Periodic Reporting for period 3 - LIVERHOPE (SIMVASTATIN AND RIFAXIMIN AS NEW THERAPY FOR PATIENTS WITH DECOMPENSATED CIRRHOSIS)
Período documentado: 2020-01-01 hasta 2021-06-30
What is the problem/issue being addressed?
The problem addressed by the LIVERHOPE project is that of chronic liver diseases, in particular, liver cirrhosis. Chronic liver diseases are diseases caused by inflammation of the liver that after a long period, more than 10 years in average, may lead to liver cirrhosis. Liver cirrhosis is a disease that is irreversible and usually progressive that causes the impairment of major functions of the liver responsible for development of many complications that usually lead to death unless liver transplantation is performed. Liver cirrhosis can also lead to development of liver cancer. There are many factors that may cause inflammation of the liver leading to liver cirrhosis, particularly excessive alcohol consumption, metabolic conditions, particularly obesity and diabetes mellitus, and chronic infections by hepatitis viruses, mainly hepatitis B and C, among others.
Why is important for the society?
Chronic liver diseases are very common worldwide and their frequency is increasing in many areas of the world. Although the frequency of hepatitis B or C infection is decreasing in many countries due to effective preventive measures, including vaccination for hepatitis C, and existence of effective drugs, the frequency of other causes of chronic liver diseases, particularly those related to alcohol consumption or metabolic factors (obesity, diabetes) is increasing in many areas of the world. Therefore, it is not surprising that the frequency of liver cirrhosis remains very high in most countries. Moreover, it is important to consider that liver cirrhosis is a major cause of death worldwide and a major cause of impaired quality of life for patients and their relatives. Liver cirrhosis is also responsible for a high number of hospitalizations and therefore the economic burden of the disease for the society is huge. Finally, it is important to note that there is no effective drug therapy to prevent progression of cirrhosis when the disease has developed. Treatment is therefore based on symptomatic management of complications and transplantation of the liver in patients who are candidates to this procedure. It is important to remind that liver transplantation is only applicable to a small proportion of patients due to shortage of donors or contraindications to the procedure. Therefore, there is need for alternative therapies for patients with liver cirrhosis that can halt liver disease and prevent progression of cirrhosis and death.
What are the overall objectives?
The LIVERHOPE project represents an international European effort to investigate the safety and efficacy of a new therapy for patients with liver cirrhosis based on the combination of simvastatin, a drug that can reduce the inflammation associated with liver disease, and rifaximin, a drug that modulates the gut microbiome and may reduce the toxic products arising from bacteria of the intestine, that are known to contribute to cirrhosis progression.
Other objectives of the LIVERHOPE project are to identify biomarkers of treatment and disease progression that can be used in clinical practice, disseminate the results of the project so that the information reaches the patient population who can benefit from the results of the study, to increase awareness about chronic liver diseases in European countries so that preventive measures can be undertaken to decrease the burden of the disease, and to reduce the social stigmatization of patients with chronic liver diseases.
The problem addressed by the LIVERHOPE project is that of chronic liver diseases, in particular, liver cirrhosis. Chronic liver diseases are diseases caused by inflammation of the liver that after a long period, more than 10 years in average, may lead to liver cirrhosis. Liver cirrhosis is a disease that is irreversible and usually progressive that causes the impairment of major functions of the liver responsible for development of many complications that usually lead to death unless liver transplantation is performed. Liver cirrhosis can also lead to development of liver cancer. There are many factors that may cause inflammation of the liver leading to liver cirrhosis, particularly excessive alcohol consumption, metabolic conditions, particularly obesity and diabetes mellitus, and chronic infections by hepatitis viruses, mainly hepatitis B and C, among others.
Why is important for the society?
Chronic liver diseases are very common worldwide and their frequency is increasing in many areas of the world. Although the frequency of hepatitis B or C infection is decreasing in many countries due to effective preventive measures, including vaccination for hepatitis C, and existence of effective drugs, the frequency of other causes of chronic liver diseases, particularly those related to alcohol consumption or metabolic factors (obesity, diabetes) is increasing in many areas of the world. Therefore, it is not surprising that the frequency of liver cirrhosis remains very high in most countries. Moreover, it is important to consider that liver cirrhosis is a major cause of death worldwide and a major cause of impaired quality of life for patients and their relatives. Liver cirrhosis is also responsible for a high number of hospitalizations and therefore the economic burden of the disease for the society is huge. Finally, it is important to note that there is no effective drug therapy to prevent progression of cirrhosis when the disease has developed. Treatment is therefore based on symptomatic management of complications and transplantation of the liver in patients who are candidates to this procedure. It is important to remind that liver transplantation is only applicable to a small proportion of patients due to shortage of donors or contraindications to the procedure. Therefore, there is need for alternative therapies for patients with liver cirrhosis that can halt liver disease and prevent progression of cirrhosis and death.
What are the overall objectives?
The LIVERHOPE project represents an international European effort to investigate the safety and efficacy of a new therapy for patients with liver cirrhosis based on the combination of simvastatin, a drug that can reduce the inflammation associated with liver disease, and rifaximin, a drug that modulates the gut microbiome and may reduce the toxic products arising from bacteria of the intestine, that are known to contribute to cirrhosis progression.
Other objectives of the LIVERHOPE project are to identify biomarkers of treatment and disease progression that can be used in clinical practice, disseminate the results of the project so that the information reaches the patient population who can benefit from the results of the study, to increase awareness about chronic liver diseases in European countries so that preventive measures can be undertaken to decrease the burden of the disease, and to reduce the social stigmatization of patients with chronic liver diseases.
The LIVERHOPE project includes two consecutive clinical trials. The first one is the LIVERHOPE Safety Trial. This trial had already been completed during the last report period, and during this period we have performed the final analysis of the results. The results were published published Pose E, Napoleone L, Amin A, et al. Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol 2020; 5: 31-41). In addition, a commentary about the study was published in the same issue of the journal: Simon TG. When less is more: dosing simvastatin in decompensated cirrhosis. Lancet Gastroenterol Hepatol 2020; 5: 3-5. Results of this first trial provided us with the safety information required to select the dose of simvastatin 20mg/day to be used in the Efficacy trial.
The EFFICACY TRIAL has to date 239 patients included. It is predicted that recruitment will end October/ November 2021. This will be dependent upon the restrictions imposed by each institution due to the COVID.19 situation.
Besides, activities are carried out for the scientific dissemination and for raising awareness about chronic liver diseases in the population
The EFFICACY TRIAL has to date 239 patients included. It is predicted that recruitment will end October/ November 2021. This will be dependent upon the restrictions imposed by each institution due to the COVID.19 situation.
Besides, activities are carried out for the scientific dissemination and for raising awareness about chronic liver diseases in the population
Currently, the treatment of patients with decompensated cirrhosis is based on management of individual complications that patients may develop during the course of their disease. In general, patients develop a large number of different complications that require frequent hospitalizations and a large array of interventions, including ICU stays and liver transplantation. Mortality is very high. The LiverHope project is unique in that it represents the first approach to develop a new combination therapy able to prevent the progression of the disease. Therefore, if the results are positive this may represent a treatment to stabilize the disease and prevent it from progressing. This will have a huge impact in the natural history of the disease by decreasing mortality and improving quality of life of patients and their families, and will reduce costs for health systems by decreasing the number of hospitalizations and need for therapeutic interventions, including liver transplantation.