ALMA MATER STUDIORUM - UNIVERSITÀ DI BOLOGNA

DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE

PROGETTO DI RICERCA

Simvastatin and Rifaximin as new therapy for patients with decompensated cirrhosis (LIVERHOPE)

Docente proponente: Prof. Paolo Caraceni
  1. BACKGROUND

Liver cirrhosis is a very common chronic disease and one of the leading causes of death in Europe. Moreover, cirrhosis has a marked impact on patients quality of life and represents a major burden for health systems. Treatment of cirrhosis is currently based on symptomatic management of complications and has not changed substantially in the last 20 years. There is an unmet need for therapies that target the pathobiology of cirrhosis.

In recent years, experimental as well as clinical evidence strongly support the concept that bacterial translocation and systemic inflammatory reaction play a key pathogenic role in disease progression and development of Acute-on-Chronic Liver Failure (ACLF). Therefore, a therapy that could prevent bacterial translocation and avoid an impending systemic inflammatory reaction may be effective in the prevention of complications and ACLF in patients with cirrhosis. This dual effect may be achieved with a drug effective in preventing bacterial translocation plus a drug with anti-inflammatory properties. The first effect may be achieved by rifaximin while the second may be achieved by statins.

Rifaximin is an oral antimicrobial agent with broad spectrum activity that is gut-selective and non-systemic. Experimental studies in rats with cirrhosis have shown that rifaximin reduces bacterial translocation. Moreover, rifaximin is effective and safe in reducing the recurrence of hepatic encephalopathy in patients with cirrhosis.

Statins, besides their role as cholesterol-reducing agents, have important anti-inflammatory properties. The main effects of statins include antinflamatory, antioxidant, inmunomodulatory, and antiapoptotic features, that have been collectively referred as pleiotropic effects.

  1. OBJECTIVES

The objective of the project is to evaluate a novel therapeutic strategy for patients with cirrhosis based on a combination of rifaximin and simvastatin, targeting the main pathophysiological mechanisms of disease progression, namely the impairment of the gut-liver axis and the persistent hepatic and systemic inflammatory response.

  1. METHODS

We will perform two randomized double-blind multicentre European trials to investigate safety, tolerability and efficacy of combination of simvastatin plus rifaximin in patients with decompensated cirrhosis.

3.1.Safety evaluation

Three cohorts of 15 patients with decompensated cirrhosis will be randomized to receive:

1) Oral simvastatin 20 mg/day and oral rifaximin 400 mg/8h

2) Oral simvastatin 40 mg/day and oral rifaximin 400 mg/8h

3) Placebo of simvastatin and placebo of rifaximin

Patients will receive treatment for 12 weeks.

Primary endpoint:

liver toxicity assessed by the development of liver injury defined as 3-fold increase in serum transaminases and/or 2-fold increase in serum levels of gamma-glutamyltransferase or alkaline phosphatase levels.

Secondary endpoints:

a) development of statin-associated myopathy defined as the incidence of muscle weakness or myalgia during treatment, assessed by a specific questionnaire, and/or changes in creatine kinase (CK) levels during treatment.

b) bioavailability of oral simvastatin in patients with decompensated cirrhosis assessed by measuring plasma levels of the drug during treatment.

c) absorption of rifaximin in patients with decompensated cirrhosis by measuring plasma levels of the drug during treatment.

d) treatment –related adverse events.

All Adverse Events, whether serious or non-serious, will be recorded until the Month 15 Follow-up visit.A Safety Monitoring Board (SMB) will review the safety and tolerability data (unblinded) from all patients from these three cohorts at the end of the study.

3.2. Efficacy evaluation

Patients with Child B/C cirrhosis will be eligible for inclusion into the study.

Patients (n=240) will be randomized 1:1 to two cohorts to receive over a 12-month period:

- Standard medical therapy + oral simvastatin + oral rifaximin;

- Standard medical therapy + placebo of simvastatin + placebo of rifaximin.

