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

Phase 2

Terminated

Conditions: Hepatitis C Virus Infection

Interventions: Drug: SOF/VEL/VOX

Registration Number: NCT03820258

Lead Sponsor: Gilead Sciences

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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 21

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Experimental: Cohort 3 (3 to < 6 years old), 12 Weeks	SOF/VEL/VOX	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.
Experimental: Cohort 2 (6 to < 12 years old), 8 Weeks	SOF/VEL/VOX	DAA-naive participants without cirrhosis in Cohort 2 (6 to \< 12 years old) will receive SOF/VEL/VOX FDC for 8 weeks.
Experimental: Cohort 3 (3 to < 6 years old), 8 Weeks	SOF/VEL/VOX	DAA-naive participants without cirrhosis in Cohort 3 (6 to \< 12 years old) will receive SOF/VEL/VOX FDC for 8 weeks.
Experimental: Cohort 1 (12 to < 18 years old), 8 Weeks	SOF/VEL/VOX	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.
Experimental: Cohort 1 (12 to < 18 years old), 12 Weeks	SOF/VEL/VOX	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.
Experimental: Cohort 2 (6 to < 12 years old), 12 Weeks	SOF/VEL/VOX	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.

Primary Outcome Measures

Name	Time	Method
Pharmacokinetic (PK) Parameter: AUCtau of SOF, GS-331007 (Metabolite of SOF), VEL, and VOX	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)	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.

Secondary Outcome Measures

Name	Time	Method
Neuropsychiatric Assessments Based on Questionnaire as Completed by Parent/Legal Guardian	Weeks 8, FU-12, and FU-24	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.
Change From Baseline in Neuropsychiatric Assessments as Completed by Participant	Baseline (Day 1); Weeks 8, FU-12, and FU-24	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.
Change From Baseline in Neuropsychiatric Assessments as Completed by Parent/Legal Guardian	Baseline (Day 1); Weeks 8, FU-12, and FU-24	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.
Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event	First dose date up to the last dose date (maximum: 8 Weeks) plus 30 days	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.
Percentage of Participants With HCV RNA < LLOQ 24 Weeks After Discontinuation of Therapy (SVR24)	Posttreatment Week 24	SVR was defined as HCV RNA \< LLOQ (ie, \< 15 IU/mL) 24 weeks after discontinuation of the study drug.
Change in HCV RNA From Day 1 Through End of Treatment	Baseline (Day 1); Weeks 1, 2 ,4, and 8
Change From Baseline in Radiographic Bone Age Assessment as a Measurement of Growth and Development	Baseline (Day 1); Week 8	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.
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)	Posttreatment Week 12	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.
Percentage of Participants Who Developed Viral Resistance to SOF, VEL, and/or VOX When Treatment is Discontinued	Up to Posttreatment Week 24	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.
Change From Baseline in Weight Percentiles as a Measurement of Growth and Development	Baseline (Day 1); Weeks 1, 2, 4, 8, FU-4, FU-12, and FU-24	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.
Percentage of Participants With HCV RNA < LLOQ 4 Weeks After Discontinuation of Therapy (SVR4)	Posttreatment Week 4	SVR was defined as HCV RNA \< LLOQ (ie, \< 15 IU/mL) 4 weeks after discontinuation of the study drug.
Percentage of Participants With Overall Virologic Failure	Up to Posttreatment Week 24	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).
Percentage of Participants With HCV RNA < LLOQ on Treatment	Weeks 1, 2, 4, and 8	Percentage of participants with HCV RNA \< LLOQ (15 IU/mL) while on treatment by analysis visit.
Change From Baseline in Procollagen Type 1 N-Terminal Propeptide (P1NP) Bone Turn-Over Biochemical Marker as a Measurement of Growth and Development	Baseline (Day 1); FU-24	Fasting blood samples for baseline values for bone age biomarkers P1NP and change from baseline were recorded.
Percentage of Participants Who Developed Viral Resistance to SOF, VEL, and/or VOX During Treatment	Up to End of Treatment (Week 8)	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.
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization	Baseline (Day 1); Week 1, 2, 4, 8, and Posttreatment/Follow-up Week 4 (FU-4)	ALT normalization was defined as ALT \> upper limit of normal (ULN) at baseline and ALT ≤ ULN at each visit.
Percentage of Participants in Each Swallowability Category of Able to Swallow or Unable to Swallow SOF/VEL/VOX 400/100/100 mg Size Tablets	Baseline (Day 1)	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.
Change From Baseline in Height Percentiles as a Measurement of Growth and Development	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)	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.
Number of Participants by Tanner Stage Assessment as a Measurement of Growth and Development	Baseline (Day 1); Weeks 8, FU-12, and FU-24	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).
Change From Baseline in C-Type Collagen Sequence (CTX) Bone Turn-Over Biochemical Marker as a Measurement of Growth and Development	Baseline (Day 1); FU-24	Fasting blood samples for baseline values for bone age biomarkers CTX and change from baseline were recorded.
Percentage of Participants With Acceptability Questionnaire Responses as Assessed by the Study Participant	Baseline (Day 1); Week 8	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.
Percentage of Participants With Acceptability Questionnaire Responses as Assessed by the Parent/Legal Guardian	Week 8	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.
Neuropsychiatric Assessments Based on Questionnaire as Completed by Participant	Weeks 8, FU-12, and FU-24	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.

Trial Locations

Locations (10): SOS-intraSOC Epatologia
🇮🇹
Firenze, Italy
US Infettivologia Pediatrica-Polo Universitario
🇮🇹
Milano, Italy
Servizio di Epatologia e Nutrizione Pediatrica
🇮🇹
Milan, Italy
UOSD Epatologia
🇮🇹
San Giovanni Rotondo, Italy
UOS Epatologia Pediatrica
🇮🇹
Napoli, Italy
Birmingham Women's and Children's NHS Foundation Trust
🇬🇧
Birmingham, United Kingdom
Uniwersytecki Szpital Kliniczny im.
🇵🇱
Wroclaw, Poland
Kings Healthcare NHS Trust Hospital
🇬🇧
London, United Kingdom
Wojewodzki Szpital
🇵🇱
Bydgoszcz, Poland
Med Polonia
🇵🇱
Poznan, Poland