High-dose intravenous silibinin infusions during 10 days as add-on treatment to triple therapy (telaprevir, peginterferon alpha and ribavirin) in cirrhotic GT 1 hepatitis C virus infected patients being null responders to prior dual therapy with peginterferon alpha and ribavirin – a proof-of-concept trial on antiviral efficacy and safety MedDRA version: 16.1 Level: LLT Classification code 10019642 Term: Hepatic cirrhosis NOS System Organ Class: 100000004871 MedDRA version: 16.1 Level: LLT Clas
Conditions
Interventions
Trade Name: Legalon SIL
Product Name: Silibinin
Pharmaceutical Form: Powder for solution for injection
Sponsors
University Leipzig
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female, age from 18 to 70 years (extremes included) 2. Chronic hepatitis C infection of genotype 1, confirmed by genotypic testing at screening 3. Compensated liver cirrhosis (Child Pugh A) assessed by either liver histology: Metavir 4 in a liver biopsy (any biopsy result will be accepted regardsless of its age) or noninvasive elastography: a Fibroscan© measurement of >14,5 kPa with an interquartile range (IQR) of less than 20% of the value and a success rate of at least 85%. At screening the Fibroscan testing should not be older than 6 months. 4. Null response to a prior treatment regimen with peginterferon alpha and ribavirin defined as one of the following: =65 years) yes F.1.3.1 Number of subjects for this age range 33
Exclusion criteria
Exclusion criteria: 1. Chronic hepatitis C with non-genotype 1 infection or mixed infection containing a genotype 2, 3, 4, 5 or 6 2. Detection of resistance associated viral mutations (RAV) in a population based sequencing analysis of the hepatitis C virus NS3/4A region at screening. RAVs are defined as any detected mutation: V36A/G/M, T54A/S, R155G/K/M/T und A156F/N/S/T/V. 3. Positiv testing for HIV-1 or HIV-2 antibodies, positive testing for HBs-Ag at screening 4. Evidence of liver disease due to causes other than hepatitis C infection 5. Decompensated liver disease or history of decompensated liver disease: Ascites, bleeding from esophageal varices, portal vein thrombosis, spontaneous bacterial peritonitis, hepatic encephalopathy. 6. Total bilirubin levels of > 1.8 mg/dL (> 1.5*ULN); INR > 1.26. 7. Combined: albumin levels 1.8 mg/dL; male: > 2.0 mg/dL 11. Impaired thyroid gland function – TSH outside 0.2 – 4.5 mU/L 12. Body Mass Index 35 kg/m2. 13. Female patients who are pregnant or breast feeding or male patients whose female partner is pregnant. 14. History of alcohol or drug abuse (except cannabis) within the past 12 months. 15. History of severe or uncontrolled psychiatric disease, especially depression, including a prior suicidal attempt. 16. Active autoimmune disease, including autoimmune hepatitis; i.e. ANA-Titers > 1:320 at screening. 17. Organ transplantation (exception: cornea or hair transplant) 18. Poor or restricted access to the venous system – patients will receive an i.v. catheter at all silibinin visits. 19. Usage of any investigational drugs within 30 days prior to enrolment 20. Any condition or comorbidity that is listed as contra-indicative for the use of Peginterferon, Ribavirin or Telaprevir – for a detailed list refer to the current SmPC of the respective medication. 21. Inadmissible concomitant medication that is known to be a strong inducer, inhibitor or substrate of cytochrome p450 subtype 3A4. A detailed list of prohibited medication is provided in Section 5.3.5. 22. Known allergies to any of the used study medication or their additives. 23. Persons that are imprisoned due to judicial or administrative order
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the rates of RVR – rapid virological response, defined as HCV RNA = LOQ (limit of quantification), defined as = 15 IU/mL at week four of an antiviral treatment with telaprevir, peginterferon alpha and ribavirin – between patients who either receive infusions of silibinin during the first ten consecutive working days of antiviral treatment or no infusions.;Secondary Objective: To compare the rate of patients with undetectable HCV-RNA (LOQ = 15 IU/mL) like in sec. 2.1) at week 12, 24 and 48 (end of treatment - EoT; oTVR-12/24/48) of antiviral treatment To compare the rate of patients with undetectable HCV-RNA at week 12 and 24 of Follow-Up (SVR-12/24) To assess intensive viral kinetics during silibinin treatment (either in arm A or B) – the time needed to achieve negative HCV RNA levels – the extend of HCV RNA level reduction with every silibinin infusion To compare the safety profile of both study arms the causally related AE and SAE to study medication, the rate of decompensated liver function as well as biochemical findings will be assessed. To assess the emergence of viral resistance mutations against telaprevir and / or silibinin in patients with viral break-through or incomplete virological response during antiviral treatment. ;Primary end point(s): The rapid viologic response (RVR) rate - assessed at week 4 of the combined antiviral treatment – is used as primary end point (pEP) of the trial. RVR, defined as HCV RNA = LOQ (limit of quantity, =15 IU/mL) will be assessed for every patient in a binary manner (Yes/No). The rate of patients in both treatment arms (either receiving infusions of silibinin during the first ten consecutive working days of antiviral treatment or no infusions) will be used in confirmatory analysis. For patients without valid HCV RNA values at week 4 conservative missing value imputation will be used to get a pEP Please enter information in English and add any other language that is applicable;Timepoint(s) of | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy endpoints • rate of patients with undetectable HCV-RNA (defined as =15 IU/mL) at week 12, 24 and 48 of antiviral treatment (? on-Treatment Virologic Responses – oTVR-12, -24 and -48) • rate of patients with undetectable HCV-RNA at week 12 and 24 of follow-up (Sustained Virologic Response: SVR-12 and -24) • rate of patients with normalized ALT (= Upper Limit of Normal: ULN ; male: =50 U/l, female =35 U/l) during antiviral treatment to be compared between groups at week 4, and to be reported for the both arms at weeks 12 and 48 • time of treatment needed until normalization of ALT is achieved to be compared between groups at week 4 To describe viral kinetics during the phase of silibinin infusions: • time until - for the first time - negative HCV RNA (= LOQ, i.e. 15 IU/mL) level is detected to be compared between groups at week 4 • number of silibinin infusions needed until – for the first time - negative HCV RNA level is detected to be reported for the arm A • Area under Curve (AUC) of HCV RNA reduction until week 4 (i.e. completion of silibinin treatment in arm A; the 2 days of weekend were considered via linear interpolation between levels of preceding Friday’s and following Monday’s measures to be compared between groups • decline of HCV RNA per single silibinin infusion, calculated via AuC until the respective day divided by number of infusions applied until the preceding day to be reported for the arm A and those patients of arm B who received the rescue treatment Safety endpoints • rate of causally related AE, for all 4 IMPs assessed and analyzed separately until visit FU12 (the first visit after EoT with Peg/Riba :end of event reporting period - EoER), • rate of causally related SAE, for all 4 IMPs assessed and analyzed separately until visit FU12 (EoER), • rate of decompensated liver function, aggregated until EoS; assessed from following clinical findings o development of ascites or o development of hepat | — |
Countries
Germany
Contacts
Public ContactAnett Schmiedeknecht
Clinical Trial Centre Leipzig (ZKS Leipzig - KKS)
Outcome results
None listed