Simvastatin Plus Rifaximin in Decompensated Cirrhosis (LIVERHOPE)

• ClinicalTrials.gov Identifier: NCT03150459
• Recruitment Status: Completed
• First Posted: May 12, 2017
• Last Update Posted: March 28, 2019
• Sponsor: Judit Pich
• Information provided by (Responsible Party): Judit Pich, Institut d'Investigacions Biomèdiques August Pi i Sunyer

Study Description

Brief Summary:

The main purpose of this study is to investigate whether the combination of two different drugs, simvastatin and rifaximin, is safe in the treatment of patients with decompensated cirrhosis.

The secondary purpose is to see if this combination results in an improvement in inflammation markers in patients with cirrhosis and in an improvement in analytic parameters of progression of liver disease.

Condition or disease	Intervention/treatment	Phase
Cirrhoses, Liver	Drug: Simvastatin 20 mg; Drug: Simvastatin 40mg; Drug: Rifaximin 400 mg; Other: Placebo of Simvastatin; Other: Placebo of Rifaximin	Phase 2

Detailed Description:

Cirrhosis is the final stage of liver diseases, and currently, there is no effective treatment, with liver transplantation being the only curative solution in selected patients. As the number of donor organs for liver transplantation is limited and criteria for transplantation are strict, the current management of cirrhosis consists of treating its complications.

However, there is no effective therapy that prevents or cures the disease itself.

Rifaximin is an antibiotic that acts in the gastrointestinal tract. It is poorly absorbed to the general circulation and has low toxicity and good tolerability. Itis currently approved for use in patients with cirrhosis to prevent recurrent hepatic encephalopathy. Rifaximin decreases the transit of bacteria and bacterial products from the gut to the general circulation, preventing the chronic inflammation that takes place in cirrhotic patients.

Recent investigations have shown that simvastatin, a drug which is widely used to treat high cholesterol levels for the prevention of cardiovascular diseases, may have beneficial effects in patients with cirrhosis by preventing the progression of the disease and its complications. Although in the past decades there was a concern about its use in patients with liver disease due to its rare adverse effects (liver and muscle toxicity), recent clinical trials have shown that it can be safely used in patients with cirrhosis.

LIVERHOPE_SAFETY clinical trial have been designed to investigate whether the combination of these two drugs is safe in patients with cirrhosis, and also if it has potential beneficial effects in decreasing inflammation and improving analytical markers of progression of liver disease.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase II, multicenter, double-blind placebo controlled, randomized clinical trial
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: As the trial is blinded neither the participants or the researchers will know which group the participants has been allocated to. In order to maintain the blind participants will take two tablets once daily for simvastatin. Group one will receive one 20mg tablet of simvastatin and one placebo table, group two will receive two 20 mg tablets of simvastatin and group three will receive two placebo tablets.
• Primary Purpose: Treatment
• Official Title: Safety and Tolerability of the Combination of Simvastatin Plus Rifaximin in Patients With Decompensated Cirrhosis: a Multicenter, Double-blind, Placebo Controlled Randomized Clinical Trial.
• Actual Study Start Date: July 26, 2017
• Actual Primary Completion Date: March 12, 2018
• Actual Study Completion Date: March 12, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Simvastatin 20 mg + Rifaximin 400 mg (group 1); Simvastatin 20 mg/day and rifaximin 400 mg/8 hours orally for 12 weeks	Drug: Simvastatin 20 mg; Simvastatin 20 mg/day for 12 weeks (Group 1); Drug: Rifaximin 400 mg; Rifaximin 400 mg/8 hours for 12 weeks (Group 1 and 2)
Experimental: Simvastatin 40 mg + Rifaximin 400 mg (group 2); Simvastatin 40 mg/day and rifaximin 400 mg/8 hours orally for 12 weeks	Drug: Simvastatin 40mg; Simvastatin 40 mg/day for 12 weeks (Group 2); Drug: Rifaximin 400 mg; Rifaximin 400 mg/8 hours for 12 weeks (Group 1 and 2)
Placebo Comparator: Placebo of Simvastatin + Placebo of Rifaximin (group 3); Placebo simvastatin and placebo rifaximin orally for 12 weeks	Other: Placebo of Simvastatin; Placebo of Simvastatin for 12 weeks (Group 3); Other: Placebo of Rifaximin; Placebo of Rifaximin for 12 weeks (Group 3)

Outcome Measures

Primary Outcome Measures :

1. Change from baseline in transaminases during the treatment period, to evaluate treatment-related toxicity. [ Time Frame: Week 12 ]
   This quantitative analysis will consist of liver toxicity assessed by the development of liver injury defined as 3-fold increase in serum transaminases to a final value at least 3 times the upper normal limit
2. Change from baseline in alkaline phosphatase during the treatment period, to evaluate treatment-related toxicity. [ Time Frame: Week 12 ]
   This quantitative analysis will consist of liver toxicity assessed by the development of liver injury defined as 2-fold increase in serum levels of alkaline phosphatase with respect to baseline value to a final value at least 2 times the upper normal limit
3. Change from baseline in creatine kinase during the treatment period, to evaluate treatment-related toxicity. [ Time Frame: Week 12 ]
   This quantitative analysis will consist of muscle toxicity defined as 5-fold increase in creatine kinase (CK) levels during treatment

Secondary Outcome Measures :

1. Appearance of muscle toxicity at weeks 2, 4, 6, 8, 10 and 12 as defined using a specific statin-associated myopathy questionnaire [ Time Frame: Weeks 2, 4, 6, 8, 10 and 12 ]
2. Changes from baseline in plasma renin concentration levels at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
3. Changes from baseline in serum aldosterone levels at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
4. Changes from baseline in plasma norepinephrine levels at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
5. Changes from baseline in plasma copeptin levels at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
6. Changes from baseline of plasma cytokine levels including, but not limited to, VCAM-1 and ICAM-1 [ Time Frame: Weeks 2, 4, 8 and 12 ]
7. Changes from baseline of plasma cytokine levels including, but not limited to, VEGF-A [ Time Frame: Weeks 2, 4, 8 and 12 ]
8. Changes from baseline of plasma cytokine levels including, but not limited to, Fractalkine [ Time Frame: Weeks 2, 4, 8 and 12 ]
9. Changes from baseline of plasma cytokine levels including, but not limited to, MIP-1α [ Time Frame: Weeks 2, 4, 8 and 12 ]
10. Changes from baseline of plasma cytokine levels including, but not limited to, Eotaxin [ Time Frame: Weeks 2, 4, 8 and 12 ]
11. Changes from baseline of plasma cytokine levels including, but not limited to, IP-10 [ Time Frame: Weeks 2, 4, 8 and 12 ]
12. Changes from baseline of plasma cytokine levels including, but not limited to, RANTES [ Time Frame: Weeks 2, 4, 8 and 12 ]
13. Changes from baseline of plasma cytokine levels including, but not limited to, GM-CSF [ Time Frame: Weeks 2, 4, 8 and 12 ]
14. Changes from baseline of plasma cytokine levels including, but not limited to, IL-1β, IL-2, IL-6 and IL-8 [ Time Frame: Weeks 2, 4, 8 and 12 ]
15. Changes from baseline of plasma cytokine levels including, but not limited to, MCP-1 [ Time Frame: Weeks 2, 4, 8 and 12 ]
16. Changes from baseline of plasma cytokine levels including, but not limited to, oxidized form of albumin [ Time Frame: Weeks 2, 4, 8 and 12 ]
17. Changes from baseline of plasma cytokine levels including, but not limited to, HNA2 [ Time Frame: Weeks 2, 4, 8 and 12 ]
18. Changes from baseline in plasma biomarker FABP4 at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
19. Changes from baseline in plasma biomarker CD-163 at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
20. Changes from baseline in urine biomarker NGAL at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
21. Changes from baseline in urine biomarker IL-18 at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
22. Changes from baseline in urine biomarker MCP-1 at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
23. Changes from baseline in urine biomarker osteopontin at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
24. Changes from baseline in urine biomarker albumin at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
25. Changes in blood levels of bacterial DNA or bacterial products at weeks 2, 4, 8 and 12. [ Time Frame: Weeks 2, 4, 8 and 12 ]
26. Number of patients with genetic polymorphisms of statins membrane transporter OATPB1 in patients developing treatment-related toxicity (defined as the primary endpoint of the study). [ Time Frame: Week 12 ]
27. Proportion of patients with treatment-related serious adverse events during the study period. [ Time Frame: Week 12 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age ≥ 18 years old.
• 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.
• Child Pugh B/C patients (from 7 to 12 points).
• 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:

