Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial
Article in the Lancet Gastroenterology & Hepatology (2019) Stefan Traussnigg et al.
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article, click here.
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article, click here.
New treatment option for nonalcoholic fatty liver disease
Article on: medicalxpress.com. 29 July 2019 by Medical University of Vienna.
Abstract below written by Prof. Joost Hoekstra.
Stefan Traussnigg et al.
Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial, The Lancet Gastroenterology & Hepatology (2019).
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article: click here.
Abstract below written by Prof. Joost Hoekstra.
Stefan Traussnigg et al.
Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial, The Lancet Gastroenterology & Hepatology (2019).
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article: click here.
Obesity and Liver Disease: The New Era of Liver Transplantation
Article in: Hepatology. Journal of the American College of Cardiology. 13 July 2019 B. Jorge A. Marrero.
Abstract below written by Prof. Joost Hoekstra.
In this editorial Marrero emphasizes that NAFLD is now the most common chronic liver disease in many developed countries. And further on that according to the relevant scientific registry of transplant recipients (SRTR), hepatitis C (HCV) is no longer the most common indication for a liver transplant. Nowadays the leading indication has become “other/unknown etiology”, which probably means NAFLD.
But what is the best management of the 2019 NAFLD-and-obesity candidate of liver transplantation? That remains undefined. Probably not weight loss, for which it seems too late. Bariatric surgery has been performed prior to transplantation, but the number of reported patients is too small for a conclusion. And what effect has the degree of obesity on the success rate of liver transplantation? It appears that in obese patients a Body Mass Index (BMI) of <40 kg/m2 does not influence the overall or graft survival after liver transplantation compared to lean individuals. However, a BMI of > 40 kg/m2 is associated with a reduced overall or graft survival. Therefore, the American Association for Study of Liver Diseases has determined a BMI of > 40 kg/m2 as a relative contraindication for liver transplantation.
Marrero further emphasizes the new role of the hepatologist of today: his role shifts from infectious disease to metabolic disease. He will become a member of the team of endocrinologists, psychologists, dieticians, health- and lifestyle advisers, endoscopists and surgeons to work on both the preventive and therapeutic interventions in NAFLD and NASH
Link to website: click here.
Abstract below written by Prof. Joost Hoekstra.
In this editorial Marrero emphasizes that NAFLD is now the most common chronic liver disease in many developed countries. And further on that according to the relevant scientific registry of transplant recipients (SRTR), hepatitis C (HCV) is no longer the most common indication for a liver transplant. Nowadays the leading indication has become “other/unknown etiology”, which probably means NAFLD.
But what is the best management of the 2019 NAFLD-and-obesity candidate of liver transplantation? That remains undefined. Probably not weight loss, for which it seems too late. Bariatric surgery has been performed prior to transplantation, but the number of reported patients is too small for a conclusion. And what effect has the degree of obesity on the success rate of liver transplantation? It appears that in obese patients a Body Mass Index (BMI) of <40 kg/m2 does not influence the overall or graft survival after liver transplantation compared to lean individuals. However, a BMI of > 40 kg/m2 is associated with a reduced overall or graft survival. Therefore, the American Association for Study of Liver Diseases has determined a BMI of > 40 kg/m2 as a relative contraindication for liver transplantation.
Marrero further emphasizes the new role of the hepatologist of today: his role shifts from infectious disease to metabolic disease. He will become a member of the team of endocrinologists, psychologists, dieticians, health- and lifestyle advisers, endoscopists and surgeons to work on both the preventive and therapeutic interventions in NAFLD and NASH
Link to website: click here.
nonalcoholic fatty liver disease and the heart
jacc state-of-the-art review
Article in: Hepatology. Journal of the American College of Cardiology. 2019 By the American College of Cardiolofy Foundation - Published by Elsavier.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 Medical Knowledge MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 Medical Knowledge MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
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NASH Clinical movie
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June 2019
Every now and then an article on NASH is published that is really relevant for both clinicians and scientists. To our opinion that is the case with the April 2019 article in Hepatology: Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations from the Liver Forum, by Cheung et al*. So, when can we speak of a real improvement due to treatment in NASH patients? If you happen to have some 5 minutes left, have a look at this NASH Clinical video! We think it is worthwhile. * Journal of the American College of Cardiology. 2019 By the American College of Cardiolofy Foundation - Published by Elsavier. |
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First Drug for Fatty Liver Disease May Hit Shelves by Year’s End
May 2019 - Source: Medicalpress.com
High rates of liver disease progression and mortality observed in patients with NAFLD/NASH
Two independent national studies have reported high rates of liver disease progression and mortality among patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The studies reported today at The International Liver Congress 2019 in Vienna, Austria, found that within 10 years of diagnosis, up to 11% of patients with NAFLD/NASH had progressed to advanced liver diseases (defined as NAFLD/NASH patients with compensated cirrhosis [CC], decompensated cirrhosis [DCC], liver transplant [LT] or hepatocellular carcinoma [HCC]), and up to 27% of patients with NAFLD/NASH and CC had developed liver decompensation.
