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Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in Adolescents and Children With Chronic HCV Infection

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ClinicalTrials.gov Identifier: NCT03022981
Recruitment Status : Completed
First Posted : January 18, 2017
Results First Posted : October 8, 2020
Last Update Posted : October 8, 2020
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Tracking Information
First Submitted Date  ICMJE January 13, 2017
First Posted Date  ICMJE January 18, 2017
Results First Submitted Date  ICMJE August 24, 2020
Results First Posted Date  ICMJE October 8, 2020
Last Update Posted Date October 8, 2020
Actual Study Start Date  ICMJE January 26, 2017
Actual Primary Completion Date November 19, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2020)
  • PK Lead-in Phase: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Velpatasvir (VEL) [ Time Frame: Day 7: 0 (predose), 0.5, 1, 2, 3, 4, 6 (Cohorts 1 and 2 only), 8, and 12 hours postdose ]
    AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval).
  • PK Lead-in Phase: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Sofosbuvir (SOF) [ Time Frame: Day 7: 0 (predose), 0.5, 1, 2, 3, 4, 6 (Cohorts 1 and 2 only), 8, and 12 hours postdose ]
    AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval).
  • PK Lead-in Phase: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of GS-331007 (Metabolite of SOF) [ Time Frame: Day 7: 0 (predose), 0.5, 1, 2, 3, 4, 6 (Cohorts 1 and 2 only), 8, and 12 hours postdose ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
  • Treatment Phase: Percentage of Participants Who Discontinued Study Drug Due to Any Treatment-Emergent Adverse Event (TEAE) [ Time Frame: From first dose through last dose of the study drug (Up to 12 weeks) plus 30 days ]
    An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.
Original Primary Outcome Measures  ICMJE
 (submitted: January 13, 2017)
  • For the PK Lead-in Phase, PK Parameter: AUCtau of Velpatasvir (VEL), Sofosbuvir (SOF), and its Metabolite GS-331007 [ Time Frame: Predose and up to 12 hours postdose ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
  • For the Treatment Phase, Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event (AE) with a Focus on AEs Leading to Discontinuation of Study Drug [ Time Frame: Up to 12 weeks plus 30 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2020)
  • PK Lead-in Phase: Change From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 7 [ Time Frame: Baseline; Day 7 ]
  • PK Lead-in Phase: Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (AE) [ Time Frame: First dose date up to Day 7 ]
    An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
  • Treatment Phase: Percentage of Participants With Sustained Virologic Response (SVR) at 12 Weeks After Discontinuation of Therapy (SVR12) [ Time Frame: Posttreatment Week 12 ]
    SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 12 weeks after stopping study treatment.
  • Treatment Phase: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) [ Time Frame: Posttreatment Week 4 ]
    SVR4 was defined as HCV RNA < LLOQ (ie, 15 IU/mL) at 4 weeks after stopping study treatment.
  • Treatment Phase: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) [ Time Frame: Posttreatment Week 24 ]
    SVR 24 was defined as HCV RNA < LLOQ (ie, 15 IU/mL) at 24 weeks after stopping study treatment.
  • Treatment Phase: Percentage of Participants With Virologic Failure [ Time Frame: Up to Posttreatment Week 24 ]
    Virologic failure was defined as: On-treatment virologic failure - Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), or Rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment); Virologic relapse: Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.
  • Treatment Phase: Percentage of Participants With HCV RNA < LLOQ On Treatment [ Time Frame: Weeks 1, 4, 8, and 12 ]
    Percentage of participants with HCV RNA < LLOQ while on treatment by analysis visit.
  • Treatment Phase: Percentage of Participants Who Develop Viral Resistance to SOF and/or VEL During Treatment and After Discontinuation of Treatment [ Time Frame: First dose date up to Posttreatment Week 24 ]
    Drug-resistant substitutions were analyzed as part of the Virology Study. 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 deep sequencing of the HCV nonstructural protein (NS)5A and NS5B genes was performed for all participants at the first time point after virologic failure if the plasma or serum sample was available. Pretreatment full-length NS5A deep sequencing data were obtained at a 15% assay cutoff for the Resistance Analysis Population which covered all NS5A and NS5B nucleoside inhibitor (NI) resistance-associated variants (RAVs).
  • Treatment Phase: Change From Baseline in HCV RNA at Weeks 1, 4, 8, and 12 [ Time Frame: Baseline; Weeks 1, 4, 8, and 12 ]
  • Treatment Phase: Quality of Life (QoL) and Neuropsychiatric Assessments as Measured by PedsQL™ Pediatric QoL Survey [ Time Frame: Baseline; Week 12, End of Treatment (EOT), Posttreatment/Follow-up (FU) Week-12 (FU-12), and FU Week-24 (FU-24) ]
    To evaluate the effect of treatment with SOF/VEL on general and disease-specific health-related QoL, the PedsQL™ Pediatric QoL Inventory V4.0 Short Form (SF15) was completed at Day 1, end of treatment, early termination (if applicable), and posttreatment Weeks 12 and 24. The SF15 questionnaire represented 4 domains: physical, emotional, social, and school functioning, with the emotional, social, and school functioning domains representing the psychosocial health summary. Neuropsychiatric assessment was conducted using the PedsQL™ Pediatric QoL Inventory V4.0 SF15 psychosocial domain-related scores. Items were calculated and transformed into an overall score with a range of 0 to 100 points, with more points indicating better QoL.
