Clinical Trial Results:
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
Summary
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EudraCT number |
2016-002446-23 |
Trial protocol |
GB BE Outside EU/EEA IT |
Global end of trial date |
26 Feb 2020
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Results information
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Results version number |
v2(current) |
This version publication date |
21 Oct 2020
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First version publication date |
09 Sep 2020
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
GS-US-342-1143
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03022981 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Gilead Sciences
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Sponsor organisation address |
333 Lakeside Drive, Foster City, CA, United States, 94404
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Public contact |
Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
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Scientific contact |
Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001646-PIP01-14 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Feb 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Nov 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Feb 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the Pharmacokinetics (PK) Lead-in Phase was 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 was to evaluate the safety and tolerability of SOF/VEL for 12 weeks in pediatric participants with chronic HCV.
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Protection of trial subjects |
The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Jan 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 15
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Country: Number of subjects enrolled |
United States: 172
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Country: Number of subjects enrolled |
Belgium: 5
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Country: Number of subjects enrolled |
Italy: 24
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Worldwide total number of subjects |
216
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EEA total number of subjects |
44
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
114
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Adolescents (12-17 years) |
102
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were enrolled at 28 study sites in Belgium, Italy, the United Kingdom, and the United States. The first participant was screened on 26 January 2017. The final on-study visit occurred on 26 February 2020. | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
221 participants were screened. | ||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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12 to < 18 Years Old | ||||||||||||||||||||||||||||||||||||||||
Arm description |
PK Lead-in Phase: Sofosbuvir/Velpatasvir (SOF/VEL) fixed-dose combination (FDC) 400/100 mg tablets or 2 * 200/50 mg tablets once daily for 7 days. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 400/100 mg tablets or 2 * 200/50 mg tablets once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SOF/VEL FDC
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet, Granules
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets or oral granules administered once daily.
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Arm title
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6 to < 12 Years Old | ||||||||||||||||||||||||||||||||||||||||
Arm description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 7 days. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SOF/VEL FDC
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Granules, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets or oral granules administered once daily.
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Arm title
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3 to < 6 Years Old | ||||||||||||||||||||||||||||||||||||||||
Arm description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 7 days for participants who weighed ≥ 17 kg. SOF/VEL 150/37.5 mg FDC oral granules once daily for 7 days for participants who weighed < 17 kg. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 12 weeks for participants who weighed ≥ 17 kg. SOF/VEL 150/37.5 mg FDC oral granules once daily for 12 weeks for participants who weighed < 17 kg. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SOF/VEL FDC
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Granules, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets or oral granules administered once daily.
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Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 17 subjects participated in the PK lead-in phase and continued treatment in the treatment phase and thus are included in the total number of subjects started, completed, and not completed. Additional participants were enrolled in the treatment phase upon confirmation of the appropriateness of the dose from the PK lead-in phase. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 20 subjects participated in the PK lead-in phase and continued treatment in the treatment phase and thus are included in the total number of subjects started, completed, and not completed. Additional participants were enrolled in the treatment phase upon confirmation of the appropriateness of the dose from the PK lead-in phase. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 19 subjects participated in the PK lead-in phase and continued treatment in the treatment phase and thus are included in the total number of subjects started, completed, and not completed. Additional participants were enrolled in the treatment phase upon confirmation of the appropriateness of the dose from the PK lead-in phase. |
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Baseline characteristics reporting groups
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Reporting group title |
12 to < 18 Years Old
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Reporting group description |
PK Lead-in Phase: Sofosbuvir/Velpatasvir (SOF/VEL) fixed-dose combination (FDC) 400/100 mg tablets or 2 * 200/50 mg tablets once daily for 7 days. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 400/100 mg tablets or 2 * 200/50 mg tablets once daily for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
6 to < 12 Years Old
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Reporting group description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 7 days. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
3 to < 6 Years Old
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Reporting group description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 7 days for participants who weighed ≥ 17 kg. SOF/VEL 150/37.5 mg FDC oral granules once daily for 7 days for participants who weighed < 17 kg. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 12 weeks for participants who weighed ≥ 17 kg. SOF/VEL 150/37.5 mg FDC oral granules once daily for 12 weeks for participants who weighed < 17 kg. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
12 to < 18 Years Old
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Reporting group description |
PK Lead-in Phase: Sofosbuvir/Velpatasvir (SOF/VEL) fixed-dose combination (FDC) 400/100 mg tablets or 2 * 200/50 mg tablets once daily for 7 days. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 400/100 mg tablets or 2 * 200/50 mg tablets once daily for 12 weeks. | ||
Reporting group title |
6 to < 12 Years Old
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Reporting group description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 7 days. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 12 weeks. | ||
Reporting group title |
3 to < 6 Years Old
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Reporting group description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 7 days for participants who weighed ≥ 17 kg. SOF/VEL 150/37.5 mg FDC oral granules once daily for 7 days for participants who weighed < 17 kg. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 12 weeks for participants who weighed ≥ 17 kg. SOF/VEL 150/37.5 mg FDC oral granules once daily for 12 weeks for participants who weighed < 17 kg. | ||
Subject analysis set title |
12 to <18 Years Old
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Treatment Phase: 2 * SOF/VEL 200/50 mg (adult and smaller size tablets based on swallowability assessment) once daily for 12 weeks.