• Patients on treatment with statins or rifaximin one month before study inclusion.
• Patients on the waiting list for liver transplantation.
• Patients with acute-on-chronic liver failure according to the criteria published by Moreau et al.
• Serum creatinine ≥2 mg/dL.
• Serum bilirubin>5 mg/dL.
• INR ≥2.5.
• Patients with CK elevation of 50% or more above the upper limit of normal at study inclusion.
• Bacterial infection within 15 days before study inclusion.
• Gastrointestinal bleeding within 15 days before study inclusion.
• Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy.
• HIV infection.
• Hepatocellular carcinoma outside Milan criteria, defined as a single nodule ≤5 cm or a maximum of 3 nodules with none >3 cm.
• Patients on antiviral therapy for HCV or those who have received it within the last 6 months.
• Patients with previous history of myopathy.
• Patients on treatment with potent inhibitors of CYP3A4 enzyme (See section 5.2: Concomitant, nonpermitted and permitted medication)
• Patients on treatment with drugs with potential interactions with simvastatin
• 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.
• Patients with current extrahepatic malignancies including solid tumours and hematologic disorders.
• Patients with previous history or increased risk of intestinal obstruction.
• Pregnancy or breastfeeding.
• Patients included in other clinical trials in the previous month.
• Patients with active alcohol consumption of more than 3 units per day.
• 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.
• Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey's Discriminant function ≥ 32 and/or ABIC score > 6.7).
• Refusal to give informed consent.
• Patients with contraindications for statins or rifaximin.
• Known hypersensitivity to rifaxamin (or rifamycin derivatives) or to simvastatin.

Contacts and Locations

Locations

France

Beajuon Hospital

Clichy, Paris, France, 92110

Germany

Universitatsklinikum Bonn

Bonn, Germany, 53127

Italy

Bologna University Hospital

Bologna, Italy

Padova University Hospital

Padova, Italy, 35128

San Giovanni Battista Hospital

Torino, Italy, 10129

Netherlands

Academic Medical Centre

Amsterdam, Netherlands, 1105 AZ

Spain

Hospital Universitari Vall d'Hebrón

Barcelona, Spain, 08035

Hospital Clínic de Barcelona

Barcelona, Spain, 08036

United Kingdom

Royal Free Hospital

London, United Kingdom, NW3 2QG

Sponsors and Collaborators

Judit Pich

Investigators

• Study Chair: Pere Ginès, MD; Hospital Clinic of Barcelona

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pose E, Napoleone L, Amin A, Campion D, Jimenez C, Piano S, Roux O, Uschner FE, de Wit K, Zaccherini G, Alessandria C, Angeli P, Bernardi M, Beuers U, Caraceni P, Durand F, Mookerjee RP, Trebicka J, Vargas V, Andrade RJ, Carol M, Pich J, Ferrero J, Domenech G, Llopis M, Torres F, Kamath PS, Abraldes JG, Sola E, Gines P. 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 Jan;5(1):31-41. doi: 10.1016/S2468-1253(19)30320-6. Epub 2019 Oct 10.

• Responsible Party: Judit Pich, Clinical Research Manager. CTU Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer
• ClinicalTrials.gov Identifier: NCT03150459
• Other Study ID Numbers: LIVERHOPE_SAFETY; 2016-004499-23 ( EudraCT Number )
• First Posted: May 12, 2017
• Last Update Posted: March 28, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Cirrhosis; Fibrosis; Pathologic Processes; Liver Diseases; Digestive System Diseases; Rifaximin; Simvastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Anti-Infective Agents; Gastrointestinal Agents