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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03439254




Registration number
NCT03439254
Ethics application status
Date submitted
14/02/2018
Date registered
20/02/2018
Date last updated
23/10/2023

Titles & IDs
Public title
Study Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis
Scientific title
A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Obeticholic Acid in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis
Secondary ID [1] 0 0
747-304
Universal Trial Number (UTN)
Trial acronym
REVERSE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Compensated Cirrhosis 0 0
Nonalcoholic Steatohepatitis 0 0
Condition category
Condition code
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Metabolic and Endocrine 0 0 0 0
Metabolic disorders
Diet and Nutrition 0 0 0 0
Obesity
Inflammatory and Immune System 0 0 0 0
Connective tissue diseases
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Obeticholic acid (10 mg)
Treatment: Drugs - Obeticholic acid (10 mg to 25 mg)
Treatment: Drugs - Placebo

Experimental: Obeticholic Acid (OCA) 10 mg - 10 mg OCA for up to 18 months

Experimental: Obeticholic Acid (OCA) 10 mg to 25 mg - 10 mg OCA for the first 3 months and then may titrate up to 25 mg OCA for the remaining 15 months of the study

Placebo comparator: Placebo - Placebo for up to 18 months


Treatment: Drugs: Obeticholic acid (10 mg)
Tablets administered orally once daily.

Treatment: Drugs: Obeticholic acid (10 mg to 25 mg)
Tablets administered orally once daily.

Treatment: Drugs: Placebo
Tablets administered orally once daily.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
DB Phase: Number of Participants Who Were Responders and Showed Improvement in Fibrosis by at Least 1 Stage Without Worsening of Nonalcoholic Steatohepatitis (NASH)
Assessment method [1] 0 0
Fibrosis stage was evaluated by NASH Clinical Research Network(CRN)Fibrosis Staging System with stages:0=no fibrosis;1=perisinusoidal/periportal;1A=mild,zone 3,perisinusoidal;1B=moderate,zone 3,perisinusoidal;1C=portal/periportal;2=perisinusoidal and portal/periportal;3=bridging fibrosis;4=cirrhosis.No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant nonalcoholic fatty liver disease activity score (NAS) categories.NAS is semiquantitative scoring system based on unweighted sum of:steatosis (0=\<5% to 3=\>66%),lobular inflammation(0=no foci to 3=\>4 foci/200x),hepatocellular ballooning(0=none to 2=many cells/prominent ballooning)scores.Total scale range:0-12;0:no features of fatty liver disease and 12:highest degree of fatty liver disease.Higher scores:worse symptoms.Responders:did not discontinue treatment due to Adverse event(AE) or did not die and had evaluable post-Baseline biopsy assessment
Timepoint [1] 0 0
Up to 18 months
Primary outcome [2] 0 0
OLE Phase: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
Assessment method [2] 0 0
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
Timepoint [2] 0 0
Up to 12 months
Primary outcome [3] 0 0
OLE Phase: Change From Baseline to Month 12 in Liver Stiffness Measurement (LSM)
Assessment method [3] 0 0
Non-invasive radiological methods to assess liver stiffness were conducted at selected study sites where the respective devices were available. These assessments were taken by vibration controlled transient elastography (TE) method using FibroScan®. Participant was included as a random effect and an unstructured covariance matrix was used assuming convergence could be attained. Baseline was defined as the last value collected prior to the first administration of the investigational product (IP). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Timepoint [3] 0 0
Baseline and up to Month 12
Primary outcome [4] 0 0
OLE Phase: Fibrosis-4 (FIB-4) at Baseline
Assessment method [4] 0 0
FIB-4 was a noninvasive assessment of liver disease assessed by a combination of age, alanine aminotransferase (ALT) and platelet results. FIB-4 was the ratio of age in years and aminotransferase to platelet count. It was a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, ALT, Aspartate aminotransferase (AST) and age that was calculated using formula: FIB-4 = (Age \[years\] x AST \[Units per Liter {U/L}\]) / (platelets \[10\^9/L\] x (square root of ALT \[U/L\])). A FIB-4 index of \<1.45 indicated no or moderate fibrosis and an index of \> 3.25 indicated extensive fibrosis/cirrhosis. Higher ratio indicated worse condition. Baseline was defined as the last value collected prior to the first administration of the IP.
Timepoint [4] 0 0
Baseline (Day 1)
Primary outcome [5] 0 0
OLE Phase: Enhanced Liver Fibrosis (ELF) at Baseline
Assessment method [5] 0 0
ELF was non-invasive panel of circulating fibrosis markers calculated from serum biomarkers. The markers of fibrosis comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP). Each of these markers was measured by an immunoassay and an ELF score was generated, from which a level of fibrosis severity could be determined. The ELF test was a composite score: \< 7.7: no to mild fibrosis; = 7.7 - \< 9.8: Moderate fibrosis; = 9.8 - \< 11.3: Severe fibrosis; = 11.3: Cirrhosis.; higher ELF scores were associated with worsening liver fibrosis. Baseline was defined as the last value collected prior to the first administration of the IP.
Timepoint [5] 0 0
Baseline (Day 1)
Primary outcome [6] 0 0
OLE Phase: Number of Participants Reporting All-cause Mortality
Assessment method [6] 0 0
All-cause mortality is defined as death due to any cause. Number of participants reporting all-cause mortality is presented
Timepoint [6] 0 0
Up to Month 12
Primary outcome [7] 0 0
OLE Phase: Number of Participants With Adjudicated Liver Related Clinical Outcomes: Ascites, Hepatocellular Carcinoma (HCC) and Non-liver Related Death
Assessment method [7] 0 0
Adjudication was performed under the review of Hepatic Safety Adjudication Committee (HSAC) of all available data for each identified participant to determine liver injury status. Number of participants with adjudicated liver related clinical outcomes for the following is presented: Ascites (secondary to cirrhosis and requiring medical intervention), Hepatocellular carcinoma (HCC) and non-liver related death.
Timepoint [7] 0 0
Up to 12 months
Primary outcome [8] 0 0
OLE Phase: Number of Participants With Adjudicated Liver Related Clinical Outcomes: Worsening of Child-Pugh Score
Assessment method [8] 0 0
The Child-Pugh classification was a scoring system used for the classification of the severity of cirrhosis. It included three continuous variables (bilirubin, albumin, and international normalized ratio) and two discrete variables (ascites and encephalopathy). Each variable was scored 1-3 with 3 indicating most severe derangement. The determination of Child-Pugh score ranged from 5 to 15. The higher the score, the sicker the participant. Adjudication was performed under the review of HSAC of all available data for each identified participant to determine liver injury status. Number of participants with adjudicated liver related clinical outcomes for worsening of Child-Pugh score is presented.
Timepoint [8] 0 0
Up to 12 months
Primary outcome [9] 0 0
OLE Phase: Number of Participants With Adjudicated Liver Related Clinical Outcomes: Model for End-Stage Liver Disease (MELD) Score =15
Assessment method [9] 0 0
MELD was a scoring system for assessing the severity of chronic liver disease and to assess prognosis and suitability for liver transplantation. It uses the participant's values for total bilirubin, serum creatinine, and the international normalized ratio for prothrombin time to predict survival. MELD score ranges from 6 (less ill) to 40 (gravely ill) with scores and mortality probability being: Score 40=71.3% mortality; Scores 30-39=52.6% mortality; Scores 20-29=19.6% mortality; Scores10-19=6.0% mortality; Score 9 or less=1.9% mortality. Higher scores indicated greater disease severity. Adjudication was performed under the review of HSAC of all available data for each identified participant to determine liver injury status. Number of participants with adjudicated liver related clinical outcomes for MELD score =15 is presented.
Timepoint [9] 0 0
Up to 12 months
Secondary outcome [1] 0 0
DB Phase: Change From Baseline to Month 18 in LSM
Assessment method [1] 0 0
Non-invasive radiological methods to assess liver stiffness were conducted at selected study sites where the respective devices were available. These assessments were taken by vibration controlled TE method using FibroScan®. Participant was included as a random effect and an unstructured covariance matrix was used assuming convergence could be attained. The principal comparison was at Month 18. Baseline was defined as the last value collected prior to the first administration of the IP. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Timepoint [1] 0 0
Baseline and up to Month 18
Secondary outcome [2] 0 0
DB Phase: FIB-4 at Baseline
Assessment method [2] 0 0
FIB-4 was a noninvasive assessment of liver disease assessed by a combination of age, ALT and platelet results. FIB-4 was the ratio of age in years and aminotransferase to platelet count. It was a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, ALT, AST and age that was calculated using formula: FIB-4 = (Age \[years\] x AST \[U/L\]) / (platelets \[10\^9/L\] x (square root of ALT \[U/L\])). A FIB-4 index of \<1.45 indicated no or moderate fibrosis and an index of \> 3.25 indicated extensive fibrosis/cirrhosis. Higher ratio indicated worse condition. Baseline was defined as the last value collected prior to the first administration of the IP.
Timepoint [2] 0 0
Baseline (Day 1)
Secondary outcome [3] 0 0
DB Phase: ELF at Baseline
Assessment method [3] 0 0
ELF was non-invasive panel of circulating fibrosis markers calculated from serum biomarkers. The markers of fibrosis comprised HA, TIMP1 and PIIINP. Each of these markers was measured by an immunoassay and an ELF score was generated, from which a level of fibrosis severity could be determined. The ELF test was a composite score: \< 7.7: no to mild fibrosis; = 7.7 - \< 9.8: Moderate fibrosis; = 9.8 - \< 11.3: Severe fibrosis; = 11.3: Cirrhosis.; higher ELF scores were associated with worsening liver fibrosis. Baseline was defined as the last value collected prior to the first administration of the IP.
Timepoint [3] 0 0
Baseline (Day 1)

