The aim of this study is to assess the safety and tolerability of oral administration of simvastatin plus rifaximin in patients with decompensated cirrhosis.
ID
Source
Brief title
Condition
- Other condition
- Hepatic and hepatobiliary disorders
Synonym
Health condition
Cirrose
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline in transaminases, alkaline phosphatase and creatine kinase
during the treatment period, to evaluate treatment-related toxicity.
Secondary outcome
- Appearance of muscle toxicity at weeks 2, 4, 6, 8, 10 and 12 as defined using
a specific statin-associated myopathy questionnaire (see appendix 2).
- Changes from baseline in plasma renin concentration, serum aldosterone,
plasma norepinephrine, and plasma copeptin levels at weeks 2, 4, 8 and 12.
- Changes from baseline in a large array of plasma cytokine levels including,
but not limited to, VCAM-1, VEGF-A, Fractalkine, MIP-1α, Eotaxin, IP-10,
RANTES, GM-CSF, IL-1β, IL-2, ICAM-1, MCP-1, L-6, and IL-8, as well as an
oxidized form of albumin, human nonmercaptalbumin-2 (HNA2) at weeks 2, 4, 8 and
12.
- Changes from baseline in plasma biomarkers FABP4 and CD-163 and urine
biomarkers NGAL, IL-18, MCP-1, osteopontin, and albumin at weeks 2, 4, 8 and 12.
- Changes in blood levels of bacterial DNA or bacterial products at weeks 2, 4,
8 and 12.
- Assessment of genetic polymorphisms of statins membrane transporter OATPB1 in
patients developing treatment-related toxicity (defined as the primary endpoint
of the study).
- Proportion of patients with treatment-related serious adverse events during
the study period.
Background summary
Chronic inflammatory diseases of the liver are very common worldwide. They may
occur either as a result of chronic viral infections, due to hepatitis B or C,
excessive alcohol consumption, non-alcoholic fatty liver disease (usually
associated with obesity and/or diabetes), autoimmune diseases or miscellaneous
conditions. The main risk of a chronic inflammatory reaction of the liver is
the development of liver cirrhosis. Cirrhosis increases markedly the risk of
carcinogenesis so that a significant proportion of patients develop primary
liver cell cancer, also known as hepatocellular carcinoma.
Because of its high frequency and high progression rate, liver cirrhosis is one
of the most common causes of death worldwide. This indicates that cirrhosis is
one of the chronic diseases with greatest impact in patients* life. In addition
to high mortality and impaired quality-of-life, cirrhosis is responsible for a
high number of hospitalizations which are very costly and represent a high
burden for health systems.
The standard of care for patients with cirrhosis is based on the management of
each complication individually (18,19). Currently, there is no an overall
therapeutic strategy based on a mechanistic approach to complications of
cirrhosis. Therefore, there is an unmet need in the management of patients with
cirrhosis of a therapy that could prevent the development of complications,
particularly ACLF, reduce hospital readmissions and overall cost, and improve
survival.
Study objective
The aim of this study is to assess the safety and tolerability of oral
administration of simvastatin plus rifaximin in patients with decompensated
cirrhosis.
Study design
This is a phase 2, multicenter, double-blind, placebo-controlled trial to
evaluate the safety and tolerability of oral administration of simvastatin plus
rifaximin in patients with decompensated cirrhosis.
Nine European tertiary care centers will participate into the clinical trial.
Three cohorts of 15 patients with descompensated 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 during 12 weeks.
Intervention
Simvastatin 20mg or 40mg tablets and placebo of simvastatin + Rifaximin 400mg
tablets and placebo of rifaximin
Study burden and risks
Statins are one of the most prescribed drugs in patients with hyperlipidemia
and for prevention of cardiovascular events, and they are in general well
tolerated. The relationship between statins and hepatotoxicity has been widely
studied in the general population. Safety of statins in patients with
decompensated cirrhosis has been assessed in two randomized, placebo-controlled
trials that evaluated the effect of statins on portal pressure and incidence of
gastrointestinal bleeding. These studies included patients from all Child-Pugh
classes (A, B and C), but excluded patients with severe liver failure defined
as prothrombin time <40%, serum bilirubin >5mg/dL, hepatic encephalopathy
grades II-IV, Child-Pugh score >12 or serum creatinine >1.5mg/dL. These studies
did not show significant elevations in serum transaminases levels in patients
treated with statins compared to the placebo group (39,41).
Rifaximin is an antibiotic with broad-spectrum antimicrobial activity with
minimal (<0.4-1%) intestinal absorption, that eliminates intestinal flora
non-selectively (39). It is a well-tolerated drug with no interactions with
other drugs, in healthy an also in cirrhotic subjects.
There are two studies that have investigated the efficacy of rifaximin for
prevention of recurrent hepatic encephalopathy in patients with cirrhosis and
have demonstrated that long treatment with rifaximin (6 and 24 months
respectively) is safe and well tolerated. Treatment with rifaximin did not
increase the frequency of adverse events or the risk of infections caused by
resistant bacteria compared to patients from the placebo group. Current
guidelines of the European Association for the Study of the Liver recommend the
use of rifaximin as a chronic treatment in the specific population of patients
with cirrhosis and hepatic encephalopathy (54).
Therefore, statins are safe drugs with a very low incidence of severe
hepatotoxicity in the general population and they appear to be safe also in
patients with chronic liver diseases. Rifaximin is also a safe antibiotic with
no evidence of an increase of infections caused by resistant-bacteria after
long-term use and a well- tolerated drug. Results from the present study will
bring us more detailed information on the safety of the combination of statins
plus rifaximin in patients with decompensated cirrhosis in order to have enough
safety information prior to the development of the efficacy study.
Rosello 149-153
Barcelona 08036
ES
Rosello 149-153
Barcelona 08036
ES
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years old.
2. Cirrhosis defined by standard clinical criteria and ultrasonographic findings and/or histology. Cirrhosis of any etiology may be included. Patients with cirrhosis of autoimmune etiology on treatment with corticosteroids must be on stable corticosteroid dose for >=3-month period before study inclusion.
3. Child Pugh B/C patients (from 7 to 12 points).
4. Women of child-bearing potential must have a negative pregnancy test in urine before the inclusion of the study and agree to use highly effective contraceptive methods (combined oral pill, injectable or implanted contraceptive, intrauterine device / intrauterine hormone-releasing system) during the study.
Exclusion criteria
1. Patients on treatment with statins or rifaximin one month before study inclusion.
2. Patients on the waiting list for liver transplantation.
3. Patients with acute-on-chronic liver failure according to the criteria published by Moreau et al. (see appendix 1)
4. Serum creatinine >=2 mg/dL.
5. Serum bilirubin>5 mg/dL.
6. INR >=2.5.
7. Patients with CK elevation of 50% or more above the upper limit of normal at study inclusion.
8. Bacterial infection within 15 days before study inclusion.
9. Gastrointestinal bleeding within 15 days before study inclusion.
10. Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy.
11. HIV infection.
12. Hepatocellular carcinoma outside Milan criteria, defined as a single nodule <=5 cm or a maximum of 3 nodules with none >3 cm.
13. Patients on antiviral therapy for HCV or those who have received it within the last 6 months.
14. Patients with previous history of myopathy.
15. Patients on treatment with potent inhibitors of CYP3A4 enzyme (See section 5.2: Concomitant, nonpermitted and permitted medication)
16. Patients on treatment with drugs with potential interactions with simvastatin (see section 5.2: Concomitant, nonpermitted and permitted medication)
17. Patients with a history of significant extrahepatic disease with impaired short-term prognosis, including congestive heart failure New York Heart Association Grade III/IV, COPD GOLD >2, chronic kidney disease with serum creatinine >2mg/dL or under renal replacement therapy.
18. Patients with current extrahepatic malignancies including solid tumours and hematologic disorders.
19. Patients with previous history or increased risk of intestinal obstruction.
20. Pregnancy or breastfeeding.
21. Patients included in other clinical trials in the previous month.
22. Patients with active alcohol consumption of more than 3 units per day.
23. Patients with mental incapacity, language barrier, bad social support or any other reason considered by the investigator precluding adequate understanding, cooperation or compliance in the study.
24. Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey*s Discriminant function >= 32 and/or ABIC score > 6.7).
25. Refusal to give informed consent.
26. Patients with contraindications for statins or rifaximin.
27. Known hypersensitivity to rifaxamin (or rifamycin derivatives) or to simvastatin.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004499-23-NL |
| CCMO | NL61020.018.17 |