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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03820258
Recruitment Status : Terminated (SOF/VEL/VOX will not be evaluated in younger age groups.)
First Posted : January 29, 2019
Results First Posted : August 31, 2020
Last Update Posted : October 23, 2020
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Hepatitis C Virus Infection Drug: SOF/VEL/VOX Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 28, 2019
Actual Primary Completion Date : December 4, 2019
Actual Study Completion Date : February 19, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental: Cohort 1 (12 to < 18 years old), 8 Weeks
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
Administered once daily with food.
Other Name: Vosevi ®

Experimental: Experimental: Cohort 1 (12 to < 18 years old), 12 Weeks
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
Administered once daily with food.
Other Name: Vosevi ®

Experimental: Experimental: Cohort 2 (6 to < 12 years old), 8 Weeks
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
Administered once daily with food.
Other Name: Vosevi ®

Experimental: Experimental: Cohort 2 (6 to < 12 years old), 12 Weeks
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
Administered once daily with food.
Other Name: Vosevi ®

Experimental: Experimental: Cohort 3 (3 to < 6 years old), 8 Weeks
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
Administered once daily with food.
Other Name: Vosevi ®

Experimental: Experimental: Cohort 3 (3 to < 6 years old), 12 Weeks
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
Administered once daily with food.
Other Name: Vosevi ®




Primary Outcome Measures :
  1. Pharmacokinetic (PK) Parameter: AUCtau of SOF, GS-331007 (Metabolite of SOF), VEL, and VOX [ Time Frame: 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 :
  1. Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event [ Time Frame: 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.

  2. Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) [ Time Frame: 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.

  3. Percentage of Participants With HCV RNA < LLOQ 4 Weeks After Discontinuation of Therapy (SVR4) [ Time Frame: Posttreatment Week 4 ]
    SVR was defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 4 weeks after discontinuation of the study drug.

  4. Percentage of Participants With HCV RNA < LLOQ 24 Weeks After Discontinuation of Therapy (SVR24) [ Time Frame: Posttreatment Week 24 ]
    SVR was defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 24 weeks after discontinuation of the study drug.

  5. Percentage of Participants With Overall Virologic Failure [ Time Frame: 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).

  6. Percentage of Participants With HCV RNA < LLOQ on Treatment [ Time Frame: Weeks 1, 2, 4, and 8 ]
    Percentage of participants with HCV RNA < LLOQ (15 IU/mL) while on treatment by analysis visit.

  7. Percentage of Participants Who Developed Viral Resistance to SOF, VEL, and/or VOX During Treatment [ Time Frame: 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.

  8. Percentage of Participants Who Developed Viral Resistance to SOF, VEL, and/or VOX When Treatment is Discontinued [ Time Frame: 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.

  9. Change in HCV RNA From Day 1 Through End of Treatment [ Time Frame: Baseline (Day 1); Weeks 1, 2 ,4, and 8 ]
  10. Percentage of Participants With Alanine Aminotransferase (ALT) Normalization [ Time Frame: 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.

  11. Change From Baseline in Height Percentiles as a Measurement of Growth and Development [ Time Frame: 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.

  12. Change From Baseline in Weight Percentiles as a Measurement of Growth and Development [ Time Frame: 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.

  13. Number of Participants by Tanner Stage Assessment as a Measurement of Growth and Development [ Time Frame: 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).

  14. Change From Baseline in Radiographic Bone Age Assessment as a Measurement of Growth and Development [ Time Frame: 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.

  15. Change From Baseline in C-Type Collagen Sequence (CTX) Bone Turn-Over Biochemical Marker as a Measurement of Growth and Development [ Time Frame: Baseline (Day 1); FU-24 ]
    Fasting blood samples for baseline values for bone age biomarkers CTX and change from baseline were recorded.

  16. Change From Baseline in Procollagen Type 1 N-Terminal Propeptide (P1NP) Bone Turn-Over Biochemical Marker as a Measurement of Growth and Development [ Time Frame: Baseline (Day 1); FU-24 ]
    Fasting blood samples for baseline values for bone age biomarkers P1NP and change from baseline were recorded.

  17. Percentage of Participants in Each Swallowability Category of Able to Swallow or Unable to Swallow SOF/VEL/VOX 400/100/100 mg Size Tablets [ Time Frame: 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.

  18. Percentage of Participants With Acceptability Questionnaire Responses as Assessed by the Study Participant [ Time Frame: 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.

  19. Percentage of Participants With Acceptability Questionnaire Responses as Assessed by the Parent/Legal Guardian [ Time Frame: 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.

  20. Neuropsychiatric Assessments Based on Questionnaire as Completed by Participant [ Time Frame: 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.

  21. Neuropsychiatric Assessments Based on Questionnaire as Completed by Parent/Legal Guardian [ Time Frame: 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.

  22. Change From Baseline in Neuropsychiatric Assessments as Completed by Participant [ Time Frame: 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.

  23. Change From Baseline in Neuropsychiatric Assessments as Completed by Parent/Legal Guardian [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03820258


Locations
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Italy
SOS-intraSOC Epatologia
Firenze, Italy, 50139
US Infettivologia Pediatrica-Polo Universitario
Milano, Italy, 20157
Servizio di Epatologia e Nutrizione Pediatrica
Milan, Italy, 20122
UOS Epatologia Pediatrica
Napoli, Italy, 80131
UOSD Epatologia
San Giovanni Rotondo, Italy, 71013
Poland
Wojewodzki Szpital
Bydgoszcz, Poland, 85-030
Med Polonia
Poznan, Poland, 60-693
Uniwersytecki Szpital Kliniczny im.
Wroclaw, Poland, 50-368
United Kingdom
Birmingham Women's and Children's NHS Foundation Trust
Birmingham, United Kingdom, B4 6NH
Kings Healthcare NHS Trust Hospital
London, United Kingdom, SE5 9RS
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Statistical Analysis Plan  [PDF] April 10, 2020
Study Protocol  [PDF] March 27, 2019

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT03820258    
Other Study ID Numbers: GS-US-367-1175
2018-000480-87 ( EudraCT Number )
First Posted: January 29, 2019    Key Record Dates
Results First Posted: August 31, 2020
Last Update Posted: October 23, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: 18 months after study completion
Access Criteria: A secured external environment with username, password, and RSA code.
URL: https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Hepatitis A
Hepatitis C
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections