| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic inflammation of the liver caused by hepatitis C virus infection |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019752 |
| E.1.2 | Term | Hepatitis C virus (HCV) |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| 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 |
| The primary objective is to demonstrate the non-inferiority in sustained viral response (SVR12planned) of telaprevir administered as 1125 mg twice daily (b.i.d.) versus 750 mg every 8 hours (q8h) in combination with pegylated interferon (Peg-IFN)-alfa-2a and ribavirin (RBV) in treatment-naïve subjects with chronic HCV genotype 1 infection. SVR12planned is defined as having plasma HCV ribonucleic acid (RNA) levels < 25 IU/mL 12 weeks after the last planned dose of study drugs. |
|
| E.2.2 | Secondary objectives of the trial |
• to evaluate tolerability and safety of telaprevir when administered as 750 mg q8h or 1125 mg b.i.d. in
combination with Peg-IFN-alfa-2a and RBV;
• to investigate the effect of IL28B genotype on viral response;
• to evaluate pharmacokinetics of telaprevir, Peg-IFN-alfa-2a, and RBV and pharmacokinetic-pharmacodynamic
relationships for safety and efficacy;
• to evaluate changes from baseline in the amino acid sequence of the HCV NS3-4A region. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Subject is a man or a woman between 18 and 70 years of age, inclusive.
-Subject has chronic HCV infection genotype 1 with HCV RNA level > 1,000 IU/mL.
Genotype must be confirmed during screening. Chronic infection status must be
confirmed by detectable HCV RNA more than 6 months before the screening visit or by histological diagnosis of chronic hepatitis based on the liver biopsy.
-Subjects should not have had any previous treatment with any approved or investigational drug or drug regimen for the treatment of hepatitis C.
-Subject is judged to be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening.
-Subject must have documentation of a liver biopsy within 2 years before the screening visit or the subject must agree to have a biopsy performed within the screening period. If a biopsy more than 2 years prior to screening has already demonstrated histological cirrhosis, the biopsy does not need to be repeated if the biopsy report can be provided.
-Subjects with cirrhosis should have serum alpha-fetoprotein (AFP) ≤ 50 ng/mL. If AFP> 50 ng/mL, absence of a mass must be demonstrated by ultrasound within the screening period. In case the ultrasound results are ambiguous, a computed tomography (CT) scan or magnetic resonance imaging (MRI) scan should be performed. If a subject was screened for hepatocellular carcinoma within 5 months of the screening visit, this screening (ultrasound, CT, or MRI) can be used to fulfill the inclusion criterion.
-If heterosexually active, a female subject of childbearing potential and a nonvasectomized male subject who has a female partner of childbearing potential must agree to the use of 2 effective methods of contraception from screening onwards until 6 months (female subject) or 7 months (male subject) after the last dose of RBV.
Note: Hormonal contraceptives may not be reliable when taking telaprevir. Therefore, to be eligible for this study, subjects should use 2 other effective birth control methods during telaprevir treatment and for 2 months after the last intake of telaprevir
-Subject or female partner is not pregnant, planning to become pregnant, or breastfeeding.
All female subjects must have a negative serum β-human chorionic gonadotropin
(β-hCG) pregnancy test at screening.
-Subject is willing/able to adhere to the prohibitions and restrictions specified in this protocol.
-Subject must have signed an Informed Consent Form (ICF) including consent to IL28B testing, indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
-Subjects should agree not to participate in other clinical studies for the duration of their participation in this study, except for noninterventional or observational studies and only after prior approval of the sponsor. |
|
| E.4 | Principal exclusion criteria |
-Subject is infected or co-infected with HCV of another genotype than genotype 1.
-Subject is infected with HCV genotype 1 exhibiting more than one subtype.
-Subject presents a contraindication to the administration of Peg-IFN-alfa-2a or RBV, including but not limited to any of the following:
- hypersensitivity to Peg-IFN-alfa-2a, RBV, or any of their components;
- hemoglobinopathies;
- history or clinical evidence of significant cardiac disease and/or clinically significant ECG abnormalities;
- abnormal thyroid function that is not adequately controlled;
- poorly controlled diabetes mellitus as evidenced by hemoglobin A1c (HbA1c) ≥ 8.5% at screening;
- creatinine clearance ≤ 50 mL/min at screening;
- antinuclear antibody (ANA) titer ≥ 1:640 at screening or other evidence of autoimmune-mediated disease.
