Study to Investigate Pharmacokinetics, Safety and Efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) Fixed Dose Combination (FDC) in Adolescents and Children With Chronic Hepatitis C Virus (HCV) Infection

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the steady-state pharmacokinetics (PK) and confirm the age-appropriate dose of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) fixed-dose combination (FDC) in pediatric participants with chronic hepatitis C virus (HCV) infection.

Detailed Description
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Participants will receive placebo to match SOF/VEL/VOX FDC to assess ability to swallow tablets at screening up to Day 1.

Official Title
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A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Pharmacokinetics, Safety and Efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir Fixed Dose Combination in Adolescents and Children With Chronic HCV Infection

Conditions
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Hepatitis C Virus Infection

Intervention / Treatment
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* Drug: SOF/VEL/VOX


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Consent of parent or legal guardian required Chronic HCV infection Screening laboratory values within defined thresholds Individuals must have a determination of prior treatment status: DAA-naive is defined as either: Treatment naive with no prior exposure to any interferon (IFN), ribavirin (RBV), or approved or experimental HCV-specific DAA Treatment experienced with an IFN-based regimen and no prior exposure to an approved or experimental HCV-specific DAA DAA-experienced is defined as prior exposure to a regimen including any DAA (eg, non-structural protein (NS)3/4A protease inhibitor, NS5A inhibitor, or NS5B nucleotide/nucleoside inhibitor) Key Exclusion Criteria: History of clinically significant illness or any other medical disorder that may interfere with subject treatment, assessment or compliance with the protocol Co-infection with human immunodeficiency virus (HIV), acute hepatitis A virus (HAV) or hepatitis B virus (HBV) Clinical hepatic decompensation (eg, clinical ascites, encephalopathy, and/or variceal hemorrhage) Pregnant or nursing females Known hypersensitivity to study medication Use of any prohibited concomitant medications as within 28 days of the Day 1 visit Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Cohort 1 (12 to < 18 years old), 8 Weeks<br>Direct-acting antiviral (DAA)-naive participants without cirrhosis in Cohort 1 (12 to < 18 years old) will receive SOF/VEL/VOX FDC 400/100/100 mg for 8 weeks. | Drug: SOF/VEL/VOX<br>* Administered once daily with food.<br>* Other names: Vosevi ®;|
| Experimental: Experimental: Cohort 1 (12 to < 18 years old), 12 Weeks<br>DAA-naive participants with cirrhosis or DAA-experienced participants with or without cirrhosis in Cohort 1 (12 to < 18 years old) will receive SOF/VEL/VOX FDC 400/100/100 mg for 12 weeks. | Drug: SOF/VEL/VOX<br>* Administered once daily with food.<br>* Other names: Vosevi ®;|
| Experimental: Experimental: Cohort 2 (6 to < 12 years old), 8 Weeks<br>DAA-naive participants without cirrhosis in Cohort 2 (6 to < 12 years old) will receive SOF/VEL/VOX FDC for 8 weeks. | Drug: SOF/VEL/VOX<br>* Administered once daily with food.<br>* Other names: Vosevi ®;|
| Experimental: Experimental: Cohort 2 (6 to < 12 years old), 12 Weeks<br>DAA-naive participants with cirrhosis or DAA-experienced participants with or without cirrhosis in Cohort 2 (6 to < 12 years old) will receive SOF/VEL/VOX FDC for 12 weeks. | Drug: SOF/VEL/VOX<br>* Administered once daily with food.<br>* Other names: Vosevi ®;|
| Experimental: Experimental: Cohort 3 (3 to < 6 years old), 8 Weeks<br>DAA-naive participants without cirrhosis in Cohort 3 (6 to < 12 years old) will receive SOF/VEL/VOX FDC for 8 weeks. | Drug: SOF/VEL/VOX<br>* Administered once daily with food.<br>* Other names: Vosevi ®;|