The dose of simvastatin used in this trial (40mg/day or 20mg/day) will be decided according to the results of the safety study.

Primary end-point:

efficacy of treatment in the prevention of ACLF.

Secondary end-points:

a) effect of treatment on survival (at 28 days, 90 days and 12 months);

b) effect of treatment on severity of ACLF;

c) effect of treatment on the frequency of hospital readmissions due to complications of cirrhosis;

d) effect of treatment on development of complications of cirrhosis during follow-up, defined as the incidence and severity of bacterial infections, hepatic encephalopathy, ascites, gastrointestinal bleeding or acute kidney injury;

e) effect of treatment on portal hypertension, assessed by hepatic venous pressure gradient (HVPG) at 6 months of treatment with respect to baseline;

f) effect of treatment on circulatory function assessed by plasma renin activity and plasma noradrenaline concentrations during treatment with respect to baseline values;

g) effect of treatment on systemic inflammatory response as assessed by changes in leukocyte count, C-reactive protein levels, and plasma cytokine levels at the end of treatment compared to baseline values;

h) effect of treatment on liver function as assessed by changes in serum bilirubin, serum albumin, INR and Child-Pugh and MELD scores during treatment;

i) Changes in quality of life during follow-up;

l) type and severity of adverse events during follow-up.

  1. EXPECTED RESULTS

The expected impact is to halt progression to acute-on-chronic liver failure, the main cause of death, to decrease complications of the disease, to reduce hospital readmissions, to improve cost-effectiveness of therapy. Moreover, the final aim is to improve patients quality-of-life and increase survival. Within the project we will also investigate biomarkers of response to treatment and disease progression that can be useful in clinical practice for improving the treatment of patients.

ALMA MATER STUDIORUM - UNIVERSITÀ DI BOLOGNA

DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE

PIANO DI FORMAZIONE CONNESSO AL

PROGETTO DI RICERCA

Simvastatin and Rifaximin as new therapy for patients with decompensated cirrhosis (LIVERHOPE)

Docente proponente: Prof. Paolo Caraceni

Il borsista svolgerà l’attività connessa al progetto presso l’U.O. Semeiotica Medica - Prof. Bernardi. In particolare, il borsista sarà inserito in uno studio multicentrico Europeofinalizzato a valutare la sicurezza ed efficacia di una nuova strategia terapeutica basata sulla combinazione di Rifaximina e Simvastatina nel paziente con cirrosi epatica non complicata. Tale studio ha ricevuto un finanziamento specifico da parte dell’Unione Europea e vede coinvolti 9diversi Centri.La fase di arruolamento inerente lo studio di safety è iniziato a settembre 2017, in tale fase è previsto l’arruolamento di 45 soggetti.Nella prima metà dell’anno 2018 avrà inoltre inizio la fase di arruolamento inerente lo studio di efficacy.

Il borsista sarà impegnato nell’attività di raccolta e revisione dei dati clinici relativi ai pazienti arruolati nel protocollo.

Il processo di formazione si svilupperà su diversi aspetti di natura etica, clinica e pratica connessi allo studio. In particolare le attività specifiche saranno:

  • Screening dei soggetti seguiti presso l’Ambulatorio Cirrosi/OLT dell’U.O. Semeiotica Medica e verifica della sussistenza dei criteri di inclusione/esclusione secondo le modalità specificate nel protocollo;
  • revisione dei dati clinici dei pazienti arruolati raccolti nell’ambito della visita di inclusione nello studio e nel corso delle visite di follow-up;
  • monitoraggio del livello di aderenza alla terapia prevista dal braccio sperimentale e del monitoraggio dell’andamento clinico dei pazienti, con particolare riguardo alla comparsa di eventi avversi alla terapia e complicanze della cirrosi;
  • gestione della biobanca dei campioni raccolti nell’ambito dello studio;
  • follow up dei pazienti che risultano già inclusi nello studio.

In tutte le fasi del progetto, il borsista sarà affiancato da personale medico strutturato che ne supervisionerà l’operato.

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