A Phase 4 clinical trial to measure the effect of Obeticholic acid against a placebo, in conjunction with standard treatment, on selected clinical measurements in patients with the liver disease, Primary Biliary Cholangitis. The COBALT Study Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT)

• Register: EUCTR
• Last refreshed on: 1 February 2022
• Main ID: EUCTR2014-005012-42-AT
• Date of registration: 28/09/2015
• Prospective Registration: Yes
• Primary sponsor: Intercept Pharmaceuticals Inc.
• Public title: A Phase 4 clinical trial to measure the effect of Obeticholic acid against a placebo, in conjunction with standard treatment, on selected clinical measurements in patients with the liver disease, Primary Biliary Cholangitis. The COBALT Study Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT)
• Scientific title: A Phase 4, Double Blind, Randomized, Placebo Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cholangitis. The COBALT Study Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT)
• Date of first enrolment: 26/11/2015
• Target sample size: 428
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-005012-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Denmark, Estonia, Finland, France, Germany, Hong Kong, Hungary, Israel, Italy, Korea, Republic of, Lithuania, Mexico, Netherlands, New Zealand, Poland, Portugal, Serbia, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States

Contacts

• Name: Project Management
• Affiliation: Syneos Health UK Limited

• Name: Project Management
• Affiliation: Syneos Health UK Limited

Key inclusion & exclusion criteria

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 Alkaline phosphatase 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. 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.
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 278
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 150

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 biliburin >5x 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, relatively benign conditions)
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 to 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 naïve (unless contraindicated)



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Primary Biliary Cholangitis
MedDRA version: 21.0 Level: LLT Classification code 10036680 Term: Primary biliary cirrhosis System Organ Class: 100000004871

Intervention(s)

Trade Name: Ocaliva
Product Name: Obeticholic acid
Product Code: OCA, INT-747
Pharmaceutical Form: Tablet
INN or Proposed INN: Obeticholic Acid
CAS Number: 459789-99-2
Current Sponsor code: 6-ECDCA
Other descriptive name: 6a-ethylchenodeoxycholic acid (6-ECDCA), OCA, INT-747
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Trade Name: Ocaliva
Product Name: Obeticholic acid
Product Code: OCA, INT-747
Pharmaceutical Form: Tablet
INN or Proposed INN: Obeticholic Acid
CAS Number: 459789-99-2
Current Sponsor code: 6-ECDCA
Other descriptive name: 6a-ethylchenodeoxycholic acid (6-ECDCA), OCA, Int-747
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

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 twice in a month)

Timepoint(s) of evaluation of this end point: 10 years

Main Objective: 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)

Secondary Objective: 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 occurence of liver related death.
To assess the effect of OCA compared to placebo on progression to cirrhosis.
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:
Liver biochemistry
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.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 10 years

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 interst including pruritus and hepatic safety, vitals, electrocardiogram, and clinical laboratory results will be summarized by treatment group for Health outcomes and pharmacokinetic analysis

Secondary ID(s)

NCT02308111

2014-005012-42-HU

747-302

Source(s) of Monetary Support

Intercept Pharmaceuticals Inc.

Ethics review

Status: Approved
Approval date: 11/11/2015
Contact: