| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C virus infection |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| 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 |
|
| 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 |
PK Lead-in phase is: To evaluate the steady state pharmacokinetics (PK) and confirm the dose of sofosbuvir/velpatasvir (SOF/VEL) in pediatric subjects with chronic hepatitis C virus (HCV) infection
Treatment Phase is: To evaluate the safety and tolerability of SOF/VEL for 12 weeks in paediatric subjects with chronic HCV |
|
| E.2.2 | Secondary objectives of the trial |
PK Lead-in Phase is: To evaluate the safety, tolerability, and antiviral activity of 7 days of dosing of SOF/VEL in
paediatric subjects with chronic HCV
Treatment Phase is: Determine the efficacy of SOF/VEL for 12 weeks in paediatric subjects with chronic HCV infection, as assessed by the proportion of subjects with SVR 12 weeks after cessation of treatment; Determine the proportion of subjects with SVR 4 and 24 weeks; Evaluate the proportion of subjects with virologic failure; Evaluate the kinetics of circulating HCV RNA during treatment and after cessation of treatment; Evaluate the emergence of viral resistance to SOF and VEL during treatment and after cessation of treatment; Evaluate the effect of treatment with SOF/VEL on QoL; Evaluate the effect of SOF/VEL on growth and development of paediatric subjects during and after treatment; Evaluate the acceptability, including palatability, of formulations used |
|
| 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 |
Pharmacogenomics substudy: In consenting subjects, a blood sample will be drawn at Day 1 visit. If not obtained at Day 1 visit, the sample may be drawn at any time during the study. To identify or validate genetic markers that may be predictive of the natural history of disease, response to therapy, and/or tolerability of medical therapies through genetic
discovery research.
An Optional Intensive Pharmacokinetics (PK) Substudy for adolescent subjects 12 to < 18 years of age enrolled in the Treatment Phase was added at Week 4 or 8 to support population PK model development. |
|
| 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, in accordance with IRB/IEC/local requirements and the Investigator’s discretion.
2) 3 years to < 18 years of age as determined at Day 1
3) Chronic HCV-infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ 1000 IU/mL at Screening
5) Subjects must have a determination of prior treatment status:
a) Treatment-naïve is defined as having never been exposed to an approved or experimental HCV-specific direct acting antiviral agents or prior treatment of HCV with interferon or ribavirin.
b) Treatment-experienced is defined as prior treatment failure or intolerance to a regimen containing interferon with or without RBV and with or without a protease inhibitor that was completed at least 8 weeks prior to Day 1.
c) Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥ 1 adverse event
6) A negative serum pregnancy test is required at screening and a negative urine test is required at Day 1 for female subjects of child bearing potential.
7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
8) Lactating females must agree to discontinue nursing before the IMP is administered.
9) Subject must be able to comply with the dosing instructions for study drug administration and be able to complete the study schedule of assessments. |
|
| E.4 | Principal exclusion criteria |
1) Prior use of an HCV NS5A inhibitor
2) Current or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, variceal hemorrhage)
3) Any of the following laboratory parameters at screening: a) INR > 1.2 x ULN b) Platelets < 50,000/mm3 c) albumin < 3.5 g/dL d) ALT > 10 x the upper limit of normal (ULN) e) AST > 10 x ULN f) Direct bilirubin > 1.5 x ULN g) Estimated glomerular filtration rate < 90 mL/min/1.73m2, as calculated by the Schwartz Formula
4) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency)
5) Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of certain resolved skin cancers)
6) Co-infection with HIV, acute HAV, or HBV (Hepatitis B Surface Ag positive at screening)
7) Current or prior history of any of the following:
a) Significant cardiovascular, pulmonary, or neurological disease
b) Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
c) History of solid organ or bone marrow transplantation
d) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 5 years.
8) Clinically-relevant alcohol or drug abuse within 12 months of screening.
9) Sexually-active males or females of childbearing potential who are not willing to use an effective method of contraception during the study
10) Use of any prohibited concomitant medications
11) Investigational agents taken within the past 28 days (except with the express approval of the Sponsor)
12) Known hypersensitivity to the study drug, the metabolites, or formulation excipients. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the PK Lead-in Phase is to determine steady-state PK, is AUCtau of VEL, SOF, and its major metabolite (GS-331007).
The primary endpoint of the Treatment Phase is assessment of any AEs with a focus on AEs that lead to discontinuation of study drug. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK lead in phase - Day 7
Treatment phase - SVR 12 weeks |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of the PK Lead-in Phase are:
- Antiviral activity measurements, including assessment of HCV RNA from baseline through Day 7.
- Any AE leading to permanent discontinuation of study drug.
The secondary endpoints of the Treatment Phase are:
- The proportion of subjects with sustained virological response (SVR) 12 weeks after cessation of treatment (SVR12). SVR12 is the key efficacy endpoint.
- The proportion of subjects with HCV RNA < LLOQ at 4 or 24 weeks after cessation of treatment (SVR4 and SVR24).
- The proportion of subjects with virologic failure, including breakthrough/nonresponse and relapse
- The proportion of subjects with HCV RNA < LLOQ on treatment
- Emergence of viral resistance to SOF and /or VEL during treatment and treatment is discontinued
- HCV RNA change from Baseline/Day 1
- Quality of life endpoints and neuropsychiatric assessments as measured by PedsQL™ Pediatric Quality of Life survey
- Growth and development measurements including height and weight percentiles, Tanner Stage, parental height, and bone age
- Acceptability assessed by swallowability and palatability
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
| Belgium |
| Italy |
| United Kingdom |
|
| 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
|
|
| 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 |
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