-Subject has known allergies, hypersensitivity, or intolerance to telaprevir or its excipients
-Subject uses disallowed therapies.
-Subject has a pre-existing psychiatric condition, including but not limited to:
- severe depression or hospitalization for depression;
- schizophrenia, bipolar illness, severe anxiety, or personality disorder;
- a period of disability or impairment due to a psychiatric disease within the past 5 years.
-Subject has history of decompensated liver disease: history of ascites, hepatic encephalopathy, or bleeding esophageal varices, and/or any of the following screening laboratory results:
- International Normalized Ratio (INR) of ≥ 1.5;
- Serum albumin < 3.3 g/dL;
- Serum total bilirubin > 1.8 times upper limit of laboratory normal range (ULN), unless isolated or in subjects with Gilbert’s Syndrome.
-Subject shows evidence of significant liver disease in addition to hepatitis C, which may include but is not limited to drug- or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, Nonalcoholic Steatohepatitis (NASH), or primary biliary cirrhosis.
-Subject has active malignant disease or history of malignant disease within the past 5 years.
-Subject has history of seizure disorders.
-Subject has congenital or acquired prolonged QT interval, a history of nonsustained or sustained ventricular tachycardia, or a history of drug-induced QT prolongation and/or Torsade de Pointes.
-Subject has history of organ transplant that requires chronic immunosuppression. Note: corneal, skin, and hair grafts are allowed.
-Subject has a medical condition that requires chronic or intermittent use of systemic corticosteroids.
-Subject has history or other evidence of clinically significant retinopathy or ophthalmological disorder, including but not limited to disorders due to diabetes mellitus or hypertension. Clearance by an ophthalmologist is required within 3 months prior to screening or within the screening period for all subjects with diabetes mellitus, hypertension, or known retinal disorders. The ophthalmologist should conduct a fundoscopic exam, which should be documented in the subjects’ records. The findings of the exam must also be recorded on the electronic Case Report Form (eCRF).
-Subject has clinical evidence of chronic pulmonary disease associated with functional impairment.
-Subject has evidence of hemophilia or other bleeding disorder.
-Subject has evidence of serious or severe bacterial or fungal infection(s), including active tuberculosis.
-Subject has human immunodeficiency virus (HIV) or hepatitis B virus (HBV) co-infection.
-Subject has a history of acute or chronic pancreatitis.
Knowledge or suspicion exists of alcohol, barbiturate, or amphetamine recreational or narcotic drug use (current or within 2 years prior to the screening visit) that in the investigator’s opinion would compromise the subject’s
safety and/or compliance with study procedures.
-Subject has a condition that, in the opinion of the investigator, would compromise the study or the well-being of the subject or prevent the subject from meeting or performing study requirements.
Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.
-Subject received an investigational drug or used an investigational medical device within 90 days before the planned start of treatment.
-Subject has a grade 4 laboratory abnormality as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events or any other clinically relevant abnormalities in the opinion of the investigator. Subjects with grade 4 elevations in gamma-glutamyltransferase (GGT) will be allowed to enter the study if there are no other clinically relevant laboratory abnormalities, as judged by the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to demonstrate the non-inferiority in sustained viral response (SVR12planned) of telaprevir administered as 1125 mg twice daily (b.i.d.) versus 750 mg every 8 hours (q8h) in combination with pegylated interferon (Peg-IFN)-alfa-2a and ribavirin (RBV) in treatment-naïve subjects with chronic HCV genotype 1 infection. SVR12planned is defined as having plasma HCV ribonucleic acid (RNA) levels < 25 IU/mL 12 weeks after the last planned dose of study drugs. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after the last planned dose of study drugs. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
-SVR week 72
-RVR
-relapse
-virologic failure
-viral breakthrough |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints:
-SVR week 72 : week 72
-RVR : week 4
-relapse : throughout the duration of the study
-virologic failure : up to week 24 or 48
-viral breakthrough : up to week 24 or 48
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Brazil |
| France |
| Germany |
| Ireland |
| Italy |
| Mexico |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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