The aim of this study is to assess the efficacy of oral administration of simvastatin plus rifaximin in patients with decompensated cirrhosis to halt the progression of the disease as assessed by prevention of the development of ACLF.
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
Efficacy of treatment in halting the progression of decompensated cirrhosis as
assessed by time to first ACLF during the treatment period, defined according
to criteria by Moreau et al., Gastroenterology 2013.
Secondary outcome
1. Time to transplant-free survival. Incidences at 1 month, 3 months, 6 months,
9 months and 12 months.
2. Severity of ACLF assessed by number and types of organ failures at baseline,
1 month, 3 months, 6 months, 9 months and 12 months.
3. Frequency of hospital admissions due to complications of cirrhosis assessed
at baseline, 1 month, 3 months, 6 months, 9 months and 12
months.
4. Development/worsening of individual complications of cirrhosis (ascites,
acute kidney injury, gastrointestinal bleeding, hepatic
encephalopathy (HE), bacterial infections) assessed at baseline, 1 month, 3
months, 6 months, 9 months and 12 months, defined as:
4.1. ASCITES:
1A. Development of new-onset ascites or worsening of preexisting ascites as
estimated by:
• Percentage of patients with new-onset ascites.
• Percentage of patients presenting worsening of ascites,
defined as:
o Increased diuretic dosage, as indicated by a double of the diuretic dose
received at entry into the study, to a dose of at least spironolactone 200
mg/day (or its equivalent dose in other aldosterone antagonists) and furosemide
20 mg/day (or its equivalent dose in other loop diuretics).
o Need for large-volume paracentesis in patients who had never been treated
with this procedure.
1B. Number of episodes of ascites per patient requiring large volume
paracentesis during the treatment period.
4.2. ACUTE KIDNEY INJURY:
• Percentage of patients developing episodes of renal function impairment
defined by AKI criteria, following criteria of the *EASL Clinical Practice
Guidelines for the management of patients with decompensated cirrhosis*.
• Percentage of patients developing episodes of renal function impairment
defined by AKI criteria as AKI IB or higher.
• Number of episodes of AKI1B or higher per patient.
• Number of patients developing severe AKI requiring RRT.
• Number of patients developing AKI-HRS syndrome (following the criteria
established by the *EASL Clinical Practice Guidelines for the management of
patients with decompensated cirrhosis*).
4.3. GASTROINTESTINAL BLEEDING:
• Percentage of patients developing the first episode of bleeding by esophageal
or gastric varices and number of bleeding episodes per patient during the
treatment period.
• Percentage of patients developing recurrent variceal bleeding, defined as a
second episode of variceal bleeding.
• Complications of variceal bleeding, defined as the percentage of patients
requiring:
o blood transfusion during an episode of variceal bleeding.
o alternative treatment to variceal bleeding (transjugular intrahepatic
portosystemic shunt).
4.4. HEPATIC ENCEPHALOPATHY
• Percentage of patients developing the first episode of HE, grade II or
greater, and number of episodes of HE (grade II or greater) per patient during
the follow-up period.
• Percentage of patients developing recurrent HE, defined as two episodes of HE
grade II or greater within a period of 6 months during the study period.
• Percentage of patients developing severe HE, defined of grade III or IV HE.
• Percentage of patients without minimal HE, as estimated by PHES
questionnaire, at entry into the study, who developed minimal HE at some point
during follow-up.
4.5. BACTERIAL INFECTIONS
• Percentage of patients developing bacterial infections during the study
follow up period, defined by one of the following:
o Presence of infection confirmed by positive cultures and need for antibiotic
treatment.
o Clinical suspicion of infection based on clinical and analytical data
requiring empirical antibiotic therapy.
• Number of infections per patient during the study period requiring hospital
admission.
• Percentage of patients developing septic shock.