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Subject analysis set title |
6 to <12 Years Old
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Treatment Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 12 weeks.
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Subject analysis set title |
3 to <6 Years Old
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
SOF/VEL FDC 150/37.5 mg oral granules once daily for 12 weeks for participants who weighed < 17 kg.
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End point title |
PK Lead-in Phase: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Velpatasvir (VEL) [1] | ||||||||||||||||
End point description |
AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). The Lead-in Phase Pharmacokinetic (PK) Analysis Set included all PK lead-in phase participants with available data who received at least 1 dose of study drug and whom at least one non-missing PK concentration data value is available from the PK Lead-in Phase intensive sampling.
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End point type |
Primary
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End point timeframe |
Day 7: 0 (predose), 0.5, 1, 2, 3, 4, 6 (Cohorts 1 and 2 only), 8, and 12 hours postdose
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical comparison was planned or performed. |
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No statistical analyses for this end point |
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End point title |
PK Lead-in Phase: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Sofosbuvir (SOF) [2] | ||||||||||||||||
End point description |
AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). Participants in the Lead-in Phase PK Analysis Set with available data were analyzed.
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End point type |
Primary
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End point timeframe |
Day 7: 0 (predose), 0.5, 1, 2, 3, 4, 6 (Cohorts 1 and 2 only), 8, and 12 hours postdose
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical comparison was planned or performed. |
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No statistical analyses for this end point |
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End point title |
PK Lead-in Phase: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of GS-331007 (Metabolite of SOF) [3] | ||||||||||||||||
End point description |
AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). Participants in the Lead-in Phase PK Analysis Set with available data were analyzed.
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End point type |
Primary
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End point timeframe |
Day 7: 0 (predose), 0.5, 1, 2, 3, 4, 6 (Cohorts 1 and 2 only), 8, and 12 hours postdose
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical comparison was planned or performed. |
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Percentage of Participants Who Discontinued Study Drug Due to Any Treatment-Emergent Adverse Event (TEAE) [4] | ||||||||||||||||
End point description |
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. The Safety Analysis Set included all participants who were enrolled into the study and received at least 1 dose of study drug (SOF/VEL FDC).
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End point type |
Primary
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End point timeframe |
From first dose through last dose of the study drug (Up to 12 weeks) plus 30 days
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical comparison was planned or performed. |
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No statistical analyses for this end point |
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End point title |
PK Lead-in Phase: Change From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 7 | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline; Day 7
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No statistical analyses for this end point |
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End point title |
PK Lead-in Phase: Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse (AE) | ||||||||||||||||
End point description |
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. Participants in the Lead-in Phase PK Analysis Set were analyzed.
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End point type |
Secondary
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End point timeframe |
First dose date up to Day 7
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Percentage of Participants With Sustained Virologic Response (SVR) at 12 Weeks After Discontinuation of Therapy (SVR12) | ||||||||||||||||
End point description |
SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 12 weeks after stopping study treatment. The Full Analysis Set included all participants who were enrolled into the study and received at least 1 dose of study drug (SOF/VEL FDC).