  • Treatment Phase: Change From Baseline in Growth and Development as Measured by Height Percentiles [ Time Frame: Baseline; Weeks 1, 4, 8, 12, Follow-up (FU) Week 4 (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.
  • Treatment Phase: Change From Baseline in Growth and Development as Measured by Weight Percentiles [ Time Frame: Baseline; Weeks 1, 4, 8, 12, FU-4, FU-12, and FU-24 ]
    An age- and sex-specific percentile was derived for each weight, height, and BMI measurement according to the SAS program available on the CDC website using the year 2000 growth charts.
  • Treatment Phase: Changes in Growth and Development as Measured by Tanner Stage Assessment From Baseline [ Time Frame: Baseline; EOT, FU-12 and FU-24 ]
    Tanner Pubertal Staging was 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 were 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 the 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, testes and penis, 3: Enlargement of penis, 4: Penis size enlargement, 5: Genitalia adult in size and shape).
  • Treatment Phase: Growth and Development as Measured by Parental Height [ Time Frame: Day 1 ]
    Mid-parental height was calculated as the average of the biological father's and mother's heights. For boys, the sex-adjusted mid-parental height was calculated by adding 2.5 inches or 6.5 cm to the mean of the parents' heights. For girls, 2.5 inches or 6.5 cm was subtracted from the mean of the parents' heights.
  • Treatment Phase: Change From Baseline in Growth and Development as Measured by Bone Age [ Time Frame: Baseline; FU-24 ]
    Bone age was determined based on x-ray of the left wrist, hand, and fingers. Baseline value is the last available value on or prior to first dose date of study drug.
  • Treatment Phase: Swallowability of SOF/VEL as Assessed by the Participant's Ability to Swallow SOF/VEL Placebo Tablets at Baseline [ Time Frame: Baseline ]
    A SOF/VEL FDC swallowability assessment was performed using placebo tablets at baseline.
  • Treatment Phase: Number of Participants With Acceptability of SOF/VEL as Measured by a Questionnaire to Assess Acceptability, Including Palatability at Day 1 [ Time Frame: Day 1 ]
    Acceptability was assessed by numeric response marked on line between numbers 0 - 100. Higher scores indicate better acceptability and/or palatability.
  • Treatment Phase: Number of Participants With Acceptability of SOF/VEL as Measured by a Questionnaire to Assess Acceptability, Including Palatability at Week 12 [ Time Frame: Week 12 ]
    Acceptability was assessed by numeric response marked on line between numbers 0 - 100. Higher scores indicate better acceptability and/or palatability.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2017)
  • For the PK Lead-in Phase, HCV RNA from Baseline Through Day 7 [ Time Frame: Up to 7 days ]
  • For the PK Lead-in Phase, Any Adverse Event Leading to Permanent Discontinuation of Study Drug [ Time Frame: Up to 7 days ]
  • For the Treatment Phase, Proportion of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) [ Time Frame: Posttreatment Week 12 ]
    SVR12 is defined as HCV RNA < the lower limit of quantitation (LLOQ) at 12 weeks after stopping study treatment.
  • For the Treatment Phase, Proportion of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) [ Time Frame: Posttreatment Week 4 ]
    SVR4 is defined as HCV RNA < LLOQ at 4 weeks after stopping study treatment.
  • For the Treatment Phase, Proportion of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) [ Time Frame: Posttreatment Week 24 ]
    SVR 24 is defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment.
  • For the Treatment Phase, Proportion of Participants With Virologic Failure [ Time Frame: Up to Posttreatment Week 24 ]
    Virologic failure is defined as:
    • On-treatment virologic failure:
      • Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), or
      • Rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or
      • Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment)
    • Virologic relapse:
      • Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.
  • For the Treatment Phase, Proportion of Participants With HCV RNA < LLOQ On Treatment [ Time Frame: Up to 12 weeks ]
  • For the Treatment Phase, Emergence of Viral Resistance to SOF and/or VEL During Treatment and When Treatment is Discontinued [ Time Frame: Up to Posttreatment Week 24 ]
  • For the Treatment Phase, HCV RNA Change from Baseline [ Time Frame: Baseline and up to 12 weeks ]
  • For the Treatment Phase, Quality of Life as Measured by PedsQL™ Pediatric Quality of Life Survey [ Time Frame: Up to Posttreatment Week 24 ]
  • For the Treatment Phase, Growth and Development as Measured by Height [ Time Frame: Up to Posttreatment Week 24 ]
  • For the Treatment Phase, Growth and Development as Measured by Weight [ Time Frame: Up to Posttreatment Week 24 ]
  • For the Treatment Phase, Growth and Development as Measured by by Tanner Stage Assessment [ Time Frame: Up to Posttreatment Week 24 ]
  • For the Treatment Phase, Growth and Development as Measured by Parental Height [ Time Frame: Day 1 ]
  • For the Treatment Phase, Growth and Development as Measured by Bone Age [ Time Frame: Up to Posttreatment Week 24 ]
  • For the Treatment Phase, Acceptability of SOF/VEL as Measured by a Questionnaire to Assess Swallowability and Palatability at Day 1 [ Time Frame: Day 1 ]
  • For the Treatment Phase, Acceptability of SOF/VEL as Measured by a Questionnaire to Assess Swallowability and Palatability at Week 12 [ Time Frame: Week 12 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in Adolescents and Children With Chronic HCV Infection
Official Title  ICMJE A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in Adolescents and Children With Chronic HCV Infection
Brief Summary

