Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
Stephen A Harrison, Mustafa R Bashir, Cynthia D Guy, Rong Zhou, Cynthia A Moylan, Juan P Frias, Naim Alkhouri, Meena B Bansal, Seth Baum, Brent A Neuschwander-Tetri, Rebecca Taub, Sam E Moussa
Lancet 2019; 394: 2012–24
Thyroid hormone receptor β (THR-β) has been recognized as an important target for the regulation of fat metabolism in the liver. Since it is highly expressed in the liver, compounds binding to this receptor are tissue specific. Harrison and colleagues carried out a randomised, double-blind, placebo-controlled clinical trial using Resmetirom (MGL-3196) which has been developed by Madrigal Pharmaceuticals for the treatment of NASH. In this elegant study, 125 patients were followed for 36 weeks. The Resmetirom group consisted of 84 subjects of whom 74 completed the 36 weeks follow up and underwent a liver biopsy. The placebo group consisted of 41 subjects; all completed the 36 weeks follow up and a liver biopsy was performed in 34.
Lancet 2019; 394: 2012–24
Thyroid hormone receptor β (THR-β) has been recognized as an important target for the regulation of fat metabolism in the liver. Since it is highly expressed in the liver, compounds binding to this receptor are tissue specific. Harrison and colleagues carried out a randomised, double-blind, placebo-controlled clinical trial using Resmetirom (MGL-3196) which has been developed by Madrigal Pharmaceuticals for the treatment of NASH. In this elegant study, 125 patients were followed for 36 weeks. The Resmetirom group consisted of 84 subjects of whom 74 completed the 36 weeks follow up and underwent a liver biopsy. The placebo group consisted of 41 subjects; all completed the 36 weeks follow up and a liver biopsy was performed in 34.
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To be eligible to participate, patients had to have biopsy confirmed NASH. It is of interest to realize that 25 centres in the USA participated and that 348 subjects were screened, so 1 out of 3 screened subjects was included. For a NASH trial, this seems an excellent outcome. Change in MRI-proton density fat fraction (MRI-PDFF) was the primary endpoint. The Resmetirom treated subjects showed a 3-fold higher reduction in hepatic fat content than the placebo group at week 12. These differences persisted at week 36.
This study is very promising and although the numbers are relatively small and the follow up short, the data support further development of compounds targeting the THR-β. Moreover, very convincing and positive results on plasma lipids were found. So, not only liver fat content was reduced but the pro-atherogenic lipid profile was also modulated by this intervention. This paper opens new ways to treat patients with NASH, but also patients in whom overproduction of atherogenic hepatic lipoproteins plays a role. One could think of subjects with familial combined hyperlipidemia in whom VLDL overproduction is one of the basic metabolic disturbances. Find the full article here. |
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(A) MRI-PDFF images with percentage fat fraction at baseline, week 12, and week 36. (B) Relative (median) fat reduction at week 12 and week 36 in placebo (n=38) and resmetirom (n=78). (C) Absolute (mean) fat reduction
at week 12 and week 36 in placebo (n=34) and resmetirom (n=74). Week 36 resmetirom 60 mg n=36 and resmetirom 80 mg n=33 (post-hoc analysis; appendix p 8). MRI-PDFF=MRI-proton density fat fraction. Source: Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The lancet. |
NON-alcoholic fatty liver disease, a new and growing risk indicator for cardiovascular disease
It is well established that NAFLD and NASH are closely associated to an increased of cardiovascular disease. The accompanying paper in the European Journal of Preventive Cardiology by Janssen and colleagues provides an excellent review of current knowledge in the field. The paper underscores the importance of early identification of these conditions and more intensive evaluation and treatment of risk factors for the prevention of cardiovascular complications. While a specific drug treatment for NAFLD and NASH is not yet available, cardiovascular risk management is indicated and should be implemented. For this purpose, close collaboration between cardiologists, hepatologists and internists-diabetologists is necessary.
Find the full article here.
Find the full article here.
Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease
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Traditionally NAFLD and NASH have been associated with an increased risk for cardiovascular disease, based on several propective studies elegantly presented in the publication by Targher et al in the New England Journal of Medicine in 2010 (1).
The mechanism proposed was chronic inflammation originating in the expanded visceral adipose tissue. Recently, Alexander and Sattar and co-workers have published data concerning a matched cohort study of 18 million European adults of whom 120.795 had the diagnosis of NAFLD or NASH (2). In this real world primary care record study the authors did not find evidence for an increased risk of acute myocardial infarction or stroke, after correction for classical risk factors. The authors did not have access to all risk factors like BMI and HDLC, for instance, which may have influenced the outcome. While the data seem robust, confounding factors could not be fully excluded. This study underscores the need for improving adequate cardiovascular risk management for traditional risk factors in patients with NAFLD and NASH to decrease the cardiovascular risk in these patients. The authors conclude that this should be carried out in a similar way as in the general population. |
- Targher G, Day ChP, Bonora E. Risk of Cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363: 1341-50
- Alexander M, Loomis AK, van der Lei A, et al. Non-alcohoic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million Euiropean adults. BMJ 2019; 367: 15367
PHASE 3 Drug pipelines in the treatment of NASH
NASH is becoming the leading cause of liver transplantation. There is an urgent need for treatment modalities that will lead to regression of the inflammation and fibrosis so characteristic of NASH. While lifestyle interventions and weight less are effective, patients have great troubles adhering in the long term to these recommendations and usually weight increases during time, leading to NASH progression and ultimately liver cirrhosis and cardiovascular disease. Therefore, pharmacotherapies are being investigated to treat NASH. In the accompanying paper Sumida and coworkers elegantly review the drugs that are being developed for this purpose and which are now in phase 3 trials. Five of these drugs (obeticholic acid, elafibranor, selonsertib, cenicriviroc and resmetirom) have a great potential to be admitted to clinical practice and the authors even foresee that the first drug may enter the market already in 2021.
This paper provides a comprehensive review of the actual development in drug therapy for NASH.
Read the full article here.
This paper provides a comprehensive review of the actual development in drug therapy for NASH.
Read the full article here.
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.
| defining_improvement_in_nonalcoholic_steatohepatitis_for_treatment_trial_endpoints_recommendations_from_the_liver_forum.pdf |
International NASH Day -
June 12
NASH Clinical team is proud to join this initiative in raising awareness of this important health issue.
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.