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End point type |
Secondary
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End point timeframe |
Posttreatment Week 12
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) | ||||||||||||||||
End point description |
SVR4 was defined as HCV RNA < LLOQ (ie, 15 IU/mL) at 4 weeks after stopping study treatment. Participants in the Full Analysis Set were analyzed.
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End point type |
Secondary
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End point timeframe |
Posttreatment Week 4
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) | ||||||||||||||||
End point description |
SVR 24 was defined as HCV RNA < LLOQ (ie, 15 IU/mL) at 24 weeks after stopping study treatment. Participants in the Full Analysis Set were analyzed.
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End point type |
Secondary
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End point timeframe |
Posttreatment Week 24
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Percentage of Participants With Virologic Failure | ||||||||||||||||
End point description |
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. Participants in the Full Analysis Set were analyzed.
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End point type |
Secondary
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End point timeframe |
Up to Posttreatment Week 24
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Percentage of Participants With HCV RNA < LLOQ On Treatment | ||||||||||||||||||||||||||||||||
End point description |
Percentage of participants with HCV RNA < LLOQ while on treatment by analysis visit. Participants in the Full Analysis Set were analyzed.
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End point type |
Secondary
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End point timeframe |
Weeks 1, 4, 8, and 12
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Percentage of Participants Who Develop Viral Resistance to SOF and/or VEL During Treatment and After Discontinuation of Treatment | ||||||||||||||||||||||||
End point description |
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).
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
First dose date up to Posttreatment Week 24
|
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|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||
End point title |
Treatment Phase: Change From Baseline in HCV RNA at Weeks 1, 4, 8, and 12 | ||||||||||||||||||||||||||||||||||||
End point description |
Participants in the Full Analysis Set with available data were analyzed.
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline; Weeks 1, 4, 8, and 12
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Quality of Life (QoL) and Neuropsychiatric Assessments as Measured by PedsQL™ Pediatric QoL Survey | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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 (baseline/BL), end of treatment (EOT), early termination (if applicable), and posttreatment Weeks (Wk) 12 (follow up-12/FU-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. Participants in the Full Analysis Set with available data were analyzed.
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End point type |
Secondary
|
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End point timeframe |
Baseline; Week 12, End of Treatment (EOT), Posttreatment/Follow-up (FU) Week-12 (FU-12), and FU Week-24 (FU-24)
|
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Change From Baseline in Growth and Development as Measured by Height Percentiles | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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. Participants in the Safety Analysis Set with available data were analyzed.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline; Weeks 1, 4, 8, 12, Follow-up (FU) Week 4 (FU-4), FU-12, and FU-24
|
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|
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No statistical analyses for this end point |
|
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End point title |
Treatment Phase: Change From Baseline in Growth and Development as Measured by Weight Percentiles | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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. Participants in the Safety Analysis Set with available data were analyzed.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline; Weeks 1, 4, 8, 12, FU-4, FU-12, and FU-24
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
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No statistical analyses for this end point |
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|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Treatment Phase: Changes in Growth and Development as Measured by Tanner Stage Assessment From Baseline | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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). Safety Analysis Set.
|
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End point type |
Secondary
|
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End point timeframe |
Up to Posttreatment Week 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Growth and Development as Measured by Parental Height | ||||||||||||||||
End point description |
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. Participants in the Safety Analysis Set with available data were analyzed.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 1
|
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|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Treatment Phase: Change From Baseline in Growth and Development as Measured by Bone Age | ||||||||||||||||||||||||
End point description |
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. Participants in the Full Analysis Set with available data were analyzed.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline; FU-24
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Treatment Phase: Swallowability of SOF/VEL as Assessed by the Participant's Ability to Swallow SOF/VEL Placebo Tablets at Baseline [5] | |||||||||||||||||||||
End point description |
A SOF/VEL FDC swallowability assessment was performed using placebo (PBO) tablets at baseline. Participants in the Full Analysis Set with available data were analyzed. Swallowability assessment was performed in 12 to <18 years old and 6 to < 12 Years old only.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline
|
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Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical comparison was planned or performed. |
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|
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No statistical analyses for this end point |
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End point title |
Treatment Phase: Number of Participants With Acceptability of SOF/VEL as Measured by a Questionnaire to Assess Acceptability, Including Palatability at Day 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Acceptability was assessed by numeric response marked on line between numbers 0 - 100. Higher scores indicate better acceptability and/or palatability. Participants in the Full Analysis Set with available data were analyzed.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1
|
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|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Treatment Phase: Number of Participants With Acceptability of SOF/VEL as Measured by a Questionnaire to Assess Acceptability, Including Palatability at Week 12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Acceptability was assessed by numeric response marked on line between numbers 0 - 100. Higher scores indicate better acceptability and/or palatability. Participants in the Full Analysis Set with available data were analyzed. Here, 99999 = Data not applicable for the oral granules group.