| Experimental: Experimental: Cohort 3 (3 to < 6 years old), 12 Weeks<br>DAA-naive participants with cirrhosis or DAA-experienced participants with or without cirrhosis in Cohort 3 (3 to < 6 years old) will receive SOF/VEL/VOX FDC for 12 weeks. | Drug: SOF/VEL/VOX<br>* Administered once daily with food.<br>* Other names: Vosevi ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: AUCtau of SOF, GS-331007 (Metabolite of SOF), VEL, and VOX | AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). For participants with separate consent to participate in the optional intensive PK substudy, intensive serial PK blood samples were collected at Week 2 or Week 4. Sparse PK samples were collected from all participants at Weeks 1, 2, 4, and end of treatment/Week 8. Plasma concentration data from all PK samples (intensive and sparse) were combined and used to generate PK parameters of SOF, GS-331007, VEL, and VOX for all participants using a population PK modeling approach. | Sparse PK Sample (all participants): At Weeks 1 and 8 at any time, Weeks 2 and 4 (predose and between 15 minutes and 4 hours postdose). Intensive PK Sample [PK Substudy (N=14)]: Week 2 or Week 4 (0 (predose), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event | Treatment-emergent Adverse Events (TEAE) were defined as events that met 1 or both of the following criteria as any AEs with onset dates on or after the study drug start date and no later than 30 days after the permanent discontinuation of study drug. It also includes the AEs that leads to premature discontinuation of study drug. | First dose date up to the last dose date (maximum: 8 Weeks) plus 30 days | 
| Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | SVR was defined as hepatitis C virus (HCV RNA) < Lower limit of quantification (LLOQ) (ie, < 15 IU/mL) 12 weeks after discontinuation of the study drug. | Posttreatment Week 12 | 
| Percentage of Participants With HCV RNA < LLOQ 4 Weeks After Discontinuation of Therapy (SVR4) | SVR was defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 4 weeks after discontinuation of the study drug. | Posttreatment Week 4 | 
| Percentage of Participants With HCV RNA < LLOQ 24 Weeks After Discontinuation of Therapy (SVR24) | SVR was defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 24 weeks after discontinuation of the study drug. | Posttreatment Week 24 | 
| Percentage of Participants With Overall Virologic Failure | Overall Virologic Failure comprises of on-treatment virologic failure and relapse. On-treatment virologic failure (breakthrough, rebound, and nonresponse) and relapse were defined as follows: Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), Rebound (confirmed > 1 log10IU/mL increase in HCV RNA from nadir while on treatment), or Nonresponse (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) and Relapse (confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on treatment visit). | Up to Posttreatment Week 24 | 
| Percentage of Participants With HCV RNA < LLOQ on Treatment | Percentage of participants with HCV RNA < LLOQ (15 IU/mL) while on treatment by analysis visit. | Weeks 1, 2, 4, and 8 | 
| Percentage of Participants Who Developed Viral Resistance to SOF, VEL, and/or VOX During Treatment | Plasma samples were collected and stored for potential HCV sequencing. Impact on the treatment outcomes of SVR12 and SVR24 were observed during the study. Baseline nonstructural protein (NS)3, NS5A, and NS5B deep sequencing analysis was performed for all participants. Sequencing for the HCV NS5A and NS5B regions was performed for all enrolled participants at baseline and for participants with virologic failure. | Up to End of Treatment (Week 8) | 
| Percentage of Participants Who Developed Viral Resistance to SOF, VEL, and/or VOX When Treatment is Discontinued | Plasma samples were collected and stored for potential HCV sequencing. Impact on the treatment outcomes of SVR12 and SVR24 were observed during the study. Baseline nonstructural protein (NS)3, NS5A, and NS5B deep sequencing analysis was performed for all participants. Sequencing for the HCV NS5A and NS5B regions was performed for all enrolled participants at baseline and for participants with virologic failure. | Up to Posttreatment Week 24 | 
| Change in HCV RNA From Day 1 Through End of Treatment |  | Baseline (Day 1); Weeks 1, 2 ,4, and 8 | 
| Percentage of Participants With Alanine Aminotransferase (ALT) Normalization | ALT normalization was defined as ALT > upper limit of normal (ULN) at baseline and ALT ≤ ULN at each visit. | Baseline (Day 1); Week 1, 2, 4, 8, and Posttreatment/Follow-up Week 4 (FU-4) | 
| Change From Baseline in Height Percentiles as a Measurement of Growth and Development | An age- and sex-specific percentile was derived for each weight, height, and body mass index (BMI) measurement according to the statistical analysis system (SAS) program available on the Centers for Disease Control and Prevention (CDC) website using the year 2000 growth charts. | Baseline (Day 1); Weeks 1, 2, 4, 8, FU-4, Posttreatment/Follow-up Week 12 (FU-12), and Posttreatment/Follow-up Week 24 (FU-24) | 
| Change From Baseline in Weight Percentiles as a Measurement of Growth and Development | An age- and sex-specific percentile was derived for each weight, height, and body mass index (BMI) measurement according to the statistical analysis system (SAS) program available on the Centers for Disease Control and Prevention (CDC) website using the year 2000 growth charts. | Baseline (Day 1); Weeks 1, 2, 4, 8, FU-4, FU-12, and FU-24 | 
| Number of Participants by Tanner Stage Assessment as a Measurement of Growth and Development | Tanner Pubertal Staging were assessed for pubic hair growth and genitalia development (males) and for pubic hair growth and breast development (females) in stages 1 to 5. Tanner stages will be used to evaluate the onset and progression of pubertal changes from stage 1 (pre-pubertal) to stage 5 (adult). If a participant had reached Tanner stage 5, no further Tanner pubertal stage assessments were to be completed.Pubic hair growth: Tanner stages (1: No hair, 2: Downy hair, 3: More coarse and curly hair, 4: Adult-like hair quality; 5: Hair extends to medial surface of the thighs); Breast development: Tanner stages (1: No glandular tissue, 2: Breast bud forms,3: More elevated, outside areola, 4: Increased breast size,5: Final adult-size breasts); Genitalia development: Tanner stages (1: Testes, scrotum, and penis about same size, 2: Enlargement of scrotum and testes, Penis (10.5-12.5); 3: Enlargement of penis (11.5-14); 4: Penis size (13.5-15); 5: Genitalia adult in size and shape). | Baseline (Day 1); Weeks 8, FU-12, and FU-24 | 
| Change From Baseline in Radiographic Bone Age Assessment as a Measurement of Growth and Development | For radiographic bone age assessment, a single x-ray of the left wrist, hand, and fingers was performed and assessed by changes from baseline through end of treatment period. | Baseline (Day 1); Week 8 | 
| Change From Baseline in C-Type Collagen Sequence (CTX) Bone Turn-Over Biochemical Marker as a Measurement of Growth and Development | Fasting blood samples for baseline values for bone age biomarkers CTX and change from baseline were recorded. | Baseline (Day 1); FU-24 | 
| Change From Baseline in Procollagen Type 1 N-Terminal Propeptide (P1NP) Bone Turn-Over Biochemical Marker as a Measurement of Growth and Development | Fasting blood samples for baseline values for bone age biomarkers P1NP and change from baseline were recorded. | Baseline (Day 1); FU-24 | 
| Percentage of Participants in Each Swallowability Category of Able to Swallow or Unable to Swallow SOF/VEL/VOX 400/100/100 mg Size Tablets | Swallowability for SOF/VEL/VOX FDC placebo to match (PTM) tablets was summarized based on the participants present in each swallowability category of Able to Swallow or Unable to Swallow a placebo tablet on one occasion during screening until Day 1. | Baseline (Day 1) | 
| Percentage of Participants With Acceptability Questionnaire Responses as Assessed by the Study Participant | A questionnaire was administered to participants to assess acceptability, including palatability, of the formulation. Acceptability and palatability were assessed by questions about how the study drug tasted, how easy it was to swallow the study drug, and also at the end of treatment about how it was to take the study drug and, as they all received a single tablet daily, how they felt about the number of tablets they had to swallow. | Baseline (Day 1); Week 8 | 
| Percentage of Participants With Acceptability Questionnaire Responses as Assessed by the Parent/Legal Guardian | A questionnaire was administered to the parent/legal guardian of participants to assess acceptability, including palatability, of the formulation. Acceptability and palatability were assessed by questions about how the study drug tasted, how easy it was to swallow the study drug, about how it was to take the study drug and, as they all received a single tablet daily, how they felt about the number of tablets they had to swallow. | Week 8 | 
| Neuropsychiatric Assessments Based on Questionnaire as Completed by Participant | Neuropsychiatric safety assessment was done using the Pediatric Quality of Life (PedsQL™ 4.0 SF15). The PedsQL™ 4.0 SF15 Questionnaires was completed by all participants. It is a comprehensive and widely used patient-reported outcome survey designed to measure health-related quality of life in healthy children and adolescents. It is presented for each of the 4 domains of the SF-15 (physical functioning, emotional functioning, social functioning, and school functioning), the psychosocial health summary (emotional, social, and school functioning domains), physical health summary and the Total Score. Total scores as well as each of the subscale scores are transformed on a scale from 0 to 100. Higher scores in each case indicate better health-related quality of life (HRQOL). A positive change from end of treatment period indicates improvement. | Weeks 8, FU-12, and FU-24 | 
| Neuropsychiatric Assessments Based on Questionnaire as Completed by Parent/Legal Guardian | Neuropsychiatric safety assessment was done using the Pediatric Quality of Life (PedsQL™ 4.0 SF15). The PedsQL™ 4.0 SF15 Questionnaires was completed by the parent/ legal guardian of the participants. It is a comprehensive and widely used patient-reported outcome survey designed to measure health-related quality of life in healthy children and adolescents. It is presented for each of the 4 domains of the SF-15 (physical functioning, emotional functioning, social functioning, and school functioning), the psychosocial health summary (emotional, social, and school functioning domains), physical health summary and the Total Score. Total scores as well as each of the subscale scores are transformed on a scale from 0 to 100. Higher scores in each case indicate better HRQOL. A positive change from end of treatment period indicates improvement. | Weeks 8, FU-12, and FU-24 | 
| Change From Baseline in Neuropsychiatric Assessments as Completed by Participant | Neuropsychiatric safety assessment was done using the Pediatric Quality of Life (PedsQL™ 4.0 SF15). The PedsQL™ 4.0 SF15 Questionnaires was completed by all the participants. It is a comprehensive and widely used patient-reported outcome survey designed to measure health-related quality of life in healthy children and adolescents. It was presented for each of the 4 domains of the SF-15 (physical functioning, emotional functioning, social functioning, and school functioning), the psychosocial health summary (emotional, social, and school functioning domains), physical health summary and the Total Score. Total scores as well as each of the subscale scores are transformed on a scale from 0 to 100. Higher scores in each case indicate better HRQOL. A positive change from baseline indicates improvement. | Baseline (Day 1); Weeks 8, FU-12, and FU-24 | 
| Change From Baseline in Neuropsychiatric Assessments as Completed by Parent/Legal Guardian | Neuropsychiatric safety assessment was done using the Pediatric Quality of Life (PedsQL™ 4.0 SF15). The PedsQL™ 4.0 SF15 Questionnaires was completed by the parent/ legal guardian of the participants. It is a comprehensive and widely used patient-reported outcome survey designed to measure health-related quality of life in healthy children and adolescents. It is presented for each of the 4 domains of the SF-15 (physical functioning, emotional functioning, social functioning, and school functioning), the psychosocial health summary (emotional, social, and school functioning domains), physical health summary and the Total Score. Total scores as well as each of the subscale scores are transformed on a scale from 0 to 100. Higher scores in each case indicate better HRQOL. A positive change from baseline indicates improvement. | Baseline (Day 1); Weeks 8, FU-12, and FU-24 |