent or ability to be compliant with the study is uncertain
13. History of known or suspected clinically significant hypersensitivity
to OCA or any of its components
14. UDCA naive unless contraindicated |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the time to first occurrence of one of the following post randomization:
a. Death (all-cause)
b. Liver transplant
c. Model of end stage liver disease (MELD) score ≥15
d. Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of:
i. Variceal bleed
ii. Hepatic Encephalopathy (as defined by a West Haven score of ≥2)
iii. Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
e. Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at least |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Analyses
The key secondary efficacy endpoints are as follows:
a. Time to first occurrence of MELD score ≥15
b. Time to liver transplant or death (all-cause)
c. Change from Baseline in total bilirubin at end of study
d. Change from Baseline in ALP at end of study
Other Efficacy Analyses
The following time to event secondary efficacy analyses will compare OCA versus placebo using the ITT population:
Time to each component of the primary efficacy endpoint (except MELD score ≥15 which is captured above)
Time to development of varix/varices
Progression to cirrhosis
Time to occurrence of HCC
Time to liver-related death
Time to liver-related death or liver transplant
Time to liver-related death, liver transplant, or MELD score ≥15
Safety Analysis
Safety data, including AEs, AEs of special interest including pruritus and hepatic safety, vitals, electrocardiogram, and clinical laboratory results will be summarized by treatment group for Health outcomes and pharmacokinetic analyses |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | 2 |
| 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 | 70 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Hong Kong |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Serbia |
| Turkey |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Argentina |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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