This study will have 2 parts: Pharmacokinetics (PK) Lead-in Phase and the Treatment Phase.

The primary objective of the PK Lead-in Phase is to evaluate the steady state PK and confirm the dose of sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) in pediatric participants with chronic hepatitis C virus (HCV) infection.

The primary objective of the Treatment Phase is to evaluate the safety and tolerability of SOF/VEL for 12 weeks in pediatric participants with chronic HCV.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatitis C Virus Infection
Intervention  ICMJE
  • Drug: SOF/VEL
    SOF/VEL fixed-dose combination (FDC) 400/100 mg tablets or SOF/VEL FDC 200/50 mg tablets (based on swallowability assessment)
    Other Names:
    • Epclusa®
    • GS-7977/GS-5816
  • Drug: SOF/VEL
    SOF/VEL FDC 200/50 mg oral granules
    Other Names:
    • Epclusa®
    • GS-7977/GS-5816
Study Arms  ICMJE
  • Experimental: 12 to < 18 Years Old

    PK Lead-in Phase: Sofosbuvir/Velpatasvir (SOF/VEL) 400/100 mg once daily for 7 days. Participants who complete the PK lead-in phase, continue into the treatment phase with no interruption of study drug administration and additional participants will be enrolled into the treatment phase once the appropriateness of the dose is confirmed by PK results from the PK lead-in phase.

    Treatment Phase: SOF/VEL 400/100 mg once daily for 12 weeks.

    Intervention: Drug: SOF/VEL
  • Experimental: 6 to < 12 Years Old

    PK Lead-in Phase: SOF/VEL 200/50 mg once daily for 7 days. Participants who complete the PK lead-in phase, continue into the treatment phase with no interruption of study drug administration and additional participants will be enrolled into the treatment phase once the appropriateness of the dose is confirmed by PK results from the PK lead-in phase.

    Treatment Phase: SOF/VEL 200/50 mg once daily for 12 weeks.

    Intervention: Drug: SOF/VEL
  • Experimental: 3 to < 6 Years Old

    PK Lead-in Phase: SOF/VEL 200/50 mg once daily for 7 days for participants who weigh ≥ 17 kg. SOF/VEL 150/37.5 mg once daily for 7 days for participants who weigh < 17 kg. Participants who complete the PK lead-in phase, continue into the treatment phase with no interruption of study drug administration and additional participants will be enrolled into the treatment phase once the appropriateness of the dose is confirmed by PK results from the PK lead-in phase.

    Treatment Phase: SOF/VEL 200/50 mg once daily for 12 weeks for participants who weigh ≥ 17 kg. SOF/VEL 150/37.5 mg once daily for 12 weeks for participants who weigh < 17 kg.

    Intervention: Drug: SOF/VEL
Publications * Jonas MM, Romero R, Sokal EM, Rosenthal P, Verucchi G, Lin CH, et al. The Safety and Efficacy of Sofosbuvir/Velpatasvir in Pediatric Patients 6 to < 18 years old with Chronic Hepatitis C Infection [Abstract]. AASLD; 2019 08-12 November; Boston, Massachusetts.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 24, 2020)
216
Original Estimated Enrollment  ICMJE
 (submitted: January 13, 2017)
200
Actual Study Completion Date  ICMJE February 26, 2020
Actual Primary Completion Date November 19, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Chronic HCV-infected, treatment-naive and treatment-experienced adolescent and pediatric individuals aged 3 to < 18 as determined at Day 1.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Italy,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03022981
Other Study ID Numbers  ICMJE GS-US-342-1143
2016-002446-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: 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
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Gilead Sciences
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP