E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis C virus infection |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019744 |
E.1.2 | Term | Hepatitis C |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008912 |
E.1.2 | Term | Chronic hepatitis C |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
The primary objective of the PK Lead-in Phase of this study is:
*To evaluate the steady state pharmacokinetics (PK) and confirm the dose of sofosbuvir (SOF) in HCV-infected pediatric subjects
The primary objectives of the Treatment Phase of this study are:
*To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV-infected pediatric subjects with genotype (GT) GT-2 or GT-3, respectively |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of the PK Lead-in Phase of this study is:
*To evaluate the safety and tolerability of 7 days of dosing of SOF + ribavirin (RBV) in HCV-infected pediatric subjects
The secondary objectives of the Treatment Phase of this study are:
*To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 HCV-infected subjects separately, as assessed by the proportion of subjects with SVR 12 weeks after completion of treatment (SVR12)
*To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 HCV-infected subjects separately, as assessed by the proportion of subjects with SVR 4 and 24 weeks after completion of treatment (SVR4 and SVR24)
*To evaluate the kinetics of circulating HCV RNA during treatment and after completion of treatment
*To evaluate the emergence of viral resistance to SOF during treatment and after completion of treatment |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
All subjects will be eligible to participate in the Pharmacogenomic (PG) Substudy. For subjects who provide written consent for the PG Substudy, a blood sample will be drawn at the Day 1 visit. If not obtained at Day 1, the sample may be drawn at any time during the study. |
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E.3 | Principal inclusion criteria |
1. Parent or legal guardian able to provide written informed consent prior to any screening evaluations and willing to comply with study requirements. Subjects will provide assent if possible.
2. 3 years to < 18 years of age (consent of parent or legal guardian required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh greater than or equal to 45 kg
4. PK Lead-in only: subjects in Cohort 2 (age 6 to <12 years of age) must weigh greater than or equal to 17 kg and < 45 kg
5. PK Lead-in only: all subjects must be treatment naïve
6. Treatment experienced subjects: prior treatment failure to a regimen including interferon either with or without RBV that was completed at least 8 weeks prior to Baseline/Day 1.
7. Chronic HCV infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV infection
8. Infection with HCV GT-2 or GT-3 as determined at Screening
9. HCV RNA ≥ 1000 IU/mL at Screening
10. Adequate hematologic function (absolute neutrophil count greater than or equal to 1,500/mm3; hemoglobin greater than or equal to 12 g/dL for males and greater than or equal to 11g/dL for females.)
11. Negative serum beta-HCG pregnancy test (for females of childbearing potential only, as defined in Appendix 5)
12. Subject able to provide written assent, if they have the ability to read and write, as determined by IRB/IEC/local requirements and Investigator’s discretion |
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an effective method of contraception during the study
3. Decompensated liver disease defined as INR > 1.2 x ULN, platelets < 50,000/mm3, serum albumin > 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage)
4. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency)
5. alpha-fetoprotein > 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate < 90 mL/min/1.73m2, as calculated by the Schwartz Formula
8. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of certain resolved skin cancers)
9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for > 5 days (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 28 days (except with the expressed approval of the Sponsor)
16. Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator
17. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
18. Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements
19. Use of any prohibited concomitant medications as described in Section 5.6 within 28 days of the Day 1 visit
20. Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 5 years. Subjects with psychiatric illness (without the prior mentioned conditions) that is well-controlled on a stable treatment regimen for at least 12 months prior to enrolled or has not required medication in the last 12 months may be included. |
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E.5 End points |
E.5.1 | Primary end point(s) |
For the PK Lead-in Phase, AUCtau of GS-331007 is considered as the primary PK parameter for determining the appropriate SOF dose.
For Treatment Phase, the primary safety endpoint is any AE leading to permanent discontinuation of study drug (s). The primary efficacy endpoint is SVR12. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after treatment end |
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E.5.2 | Secondary end point(s) |
For the PK Lead-in Phase, the secondary PK endpoints include AUCtau, Cmax, AUClast, Tmax, Clast, Tlast, Ctau and t1/2 for GS-331007 and SOF as appropriate. AEs leading to permanent discontinuation of study drug(s) will be evaluated as a secondary safety endpoint.
For Treatment Phase, secondary efficacy endpoints include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include HCV RNA change from Day 1; ALT normalization; and viral kinetic parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints at 4 and 24 weeks after treatment end
PK and safety endpoints are accessed during the course of treatment
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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) | No |
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 | 3 |
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 |
Belgium |
Germany |
Italy |
New Zealand |
Russian Federation |
United Kingdom |
United States |
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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
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 |