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Simvastatin Plus Rifaximin in Decompensated Cirrhosis (LIVERHOPE)

Primary Purpose

Cirrhoses, Liver

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Simvastatin 20 mg
Simvastatin 40mg
Rifaximin 400 mg
Placebo of Simvastatin
Placebo of Rifaximin
Sponsored by
Judit Pich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cirrhoses, Liver

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Beajuon Hospital
  • Universitatsklinikum Bonn
  • Bologna University Hospital
  • Padova University Hospital
  • San Giovanni Battista Hospital
  • Academic Medical Centre
  • Hospital Universitari Vall d'Hebrón
  • Hospital Clínic de Barcelona
  • Royal Free Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Simvastatin 20 mg + Rifaximin 400 mg (group 1)

Simvastatin 40 mg + Rifaximin 400 mg (group 2)

Placebo of Simvastatin + Placebo of Rifaximin (group 3)

Arm Description

Simvastatin 20 mg/day and rifaximin 400 mg/8 hours orally for 12 weeks

Simvastatin 40 mg/day and rifaximin 400 mg/8 hours orally for 12 weeks

Placebo simvastatin and placebo rifaximin orally for 12 weeks

Outcomes

Primary Outcome Measures

Change from baseline in transaminases during the treatment period, to evaluate treatment-related toxicity.
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
Change from baseline in alkaline phosphatase during the treatment period, to evaluate treatment-related toxicity.
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
Change from baseline in creatine kinase during the treatment period, to evaluate treatment-related toxicity.
This quantitative analysis will consist of muscle toxicity defined as 5-fold increase in creatine kinase (CK) levels during treatment

Secondary Outcome Measures

Appearance of muscle toxicity at weeks 2, 4, 6, 8, 10 and 12 as defined using a specific statin-associated myopathy questionnaire
Changes from baseline in plasma renin concentration levels at weeks 2, 4, 8 and 12.
Changes from baseline in serum aldosterone levels at weeks 2, 4, 8 and 12.
Changes from baseline in plasma norepinephrine levels at weeks 2, 4, 8 and 12.
Changes from baseline in plasma copeptin levels at weeks 2, 4, 8 and 12.
Changes from baseline of plasma cytokine levels including, but not limited to, VCAM-1 and ICAM-1
Changes from baseline of plasma cytokine levels including, but not limited to, VEGF-A
Changes from baseline of plasma cytokine levels including, but not limited to, Fractalkine
Changes from baseline of plasma cytokine levels including, but not limited to, MIP-1α
Changes from baseline of plasma cytokine levels including, but not limited to, Eotaxin
Changes from baseline of plasma cytokine levels including, but not limited to, IP-10
Changes from baseline of plasma cytokine levels including, but not limited to, RANTES
Changes from baseline of plasma cytokine levels including, but not limited to, GM-CSF
Changes from baseline of plasma cytokine levels including, but not limited to, IL-1β, IL-2, IL-6 and IL-8
Changes from baseline of plasma cytokine levels including, but not limited to, MCP-1
Changes from baseline of plasma cytokine levels including, but not limited to, oxidized form of albumin
Changes from baseline of plasma cytokine levels including, but not limited to, HNA2
Changes from baseline in plasma biomarker FABP4 at weeks 2, 4, 8 and 12.
Changes from baseline in plasma biomarker CD-163 at weeks 2, 4, 8 and 12.
Changes from baseline in urine biomarker NGAL at weeks 2, 4, 8 and 12.
Changes from baseline in urine biomarker IL-18 at weeks 2, 4, 8 and 12.
Changes from baseline in urine biomarker MCP-1 at weeks 2, 4, 8 and 12.
Changes from baseline in urine biomarker osteopontin at weeks 2, 4, 8 and 12.
Changes from baseline in urine biomarker 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.
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).
Proportion of patients with treatment-related serious adverse events during the study period.

Full Information

First Posted
May 3, 2017
Last Updated
March 26, 2019
Sponsor
Judit Pich
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1. Study Identification

Unique Protocol Identification Number
NCT03150459
Brief Title
Simvastatin Plus Rifaximin in Decompensated Cirrhosis
Acronym
LIVERHOPE
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.
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
July 26, 2017 (Actual)
Primary Completion Date
March 12, 2018 (Actual)
Study Completion Date
March 12, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Judit Pich

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhoses, Liver

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Phase II, multicenter, double-blind placebo controlled, randomized clinical trial
Masking
ParticipantCare ProviderInvestigator
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.
Allocation
Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Simvastatin 20 mg + Rifaximin 400 mg (group 1)
Arm Type
Experimental
Arm Description
Simvastatin 20 mg/day and rifaximin 400 mg/8 hours orally for 12 weeks
Arm Title
Simvastatin 40 mg + Rifaximin 400 mg (group 2)
Arm Type
Experimental
Arm Description
Simvastatin 40 mg/day and rifaximin 400 mg/8 hours orally for 12 weeks
Arm Title
Placebo of Simvastatin + Placebo of Rifaximin (group 3)
Arm Type
Placebo Comparator
Arm Description
Placebo simvastatin and placebo rifaximin orally for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Simvastatin 20 mg
Intervention Description
Simvastatin 20 mg/day for 12 weeks (Group 1)
Intervention Type
Drug
Intervention Name(s)
Simvastatin 40mg
Intervention Description
Simvastatin 40 mg/day for 12 weeks (Group 2)
Intervention Type
Drug
Intervention Name(s)
Rifaximin 400 mg
Intervention Description
Rifaximin 400 mg/8 hours for 12 weeks (Group 1 and 2)
Intervention Type
Other
Intervention Name(s)
Placebo of Simvastatin
Intervention Description
Placebo of Simvastatin for 12 weeks (Group 3)
Intervention Type
Other
Intervention Name(s)
Placebo of Rifaximin
Intervention Description
Placebo of Rifaximin for 12 weeks (Group 3)
Primary Outcome Measure Information:
Title
Change from baseline in transaminases during the treatment period, to evaluate treatment-related toxicity.
Description
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
Time Frame
Week 12
Title
Change from baseline in alkaline phosphatase during the treatment period, to evaluate treatment-related toxicity.
Description
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
Time Frame
Week 12
Title
Change from baseline in creatine kinase during the treatment period, to evaluate treatment-related toxicity.
Description
This quantitative analysis will consist of muscle toxicity defined as 5-fold increase in creatine kinase (CK) levels during treatment
Time Frame
Week 12
Secondary Outcome Measure Information:
Title
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
Title
Changes from baseline in plasma renin concentration levels at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in serum aldosterone levels at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in plasma norepinephrine levels at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in plasma copeptin levels at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
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
Title
Changes from baseline of plasma cytokine levels including, but not limited to, VEGF-A
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, Fractalkine
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, MIP-1α
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, Eotaxin
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, IP-10
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, RANTES
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, GM-CSF
Time Frame
Weeks 2, 4, 8 and 12
Title
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
Title
Changes from baseline of plasma cytokine levels including, but not limited to, MCP-1
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, oxidized form of albumin
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline of plasma cytokine levels including, but not limited to, HNA2
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in plasma biomarker FABP4 at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in plasma biomarker CD-163 at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in urine biomarker NGAL at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in urine biomarker IL-18 at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in urine biomarker MCP-1 at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in urine biomarker osteopontin at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
Changes from baseline in urine biomarker albumin at weeks 2, 4, 8 and 12.
Time Frame
Weeks 2, 4, 8 and 12
Title
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
Title
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
Title
Proportion of patients with treatment-related serious adverse events during the study period.
Time Frame
Week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pere Ginès, MD
Organizational Affiliation
Hospital Clinic of Barcelona
Official's Role
Study Chair
Facility Information:
Facility Name
Beajuon Hospital
City
Clichy
State/Province
Paris
ZIP/Postal Code
92110
Country
France
Facility Name
Universitatsklinikum Bonn
City
Bonn
ZIP/Postal Code
53127
Country
Germany
Facility Name
Bologna University Hospital
City
Bologna
Country
Italy
Facility Name
Padova University Hospital
City
Padova
ZIP/Postal Code
35128
Country
Italy
Facility Name
San Giovanni Battista Hospital
City
Torino
ZIP/Postal Code
10129
Country
Italy
Facility Name
Academic Medical Centre
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Hospital Universitari Vall d'Hebrón
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Royal Free Hospital
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31607677
Citation
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.
Results Reference
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Simvastatin Plus Rifaximin in Decompensated Cirrhosis

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