ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    Interventional Studies | LIVERHOPE | France
Previous Study | Return to List | Next Study

Simvastatin Plus Rifaximin in Decompensated Cirrhosis (LIVERHOPE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03150459
Recruitment Status : Active, not recruiting
First Posted : May 12, 2017
Last Update Posted : March 7, 2018
Sponsor:
Information provided by (Responsible Party):
Judit Pich, Institut d'Investigacions Biomèdiques August Pi i Sunyer

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 Type : Interventional
Estimated Enrollment : 45 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
Estimated Primary Completion Date : March 2018
Estimated Study Completion Date : March 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cirrhosis
U.S. FDA Resources

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)



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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03150459


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 Clínic de Barcelona

Responsible Party: Judit Pich, Clinical Research Manager. CTU Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer
ClinicalTrials.gov Identifier: NCT03150459     History of Changes
Other Study ID Numbers: LIVERHOPE_SAFETY
2016-004499-23 ( EudraCT Number )
First Posted: May 12, 2017    Key Record Dates
Last Update Posted: March 7, 2018
Last Verified: March 2018
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:
Fibrosis
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Simvastatin
Rifaximin
Rifamycins
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Anti-Infective Agents
Gastrointestinal Agents
Nucleic Acid Synthesis Inhibitors
Anti-Bacterial Agents