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    Summary
    EudraCT Number:2018-001698-25
    Sponsor's Protocol Code Number:LIVERHOPE_EFFICACY
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-08-01
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-001698-25
    A.3Full title of the trial
    Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development: a multicenter, double-blind, placebo controlled randomized clinical trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis
    A.4.1Sponsor's protocol code numberLIVERHOPE_EFFICACY
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIDIBAPS
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportH2020
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospital Clínic
    B.5.2Functional name of contact pointPere Ginés
    B.5.3 Address:
    B.5.3.1Street AddressVillarroel, 170
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08036
    B.5.3.4CountrySpain
    B.5.4Telephone number+349322754001713
    B.5.5Fax number+34932279877
    B.5.6E-mailpgines@clinic.cat
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRifaximin-EIR
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRIFAXIMIN
    D.3.9.1CAS number 80621-81-4
    D.3.9.4EV Substance CodeSUB10312MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Sivastin
    D.2.1.1.2Name of the Marketing Authorisation holderAlfasigma SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSivastin
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSIMVASTATIN
    D.3.9.2Current sponsor codeSIVASTIN
    D.3.9.4EV Substance CodeSUB10529MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with decompensated cirrhosis
    E.1.1.1Medical condition in easily understood language
    Patients with decompensated cirrhosis
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009209
    E.1.2Term Cirrhosis bilary
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of oral administration of Simvastatin plus Rifaximin in halting the progression of decompensated cirrhosis as assessed by the time to first incidence of ACLF during treatment period.
    E.2.2Secondary objectives of the trial
    -Time to transplant-free survival and incidence
    -Severity of ACLF
    -Frequency of hospital admissions due to complications of cirrhosis
    -Development/worsening of complications of cirrhosis
    -Systemic inflammatory response
    -Plasma and urine levels of biomarkers
    -Vasoactive hormones
    -Blood levels of bacterial DNA
    -Changes in fecal microbiome composition
    -Liver function, evaluated by MELD CLIF-C AD and Child-Pugh Scores
    -Quality of life, functional assessment and minimal hepatic encephalopathy, as assessed by CLDQ , Liver Frailty score and PHES questionnaires
    -Stigmatization in patients as assessed by a specific questionnaire
    -Appearance of muscle toxicity assessed by specific statin-associated myopathy questionnaire
    -Genetic polymorphisms of statins membrane transporter OATP1B1
    -Muscle or liver toxicity assessed by analytical changes
    -Type and severity of treatment-related adverse events
    -Annualized incidence of ACLF
    -Time to overall and time to disease related survival
    E.2.3Trial contains a sub-study No
    E.3Principal 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).
    ** Sexual abstinence should only be used as a contraceptive method if it is in line with the subjects’ usual and preferred lifestyle. Periodic abstinence
    (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
    E.4Principal exclusion criteria
    Potential participants who meet any of the following criteria will be excluded from participation in this study:
    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.
    E.5 End points
    E.5.1Primary end point(s)
    Time to ACLF in the two groups during follow-up..
    E.5.1.1Timepoint(s) of evaluation of this end point
    months 1, 3, 6, 9 and 12
    E.5.2Secondary end point(s)
    -Time to transplant-free survival. Incidences at 1 month, 3 months, 6 months, 9 months and 12 months
    -Severity of ACLF assessed by number and types of organ failures at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
    -Frequency of hospital admissions due to complications of cirrhosis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
    -Development/worsening of individual complications of cirrhosis (ascites, acute kidney injury, gastrointestinal bleeding, hepatic encephalopathy (HE), bacterial infections) assessed at baseline and at 1, 3, 6, 9 and 12 months
    -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-ɣ, G-CSF, VCAM, VEGF, as well as an oxidized form of albumin, human nonmercaptalbumin-2 (HNA2), dimethylarginine (ADMA and SDMA) at 3, 6 and 12 months
    -Changes from baseline in plasma biomarkers (FABP4, sCD-163), von Willebrand factor (vWF) and urine biomarkers (NGAL, MCP-1, and albumin) at 3 , 6 and 12 months
    -Changes from baseline in vasoactive hormones: plasma renin concentration, plasma norepinephrine and plasma copeptin at 3, 6 and 12 months
    -Changes from baseline in blood levels of bacterial DNA or bacterial products at 3, 6 and 12 months
    -To evaluate changes in microbiome composition by analysis of microbial genes and signature in patients included in the study at baseline and 3, 6 and 12 months
    -Changes from baseline in liver function, evaluated by MELD score, CLIF-AD score and Child Pugh Score at 1 3, 6, 9 and 12 months.
    -Quality of life, functional assessment and in Minimal Hepatic Encephalopathy during treatment period, as assessed by CLDQ, Liver Frailty Index and PHES questionnaires at baseline and 1 3, 6, 9 and 12 months
    -Changes from baseline in stigmatization in patients with decompensated cirrhosis as assessed by a previously validated specific questionnaire at 3 months, 6 months and 12 months.
    -Appearance of muscle toxicity at baseline, 1 month, 3 months, 6 months, 9 months and 12 months as defined using a specific statin-associated myopathy questionnaire
    -Assessment of genetic polymorphisms of statins membrane transporter OATP1B1 in all the patients included in the study.
    -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.
    -Proportion of patients and severity of treatment-related adverse events during the study period.
    -Annualized incidence of ACLF.
    -Time to overall and time to disease related survival.
    E.5.2.1Timepoint(s) of evaluation of this end point
    months 1, 3, 6, 9 and 12
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months48
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months48
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 240
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state240
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 240
    F.4.2.2In the whole clinical trial 240
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Expected normal treatment
    Tratamiento clínico habitual
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-12-01
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