The REVERSE study
Research type
Research Study
Full 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 Protocol 747-304
IRAS ID
242919
Contact name
Ingrid Delaet
Contact email
Sponsor organisation
Intercept Pharmaceuticals, Inc.
Eudract number
2017-000474-11
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 8 months, 30 days
Research summary
Research Summary:
The Sponsor is conducting this study to find out how safe and effective the study drug, obeticholic acid (also known as OCA), may be in improving compensated cirrhosis as the result of nonalcoholic steatohepatitis (NASH).
NASH is the result of too much fat within the liver, resulting in injury and death to individual liver cells; the presence of injury like this is followed by progressive formation (laying down) of liver fibrosis (scar tissue); the result of this is increased liver stiffness. As more and more fibrosis is laid down in the liver, the outcome is cirrhosis. Compensated cirrhosis means the liver has become very scarred but can still perform many important bodily functions
Currently, there are no therapies approved for the treatment of NASH. OCA (the brand name is Ocaliva) has been approved in several regions (including North America and Europe) for the treatment of another form of chronic liver disease called Primary Biliary Cholangitis (PBC).
In this study, OCA is an investigational drug (study drug) because it has not been approved to treat cirrhosis as the result of NASH. OCA is a modified (manmade) version of a natural compound made in the liver called bile acid. Bile acids are used by the body to help with digestion, and also have additional effects on liver functionA total of 540 participants at approximately 225 centres worldwide.
To participate in this research study participants must have a confirmed diagnosis of NASH and a fibrosis score of 4.
The study is conducted in 2 parts.
Double-Blind Period is approximately 12 months with 9 Hospital visits.
Optional Open-Label Extension Period is approximately 12 months with 8 Hospital visits.The following procedures may be performed: physical exam, height, weight, hip circumference, vital signs, questionnaires, Electrocardiogram, endoscopy, ultrasound scans, blood and urine samples and possible liver biopsies.
Summary of research:
• In this study, researchers tested an experimental drug called obeticholic acid (OCA) to see how safe and effective it is in reducing liver scar tissue in participants with compensated cirrhosis.
• 295 participants in one group received 10 mg OCA; 309 participants received 10 mg with an option to increase up to 25 mg OCA, and 312 participants received placebo.
• At the end of the study, researchers found that there was no difference between the three groups with respect to reversal of liver scar tissue after 12 to 18 months of treatment.
• 565 participants had at least one side effects during the study, and 16 had one or more serious side effect. 7 participants died in the double-blind part, all were considered not related to OCA.WHY WAS THIS STUDY DONE?
Nonalcoholic steatohepatitis (NASH) is a form of liver disease where the liver becomes inflamed and damaged due to a build-up of fat, causing scar tissue (called ‘fibrosis’) in the liver. It is a part of a group of conditions called nonalcoholic fatty liver disease. NASH, when left untreated, can progress to advanced scarring (called ‘cirrhosis’), liver failure, liver cancer, and liver-related death.
Despite the seriousness of this disease, especially when advanced scarring is present, there are no approved medicines available. Current treatment is supportive, concentrating on managing complications, and as a last resort, liver transplantation.
Obeticholic acid (OCA) is a modified bile acid and farnesoid X receptor agonist, meaning that it has effects on bile acids and fat and sugar metabolism. It is possible that OCA can affect the formation of scarring in the liver and have some protective ability against bile acid-caused liver cell damage.
This study included:
• Three groups of participants which were randomly assigned to one of the following groups:
o 1) a once daily dose of 10 mg OCA
o 2) a once daily dose of 10 mg OCA increasing to 25 mg depending on the results of laboratory testing
o 3) a placebo taken once dailyThis study had 3 parts: a 12-week screening part, a 12- or 18-month double-blind placebo controlled part, and a 12-month OCA extension (open-label) part.
• In the double-blind part of the study, neither the participants nor the study doctor could choose the medicine the participants received. Participants agreed to be put into a medicine group by chance (“randomized”). This is like flipping a coin or drawing numbers out of a hat.
o This was done to make sure the study results were not influenced in any way.
• Open-label means that both the participants and the study doctors knew what medicine the participants received.
The main purpose of this study was to assess the effect of OCA compared to placebo.
The main questions researchers asked in this study were:
1. What effect does OCA have on liver scarring compared to placebo?WHO WAS IN THE TRIAL?
Men and women aged 18 years and over who had a confirmed diagnosis of NASH, diagnosed by a liver biopsy not more than 12 months before the study start, and with a fibrosis score of 4 based upon the NASH Clinical Research Network (CRN) scoring system, were invited to participate.
• The NASH CRN score is a standardized score based on three areas. When you add up the total, if you have a score of five or more, it is “definite NASH”:
o How fatty the liver is (steatosis) is scored from 0 to 3
o The amount of inflammation (lobular inflammation) is scored from 0 to 3
o The amount of swelling the liver cells have (hepatoellular ballooning) is scored from 0 to 2
919 participants were enrolled in the study and 916 participants received 1 or more doses of OCA or placebo.
314 (34%) were men and 605 (66%) were women; the average age of participants was 60 years.
Participants were assigned to each treatment by chance (“randomized”):
• Group 1: 296 participants were assigned to get 10 mg of OCA once daily.
• Group 2: 310 participants were assigned to get 10 mg of OCA with an option to increase to 25 mg after 3 months.
• Group 3: 313 participants were assigned to get placebo once daily.After 12 or 18 months (depending on the version of the protocol which was in use at the time the participant started the study), participants were able to enter an open label extension. Participants stayed on the dose of study medication they took in the double-blind part. Those participants who were assigned to placebo during the double-blind part changed to OCA.
• 190 participants changed from placebo to 10 mg of OCA once daily.
• 41 participants changed from placebo to 10 mg of OCA and increased to 25 mg.HOW LONG DID THE STUDY LAST?
Participants were supposed to be treated until the end of the open label extension. Of the 919 participants who entered the study, 255 participants did not go on to the open label extension; of these, 150 participants discontinued the study medicine early and 105 participants completed the double-blind part but did not go on to the open-label extension. A total of 555 participants completed both the double-blind phase and the open label extension.
The entire trial lasted for 5 years but participants were only in the trial for about 2 years. The study began 30 August 2017 and ended 08 September 2022.WHAT WERE THE STUDY RESULTS?
The results showed there was no difference between the participants treated with OCA or placebo.
This does not mean that everyone in this study had these results, and individual results could be better or worse than the overall group. Other studies may have different results. These are just some of the main results of this study. More results may be available at the websites listed at the end of this summary.WHAT SIDE EFFECTS DID PARTICIPANTS HAVE DURING THE STUDY?
Side effects are unwanted health problems that happen during the study. They may or may not be related to the medicine tested in the study. Side effects are also known as “adverse events.” Not all the participants in this study had side effects.
857 participants (94%) had one or more side effect during the study. The table below shows the most common side effects that happened during the study.Some side effects are considered “serious,” which means they may be life threatening, cause long term problems, or cause a person to need hospital care.
13 participants (1%) had one or more serious side effects during the study. Most of the serious side effects were reported only once, though atrial fibrillation was reported by two patients in the double-blind part; cholecystitis (inflammation of the gall bladder) was reported by 3 participants in the open-label part.
7 (1%) participants died during the double-blind part of the study; 4 participants were in the placebo group and 3 were in the OCA 10 mg group. None of the deaths were considered to be due to the study medication. No participants died in the open-label part.
This report only shows the most frequently reported side effects and serious side effects that happened during the study. Information about other side effects may be available at the websites listed at the end of this summary.REC name
North East - Tyne & Wear South Research Ethics Committee
REC reference
18/NE/0142
Date of REC Opinion
23 Jul 2018
REC opinion
Further Information Favourable Opinion