| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Genotype 2 or 3 HCV Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| 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 |
| To determine the efficacy of PSI-7977 in combination with RBV administered for 12 weeks compared with PEG/RBV administered for 24 weeks in treatment-naïve patients with HCV genotype 2 or 3 as assessed by the rate of SVR12 (HCV RNA <LOQ 12 weeks after cessation of therapy) |
|
| E.2.2 | Secondary objectives of the trial |
1) To assess the safety and tolerability of PSI-7977/RBV administered for 12 weeks as measured by the frequency of deaths, serious adverse events (SAEs), discontinuations due to AEs, and Grade 3 or 4 laboratory abnormalities
2) To determine the SVR at Week 24 (SVR24) following completion of treatment for each investigational arm (HCV RNA <LOQ 24 and 48 weeks after cessation of therapy)
3) To evaluate the change in circulating HCV RNA in patients over 12 or 24 weeks of dosing
4) To determine the proportion of patients with HCV RNA below the lower limit of quantitation (LOQ) and lower limit of detection (LOD) at various time points thoughout the study
5) To determine the proportion of patients whose ALT normalizes during therapy
6) To describe rates of virologic failure
7) To characterize HCV drug resistance substititions at baseline, during, and after therapy with PSI-7977 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Males or females at least 18 years old, or the legal age of consent, whichever is older, at Screening. Subjects or their heterosexual partner(s) must either be of non-childbearing potential or they must use effective contraception from 2 weeks before the initiation of therapy until 6 months (or the duration recommended locally for ribavirin if longer) after the last dose of study medication.
2) Chronic Genotype 2 or 3 HCV-infection documented by at least one measurement of serum HCV RNA ≥ 10,000 IU/mL
3) Patients with Childs A cirrhosis may be included (up to 20% of patients randomized)
4) Subjects must be naïve to all HCV antiviral treatment(s), including but not limited to immunomodulatory and nucleoside/tide treatments for chronic HCV infection.
5) A body mass index (BMI) of ≥18kg/m2
6) Otherwise suitable for participation as determined by the medical history, physical examination, ECG, and clinical laboratory measurements performed at Screening
7) Able to effectively communicate with the Investigator and other center personnel. Willing to give written informed consent and comply with the study restrictions and requirements |
|
| E.4 | Principal exclusion criteria |
1) Positive test at Screening for HBsAg, anti-HBc IgM Ab, or anti-HIV Ab.
2) History of any other clinically significant chronic liver disease.
3) A history of consistent with decompensated liver disease including ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome and hepatopulmonary syndrome, among others.
4) History or current evidence of psychiatric illness, immunologic disorder, hemoglobinopathy, pulmonary disease (including pneumonia or pneumonitis), cardiac disease, seizure disorder or anticonvulsant use, poorly controlled diabetes, cancer, or a history of malignancy that in the opinion of the investigator makes the patient unsuitable for the study. Chronic medical conditions, especially if treated with medications (such as hypertension), must be stable at the time of screening. No new therapies should be started prior to the study that may confound the assessment of study drug safety.
5) Clinical signs and symptoms of acute pancreatitis with elevated lipase
6) Clinically significant ECG findings at screening, screening QTc ≥ 450 ms (non-cirrhotic) or ≥ 500 ms (cirrhotic), or a personal or family history of Torsades de pointes.
7) History of major organ transplantation with an existing functional graft.
8) Active substance abuse which, in the opinion of the investigator, would make the candidate inappropriate for participation in this study.
9) History of uncontrolled thyroid disease or abnormal TSH levels as defined <0.8 x LLN or >1.2 x ULN at Screening (subjects will be eligible with an abnormal TSH if the T3 and T4 are within normal limits).
10) Abnormal haematological and biochemical parameters.
11) Donation or loss of more than 400 mL blood within 2 months prior to first dose administration.
12) History of clinically significant drug allergy to nucleoside/nucleotide analogs.
13) History of having received any systemic antineoplastic or radiation therapy within 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.
14) Subjects receiving oral or intravenous strong p-glycoprotein inhibitors (including cyclosporine, quinidine, dronedarone, itraconazole, verapamil or ritonavir) within 28 days of dosing. Additional concomitant medications disallowed in this study are
outlined in Section 7.7. of the protocol.
15) Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration.
16) Pregnant/Breastfeeding women or males whose partners are currently pregnant.
17) Poor venous access making the patient unable to complete the required laboratory testing
schedule. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Serum HCV RNA, viral resistance testing |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary study hypothesis is that PSI-7977/RBV administered for 12 weeks will be superior to PEG/RBV administered for 24 weeks. The primary efficacy endpoint is sustained viral response 12 weeks post last dose of any treatment (HCV RNA <LOQ 12 weeks after cessation of therapy) in the ITT population. The primary analyses will include the assessments non-inferiority (with a non-inferiority margin of 15%) and the superiority PSI-7977/RBV (Arm A) to the control (Arm B). A closed testing procedure will be performed for the primary analyses |
|
| E.5.2 | Secondary end point(s) |
1) Safety: Adverse events (AE), safety labs, electrocardiograms (ECGs) and vital signs.
2) Pharmacokinetic parameters: Population pharmacokinetic parameters for PSI-6206. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety endpoints will be analyzed as the number and percent of subjects with events or abnormalities for categorical values or descriptive statistics. |
|
| 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 | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| Canada |
| Estonia |
| Netherlands |
| New Zealand |
| Puerto Rico |
| Spain |
| Sweden |
| United States |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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