Project acronym: LIVERHOPE

Project full title: "Simvastatin and Rifaximin as new therapy for patients with decompensated cirrhosis"

Clinical trials

The standard of care for patients with cirrhosis is based on individual management of each of the complications of the disease. Currently, there is not an overall therapeutic strategy based on a mechanistic approach to complications of cirrhosis. The current standard of care is clearly insufficient because mortality rate is still very high unless a liver transplant is performed. In this regard, it should be emphasized that liver transplant is a solution for only a small proportion of patients. In fact, the average number of transplants performed per year in Europe is of approximately 5,500 while the estimated number of deaths due to cirrhosis per year in Europe is of 170,000. Therefore, the majority of patients cannot be treated with liver transplantation, mainly because of insufficient organ donors.

There is an unmet need of a therapeutic strategy that targets the main pathopysiological mechanisms of disease progression in cirrhosis that could have a significant impact on disease burden of individual patients, families, and health care systems. With LIVERHOPE we will address this need, proposing and validating a novel therapeutic strategy based on a combination of rifaximin and simvastatin. This approach goes beyond the current state-of-the art which is based on symptomatic treatment and management of complications (see Fig. 1).

figure 1

Figure 1. Target of the Liverhope therapeutic approach in comparison to the current available medical therapy for patients with decompensated cirrhosis. Current therapeutic approach is based on the management of each individual complication of the disease, without effect on the pathophysiology of the disease. The innovative approach of the Liverhope project is to target the pathobiology of disease progression to avoid development of complications, including ACLF, and improve prognosis.

LIVERHOPE envisions performing a double-blind clinical trial of safety and tolerability, followed by a double-blind clinical trial assessing efficacy.

References
EASL Clinical Guidelines, J Hepatol 2010


Safety and Tolerability study
Phase II, multicenter, double-blind, placebo-controlled trial to evaluate the safety and tolerability of oral administration of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis. The study is conducted in 9 European tertiary care hospitals with extensive clinical and research experience in liver diseases (regular and intensive care units, outpatient clinics, transplant units and research laboratories). Three cohorts of 15 patients each are randomized 1:1:1 to receive 3-month treatment with:

- Standard medical therapy (SMT) plus oral simvastatin 20mg/day and oral rifaximin    400mg/8h.
- SMT plus oral oral simvastatin 40mg/day and oral rifaximin 400mg/8h.
- SMT plus placebo of simvastatin and placebo of rifaximin. Randomization is stratified    according to Child Pugh class (B vs C).


Efficacy Study
This is a phase 2, randomized, double-blind, placebo-controlled study aimed at assessing the effect of oral administration of simvastatin plus rifaximin for a 12 month-period to reduce ACLF development in patients with decompensated cirrhosis. The study is performed in 9 European referral hospitals with extensive clinical and research experience in liver diseases. Sample size: It has been assumed that 30% of the patients discharged from hospital after an acute decompensation of cirrhosis will develop ACLF during 1-year period of follow-up. Assuming a 5% two-sided type-I error and 80% power, a sample size of 120 patients per arm would allow to detect a 15% reduction in the primary end-point.

Two hundred-and-forty patients with decompensated cirrhosis (Child-Pugh B/C) will be randomized 1:1 into two cohorts to receive:
- Standard medical therapy (SMT) plus oral simvastatin and oral rifaximin during 12 months.
- SMT plus placebo of both drugs during 12 months.
Randomization will be stratified according to Child Pugh class (B vs C).
As in the safety and tolerability study, the new formulation of rifaximin, rifaximin-EIR (400mg/8h) will be used. The dose of simvastatin used in this trial (40mg/day or 20mg/day) will be decided according to the results of the safety study. In conditions of similar safety, the highest dose will be used. After the end of treatment there will be a 3-month follow-up period.


Identification of biomarkers of treatment response and disease progression by systems biology approach
The goal of using this systems biology approach in the clinical trials is to make the predictive and personalized medicine a reality in the patient care. LIVERHOPE will take advantage of the data compiled in the proposed clinical trials to further explore previously identified biomarkers of cirrhosis progression and identify new prognostic biomarkers (markers able to predict the evolution of the disease) and predictive biomarkers (markers able to predict the response to the drug combination treatment) to benefit further implementation of the therapy.

The analysis of the clinical trial results with Anaxomics’ systems biology approach will complement the conventional statistical analysis through individually modelling the patients and then segmenting them according to qualitative or quantitative characteristics that are somehow related to the mechanism of the treatment under study. The biomolecular data analysis of the individual clinical trial data in the context of network-models will allow establishing individual plausible mechanism of action (MoA). The patients are then placed into clusters based on their unique molecular profile and roughly the same physiological response, providing a mechanistic rationale for clinical observations (Fig 2).

figure 2

Figure 2. Identification of patient subgroups
on a mechanistic basis

 

 

 

 

By analysing the mechanism of action (MoA) of the drug in each of the subpopulations defined in the previous step, Anaxomics can identify certain measurable traits (biomarkers) that are specifically associated with the therapeutic response to the drug only in a population subset. These biomarkers have been claimed to be superior to descriptive biomarkers for a number of reasons: they are more likely to be specific to the disease, they enable differentiation of distinct subtypes of the same disease, allowing for target treatment, and they can reveal if the therapy is efficacious at targeting the cause of a disease, rather than simply improving the symptoms. It is also important to note that the mechanistic biomarkers discovered in this project will rather be a combination of biomarkers than a single one. It is now well-accepted that for the diagnosis and prognosis of most of the complex diseases a single biomarker is not useful, but rather a combination of those. For example, recently, it has been described that a combination of 10 protein biomarkers can identify, with an accuracy of 87%, patients with a mild cognitive impairment that will progress to Alzheimer’s disease.

Reference
Mapstone M, Nat Med 2014