Simvastatin Plus Rifaximin in Decompensated Cirrhosis

NCT03150459 | Completed Phase 2 DMC

• 2 other identifiers: LIVERHOPE_SAFETY2016-004499-23
• Study Type: interventional
• Target: 44
• Locations: 6 countries
• Sites: 9

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.

Conditions

Cirrhoses, Liver

Outcome Measures

Primary Outcomes (3)

• 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

  Week 12

• 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

  Week 12

• 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

  Week 12

Secondary Outcomes (27)

• Appearance of muscle toxicity at weeks 2, 4, 6, 8, 10 and 12 as defined using a specific statin-associated myopathy questionnaire

  Weeks 2, 4, 6, 8, 10 and 12

• Changes from baseline in plasma renin concentration levels at weeks 2, 4, 8 and 12.

  Weeks 2, 4, 8 and 12

• Changes from baseline in serum aldosterone levels at weeks 2, 4, 8 and 12.

  Weeks 2, 4, 8 and 12

• Changes from baseline in plasma norepinephrine levels at weeks 2, 4, 8 and 12.

  Weeks 2, 4, 8 and 12

• Changes from baseline in plasma copeptin levels at weeks 2, 4, 8 and 12.

  Weeks 2, 4, 8 and 12

Study Arms (3)

Simvastatin 20 mg + Rifaximin 400 mg (group 1)

EXPERIMENTAL

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

Drug: Simvastatin 20 mg; Drug: Rifaximin 400 mg

Simvastatin 40 mg + Rifaximin 400 mg (group 2)

EXPERIMENTAL

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

Drug: Simvastatin 40mg; Drug: Rifaximin 400 mg

Placebo of Simvastatin + Placebo of Rifaximin (group 3)

PLACEBO COMPARATOR

Placebo simvastatin and placebo rifaximin orally for 12 weeks

Other: Placebo of Simvastatin; Other: Placebo of Rifaximin

Interventions

Simvastatin 20 mg DRUG

Simvastatin 20 mg/day for 12 weeks (Group 1)

Simvastatin 20 mg + Rifaximin 400 mg (group 1)

Simvastatin 40mg DRUG

Simvastatin 40 mg/day for 12 weeks (Group 2)

Simvastatin 40 mg + Rifaximin 400 mg (group 2)

Rifaximin 400 mg DRUG

Rifaximin 400 mg/8 hours for 12 weeks (Group 1 and 2)

Simvastatin 20 mg + Rifaximin 400 mg (group 1); Simvastatin 40 mg + Rifaximin 400 mg (group 2)

Placebo of Simvastatin OTHER

Placebo of Simvastatin for 12 weeks (Group 3)

Placebo of Simvastatin + Placebo of Rifaximin (group 3)

Placebo of Rifaximin OTHER

Placebo of Rifaximin for 12 weeks (Group 3)

Placebo of Simvastatin + Placebo of Rifaximin (group 3)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Judit Pich: lead

Study Sites (9)

Beajuon Hospital

Clichy, Paris, 92110, France

Location

Universitatsklinikum Bonn

Bonn, 53127, Germany

Location

Bologna University Hospital

Bologna, Italy

Location

Padova University Hospital

Padua, 35128, Italy

Location

San Giovanni Battista Hospital

Torino, 10129, Italy

Location

Academic Medical Centre

Amsterdam, 1105 AZ, Netherlands

Location

Hospital Universitari Vall d'Hebrón

Barcelona, 08035, Spain

Location

Hospital Clínic de Barcelona

Barcelona, 08036, Spain

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 31607677 DERIVED

MeSH Terms

Interventions

Simvastatin; Rifaximin

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds

Study Officials

• Pere Ginès, MD

  Hospital Clinic of Barcelona

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Research Manager. CTU Clínic

Model Details: Phase II, multicenter, double-blind placebo controlled, randomized clinical trial

Study Record Dates

• First Submitted: May 3, 2017
• First Posted: May 12, 2017
• Study Start: July 26, 2017
• Primary Completion: March 12, 2018
• Study Completion: March 12, 2018
• Last Updated: March 28, 2019

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); FR (1); DE (1); ES (2); GB (1); IT (3)