Eligibility
Key inclusion criteria
Key inclusion criteria:

1. Subjects with a confirmed diagnosis of NASH and a fibrosis score of 4 based upon the NASH CRN scoring system determined by central reading

Key exclusion criteria:

1. Current or past history of a clinically evident hepatic decompensation event, such as ascites, hepatic encephalopathy (HE), or variceal bleeding
2. Current or past history of CP score =7 points
3. Model for End-stage Liver Disease (MELD) score > 12
4. ALT = 5 X ULN
5. Calculated creatinine clearance <60mL/min using Cockcroft-Gault method
6. Hemoglobin A1c (HbA1c) = 9.5 %
7. Evidence of other known forms of chronic liver disease such as alcoholic liver disease, hepatitis B, hepatitis C, PBC, PSC, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC)
8. History of liver transplant, or current placement on a liver transplant list
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/08/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
8/09/2022
Sample size
Target
Accrual to date
Final
919
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
Nepean Blue Mountains Local Health District, Nepean Hospital - Kingswood
Recruitment hospital [2] 0 0
Mater Misericordiae Limited - South Brisbane
Recruitment hospital [3] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [5] 0 0
St Vincent's Hospital - Fitzroy
Recruitment hospital [6] 0 0
Austin Health - Heidelberg
Recruitment hospital [7] 0 0
Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
2747 - Kingswood
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
5042 - Bedford Park
Recruitment postcode(s) [5] 0 0
3065 - Fitzroy
Recruitment postcode(s) [6] 0 0
3084 - Heidelberg
Recruitment postcode(s) [7] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
Arkansas
Country [4] 0 0
United States of America
State/province [4] 0 0
California
Country [5] 0 0
United States of America
State/province [5] 0 0
Colorado
Country [6] 0 0
United States of America
State/province [6] 0 0
Florida
Country [7] 0 0
United States of America
State/province [7] 0 0
Georgia
Country [8] 0 0
United States of America
State/province [8] 0 0
Idaho
Country [9] 0 0
United States of America
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Illinois
Country [10] 0 0
United States of America
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Indiana
Country [11] 0 0
United States of America
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Kansas
Country [12] 0 0
United States of America
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Kentucky
Country [13] 0 0
United States of America
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Louisiana
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United States of America
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Maryland
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United States of America
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Massachusetts
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Michigan
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Minnesota
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Mississippi
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Missouri
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Nebraska
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Nevada
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New Jersey
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New York
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North Carolina
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Pennsylvania
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Rhode Island
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South Carolina
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South Dakota
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Tennessee
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Texas
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Vermont
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Virginia
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Washington
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British Columbia
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Nova Scotia
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Ontario
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Amiens
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Clichy
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La Tronche
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Lyon Cedex 04
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France
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Nice
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France
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Paris
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France
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Rouen
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France
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Strasbourg
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France
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Toulouse
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France
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Vandoeuvre-les-Nancy
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France
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Villejuif
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Germany
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Bayern
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Germany
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Hessen
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Germany
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Rheinland-Pfalz
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Germany
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Sachsen
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Germany
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Schleswig-Holstein
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Germany
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Berlin
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Germany
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Hamburg
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Hungary
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Budapest
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Hungary
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Debrecen
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Hungary
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Gyula
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Auckland
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New Zealand
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Christchurch
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New Zealand
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Dunedin
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Wellington
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Poland
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Czestochowa
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Gdansk
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Gdynia
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Katowice
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Poznan
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Warszawa
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Wroclaw
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Poland
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Lódz
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Puerto Rico
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San Juan
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Spain
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Barcelona
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Spain
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Madrid
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Spain
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Santander
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Spain
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Sevilla
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Spain
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Valencia
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Ukraine
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Kyiv
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United Kingdom
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Derbyshire
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United Kingdom
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England
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United Kingdom
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Oxfordshire
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United Kingdom
State/province [84] 0 0
Tyne And Wear

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Intercept Pharmaceuticals
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

TypeOther DetailsAttachment
Study protocol
Statistical analysis plan



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT03439254