| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 |
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| E.1.1.1 | Medical condition in easily understood language |
| 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 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019642 |
| E.1.2 | Term | Hepatic cirrhosis NOS |
| E.1.2 | System Organ Class | 100000004871 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072848 |
| E.1.2 | Term | Hepatitis C virus genotype 1 positive |
| E.1.2 | System Organ Class | 100000004848 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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: <1 log10 drop at week 4 and/or <2 log10 decline of HCV RNA at treatment week 12 or an absolute viral count of ≥30.000 IU/ml at treatment week 12.
5.A) Female patients who are
- infertile with documentation, surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)
- postmenopausal for longer than 2 years at screening
- completely abstinent from sexual intercourse
- having sexual intercourse with female partners only or with a vasectomized male partner (bilateral vasectomy at least 6 months prior to screening)
- of childbearing potential and must use two highly effective contraceptive methods. Accepted examples are: Condom with spermicide, diaphragm or cervical cap with spermicide, intrauterine device.
Female subjects may continue to use hormonal contraceptives during administration of study drug. Due to potential drug to drug interactions with telaprevir hormonal contraceptives may be less effective and are not an accepted contraceptive method during the study. Female subjects must continue to use effective contraceptive methods until at least 4 months after the end of dosing.
B) Male patients who are sterile (documented bilateral vasectomy at least 6 months prior to screening) or who agree to abstain from sexual intercourse or who are sexually active with male partners only or with female partners who are not of childbearing potential. Male subjects with female partners of child bearing potential must use two accepted contraceptive methods as listed in 5. A). In addition hormonal contraception in female partners of male study subjects is accepted. Male subjects must continue to use effective contraceptive methods until at least 7 months after the end of dosing.
6. Willing and able to give written informed consent prior to any study related procedure.
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| E.4 | Principal 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 < 30 g/L and thrombocyte count < 100/nL (Fontaine et al. 2013)
8. Hematologic lab values out of acceptable ranges:
• Thrombocyte count <80/nL.
• Hemoglobin <12.0 g/dL for men and <11.0 g/dL for women.
• Absolute neutrophil count (ANC) of <1/nL
9. Active or suspected nonhepatic malignancy or history of malignancy within the last 5 years – patients with hepatocellular carcinoma that is solely localized to the liver can be included at the judgement of the investigator.
10. Impaired renal function defined as creatinine levels - female: > 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 <16 or >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
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| E.5 End points |
| E.5.1 | 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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| assessed at week 4 of the combined antiviral treatment |
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| E.5.2 | 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 hepatic encephalopathy or
o bleeding from esophageal varices
(Any event of these defines decompensation of liver function.)
or pathologic values of single biochemical measures
o reduced albumin level of <25 g/L or
o elevated INR > 1.63
(Any event of these defines decompensation of liver function)
or combined biochemical measures
o increased bilirubin > 5*ULN (corresponds to >6 mg/dL) and
o increased ALT >5* UNL (corresponds to >250 U/L in males and >175 U/L in females) and >2*ALTBL (compared to individual initial ALT).
Further endpoints with descriptive intentions only and with regard to additional secondary objectives will be investigated:
• rate of RAVs acquired during the observation period within the treatment failure population (independent of treatment arm); blood samples will be analysed as long as HCV RNA is not negative or became positive after earlier negativity.
- associated with silibinin
- associated with telaprevir
• rate of patients with bilirubin elevation > 2*ULN (corresponds > 2.4 mg/dL) at week 4, to be compared between groups
• increased ALT >2*ALTBL (compared to individual initial ALT) at week 4 to, be compared between groups
- rate of event occurrence
- time to event occurrence
• rate of patients with reduced thrombocyte count reduction <60/nL at week 4, to be compared between groups
• rate of patients with reduced hemoglobin <10 g/dL and <8,5 g/dL at week 4, to be compared between groups
• rate of patients with absolute neutrophile count <0,5/nL at week 4, to be compared between groups
• reduced creatinine clearance (MDRD) <0.8*MDRDBL (compared to individual initial MDRD) at week 4, to be compared between groups
- rate of event occurrence
- time of event occurrence
• rate of patients with increase of bile acids >5*ULN (corresponds > 40 µmol/L) times the upper limit of normal at week 4, to be compared between groups
- rate of event occurrence
- time to event occurrence
Furthermore, for
• local laboratory measures,
• vital signs and
• physical examinations (of relevant organ systems)
at various time points an investigators’ judgement will be done where normal / clinically unsuspicious / or clinically significant findings will be explicitly assessed.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- at week 12, 24 and 48 of antiviral treatment
- at week 12 and 24 of follow-up |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| The last patient out of the follow-up phase will be in September 2015. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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