Read the full article here.
High rates of liver disease progression and mortality observed in patients with NAFLD/NASH
Two independent national studies have reported high rates of liver disease progression and mortality among patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The studies reported today at The International Liver Congress 2019 in Vienna, Austria, found that within 10 years of diagnosis, up to 11% of patients with NAFLD/NASH had progressed to advanced liver diseases (defined as NAFLD/NASH patients with compensated cirrhosis [CC], decompensated cirrhosis [DCC], liver transplant [LT] or hepatocellular carcinoma [HCC]), and up to 27% of patients with NAFLD/NASH and CC had developed liver decompensation.
Read the full article here.
First Drug for Fatty Liver Disease May Hit Shelves by Year’s End
March 2019 - Source: Healthline.com
Intercept Pharmaceuticals officials say their new drug performed well in a phase III clinical trial, so they’ll ask for FDA approval.
Nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease, is a tough condition to live with — namely because there are no drugs on the market designed to treat it.
That could soon change, however, if a pharmaceutical company is able to push a new drug onto pharmacy shelves.
Intercept Pharmaceuticals, a company known for developing treatments for chronic liver diseases, announced earlier this month that they’ve successfully completed a phase III trial of the REGENERATE study.
The goal? Creating a drug designed to treat NASH as well as liver fibrosis.
Intercept Pharmaceuticals officials say their new drug performed well in a phase III clinical trial, so they’ll ask for FDA approval.
Nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease, is a tough condition to live with — namely because there are no drugs on the market designed to treat it.
That could soon change, however, if a pharmaceutical company is able to push a new drug onto pharmacy shelves.
Intercept Pharmaceuticals, a company known for developing treatments for chronic liver diseases, announced earlier this month that they’ve successfully completed a phase III trial of the REGENERATE study.
The goal? Creating a drug designed to treat NASH as well as liver fibrosis.
Some impressions of the 2nd Global NASH Congress 2019 in London UK, 25-26 February
19 March 2019 - Prof. dr. Joost Hoekstra
The large inter-individual difference in progression of NAFLD to NASH was stressed by Cynthia Moylan, Duke University, Texas, USA. How to explain this difference? A help in predicting disease progression appeared to be the determining of DNA methylation, as was performed in a child cohort. More research, however, is necessary before a firm prediction model can be established.
Several speakers discussed the potential benefit of weight loss in NAFLD patients. Does losing weight really help? Unfortunately, no new data were available. So, we have to stick to reviews such as the one by Romero-Gomez (J.Hepatol. 2017) concluding that a 10 % weight reduction can induce a resolution of NASH and probably diminish fibrosis with one stage. The Mediterranean diet including reduced carbohydrate intake (especially sugars) and increased intake of monounsaturated fat and omega-3 fatty acids might reduce liver fat even without weight loss. All speakers stressed to enormous burden for the patients to considerably lose weight.
Is there a causal relation between NASH and cardiovascular disease (CVD) or is there only an association? Quite a relevant question. This topic was discussed in depth in a round table. It was concluded that we cannot establish causality unless there are results of well designed, prospective long lasting trials with effective drugs.
The large inter-individual difference in progression of NAFLD to NASH was stressed by Cynthia Moylan, Duke University, Texas, USA. How to explain this difference? A help in predicting disease progression appeared to be the determining of DNA methylation, as was performed in a child cohort. More research, however, is necessary before a firm prediction model can be established.
Several speakers discussed the potential benefit of weight loss in NAFLD patients. Does losing weight really help? Unfortunately, no new data were available. So, we have to stick to reviews such as the one by Romero-Gomez (J.Hepatol. 2017) concluding that a 10 % weight reduction can induce a resolution of NASH and probably diminish fibrosis with one stage. The Mediterranean diet including reduced carbohydrate intake (especially sugars) and increased intake of monounsaturated fat and omega-3 fatty acids might reduce liver fat even without weight loss. All speakers stressed to enormous burden for the patients to considerably lose weight.
Is there a causal relation between NASH and cardiovascular disease (CVD) or is there only an association? Quite a relevant question. This topic was discussed in depth in a round table. It was concluded that we cannot establish causality unless there are results of well designed, prospective long lasting trials with effective drugs.