5. Changes from baseline in systemic inflammatory response, evaluated by
measurement in a large array of plasma cytokine levels including, but not
limited to TNFα, IL-6, IL8, IL-10, IL-1β, IFN-*, G-CSF, VCAM, VEGF, as well as
an oxidized form of albumin, human nonmercaptalbumin-2 (HNA2), dimethylarginine
(ADMA and SDMA) at 3 months, 6 months and 12 months.
6. Changes from baseline in plasma biomarkers (FABP4, sCD-163), von Willebrand
factor (vWF) and urine biomarkers (NGAL, MCP-1 and
albumin) at 3 months, 6 months and 12 months.
7. Changes from baseline in vasoactive hormones: plasma renin concentration,
plasma norepinephrine and plasma copeptin at 3
months, 6 months and 12 months.
8. Changes from baseline in blood levels of bacterial DNA or bacterial products
at 3 months, 6 months and 12 months.
9. To evaluate changes in microbiome composition by analysis of microbial genes
and signature in patients included in the study at baseline, 3 months, 6 months
and 12 months.
10. Changes from baseline in liver function, evaluated by MELD score, CLIF-AD
score and Child Pugh Score (see Appendix 4) at 1 month, 3
months, 6 months, 9 months and 12 months.
11. Quality of life, functional assessment and in Minimal Hepatic
Encephalopathy during treatment period, as assessed by CLDQ (Chronic Liver
Disease Questionnaire), Liver Frailty Index and PHES (Psychometric Hepatic
Encephalopathy Score) questionnaires at baseline, 1 month, 3 months, 6 months,
9 months and 12 months.
12. Changes from baseline in stigmatization in patients with decompensated
cirrhosis as assessed by a previously validated specific questionnaire (see
appendix 8) at 3 months, 6 months and 12 months.
13. Appearance of muscle toxicity at baseline, 1 month, 3 months, 6 months, 9
months and 12 months as defined using a specific statinassociated
myopathy questionnaire.
14. Assessment of genetic polymorphisms of statins membrane transporter OATP1B1
in all the patients included in the study.
15. To evaluate liver or muscle toxicity as defined by analytical changes from
baseline in liver or muscle enzymes (transaminases, alkaline
phosphatase and creatine kinase) at 1 month, 3 months, 6 months, 9 months and
12 months.
16. Proportion of patients and severity of treatment-related adverse events
during the study period.
17. Annualized incidence of ACLF.
18. Time to overall and time to disease related survival.
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 fora high number of
hospitalizations which are very costly and represent a high
burden tor health systems.
The standard of care for patients with cirrhosis is based on the management of
each complication individually. 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 efficacy of oral administration of
simvastatin plus rifaximin in patients with decompensated cirrhosis to halt the
progression of the disease as assessed by prevention of the development of
ACLF.
Study design
This is a phase 3, multicentre, double-blind, placebo-controlled trial to
evaluate the efficacy of oral administration of simvastatin plus rifaximin in
patients with decompensated cirrhosis for prevention of disease progression and
ACLF development.
European tertiary care centres will participate into the clinical trial.
Two cohorts of 120 patients with decompensated cirrhosis will be randomized to
receive:
1) Oral Simvastatin 20mg/day and oral Rifaximin 400 mg/8h.
2) Placebo of simvastatin and placebo of rifaximin.
Patients will receive treatment during 12 months.
Intervention
Oral Simvastatin 20mg/day and oral Rifaximin 400 mg/8h OR placebo of
simvastatin 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 Il-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
Rifaximin is an antibiotic with braad-spectrum antimicrobial activity with
minimal (<0.4-1 %) intestinal absorption, that eliminates intestinal flora
non-selectively lt is a well-tolerated drug with no interactions with ether
drugs, in healthy an also in cirrhotic subjects.
There are two studies that have investigated the eflicacy 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 treatrnent in the specific population of patients
with cirrhosis and hepatic encephalopathy.
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 eflicacy study.
As a preliminary result of the Liverhope Safety Trial, it was concluded that
the dose of Simvastatin 40mg per day in patients with decompensated cirrhosis
was associated with an increased risk of liver and muscle toxicity. On the
other hand, Simvastatin 20mg per day plus Rifaximin is not associated to a
higher risk of liver or muscle toxicity in patients with decompensated
cirrhosis.
These results suggested that Simvastatin 20mg/day should be preferred to 40
mg/day in studies investigating the effects of statins in patients with
decompensated cirrhosis. As a result of this first safety trial, the dose of
Simvastatin 20mg per day was established for
the Liverhope Efficacy Trial.
Roselló 149-153
Barcelona 08036
ES
Roselló 149-153
Barcelona 08036
ES
Listed location countries
Age
Inclusion criteria
Patients included into the study must meet all the following criteria:
1. Age >= 18 years old.
2. Cirrhosis defined by standard clinical criteria, ultrasonographic findings
and/or histology. Cirrhosis of any aetiology may be included. However, patients
with cirrhosis due to autoimmune hepatitis must be on stable corticosteroid
dose for >=3-month period before study inclusion.
3. Child-Pugh B patients or Child-Pugh C patients (up to 12 points).
4. Women of child-bearing potential must have a negative pregnancy test in
serum before the inclusion in the study and agree to use highly effective
contraceptive methods during the study. Highly effective contraceptive methods
will include: intrauterine device, bilateral tubal occlusion, vasectomized
partner and sexual abstinence. (only if refraining from heterosexual
intercourse during the period of twelve months of duration of the study and
extended to 30 days after the end of the study treatment) Hormonal
contraceptive methods will be avoided due to the risk of adverse events and
impairment of liver function.
Exclusion criteria
1. Patients on treatment with statins or rifaximin up to one month before study
inclusion.
2. Patients with contraindications for statins or rifaximin therapy.
3. Known hypersensitivity to simvastatin or rifaximin (or rifamycin
derivatives).
4. Patients with CK elevation of 50% or more above the upper limit of normal at
study inclusion.
5. Patients on treatment with potent inhibitors of CYP3A4 enzyme (see section
5.2: Concomitant, nonpermitted and permitted medication).
6. Patients on treatment with drugs with potential interactions with
simvastatin (see section 5.2: Concomitant, nonpermitted and permitted
medication).
7. Patients with previous history of myopathy.
8. Patients with previous history of intestinal obstruction or those who are at
increased risk of this complication.
9. Patients with ACLF according to the criteria published by Moreau et al. (see
appendix 2).
10. Serum creatinine >=2 mg/dL (176.8 µmol/L).
11. Serum bilirubin>5 mg/dL (85.5 µmol/L).
12. INR >=2.5. Patients under anticoagulant therapy will be excluded if the INR
values are >= 3.5
13. Bacterial infection within 10 days before study inclusion.
14. Gastrointestinal bleeding within 10 days before study inclusion.
15. Current overt hepatic encephalopathy, defined as grade II-IV hepatic
encephalopathy according to the New-Haven classification.
16. Patients with active hepatocellular carcinoma or history of hepatocellular
carcinoma that is in remission for less than six months for uninodular HCC or
for less than 12 months for multinodular HCC within Milan criteria.
17. Patients on antiviral therapy for HCV or those who have received it within
the last 6 months.
18. Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey*s
Discriminant function >= 32 and/or ABIC score > 6.7).
19. Patients with active alcohol consumption of more than 21 units per week.
20. HIV infection.
21. Patients with a history of significant extra hepatic 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.
22. Patients with current extra hepatic malignancies including solid tumours
and hematologic disorders.
23. Pregnancy or breastfeeding.
24. Patients included in other clinical trials in the month before inclusion.
25. 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.
26. Refusal to give informed consent.
27. Creatinine clearance < 30 ml/min
28. Patients with cirrhosis due to cholestatic liver disease can only be
included in the study if they present clinical decompensation of cirrhosis
(i.e. ascites).
29. Patients with previous organ transplantation.
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 | EUCTR2018-001698-25-NL |
| ClinicalTrials.gov | NCT03780673 |
| CCMO | NL66707.018.18 |