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End point type |
Secondary
|
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End point timeframe |
Week 12
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No statistical analyses for this end point |
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Adverse events information
|
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Timeframe for reporting adverse events |
Adverse Events: From first dose through last dose of the study drug (Up to 12 weeks) plus 30 days; All-Cause Mortality: First dose date up to Posttreatment Week 24
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Adverse event reporting additional description |
The Safety Analysis Set included all participants who were enrolled into the study and received at least 1 dose of study drug (SOF/VEL FDC).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.1
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Reporting groups
|
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Reporting group title |
12 to < 18 Years Old
|
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Reporting group description |
PK Lead-in Phase: Sofosbuvir/Velpatasvir (SOF/VEL) fixed-dose combination (FDC) 400/100 mg tablets or oral granules once daily for 7 days. Participants who completed the PK lead-in phase and other additional participants were enrolled into the treatment phase with no interruption of study drug administration until the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 400/100 mg tablets or oral granules once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
6 to < 12 Years Old
|
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Reporting group description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 7 days. Participants who completed the PK lead-in phase, continued into the treatment phase with no interruption of study drug administration and additional participants were enrolled into the treatment phase once the appropriateness of the dose was confirmed by PK results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg tablets or oral granules once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
3 to < 6 Years Old
|
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Reporting group description |
PK Lead-in Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 7 days for participants who weighed ≥ 17 kg. SOF/VEL FDC 150/37.5 mg oral granules once daily for 7 days for participants who weighed < 17 kg. Participants who completed the PK lead-in phase, continued into the treatment phase with no interruption of study drug administration and additional participants were enrolled into the treatment phase once the appropriateness of the dose was confirmed by PK results from the PK lead-in phase. Treatment Phase: SOF/VEL FDC 200/50 mg oral granules once daily for 12 weeks for participants who weighed ≥ 17 kg. SOF/VEL FDC 150/37.5 mg oral granules once daily for 12 weeks for participants who weighed < 17 kg. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
20 Sep 2016 |
• Added clarification that all adverse events (AEs) were recorded with a focus on those AEs leading to study drug discontinuation for evaluation of the primary safety endpoint
• Updated the SOF/VEL stopping criteria to align with the LDV/SOF and SOF laboratory stopping criteria in adult and pediatric clinical studies
• Added eligibility criteria pertaining to liver enzymes and bilirubin to align with the exclusion criteria parameters in SOF/VEL adult clinical studies
• Clarified that only the subject was required to complete the acceptability questionnaire at Day 1, but it may be completed by the parent or legal guardian if the subject is unable to read
• Clarified that the Day 3 study visit was performed over the phone and the site assessed the subject’s dosing compliance by reviewing the dosing diary remotely with the subject, parent, or legal guardian
• Added SOF/VEL Acceptability Questionnaire assessment to the early termination visit
• Appendix 3 (Management of Clinical and Laboratory AEs) was removed due to a discrepancy in the protocol stopping rules within the protocol |
||
01 Dec 2016 |
• Added serial hepatitis B virus (HBV) DNA monitoring for any subject with hepatitis B core antibody (HBcAb)-positive status at screening, per a US Food and Drug Administration Drug Safety Communication
• Added formulation, packaging, labeling, storage, and handling information for the SOF/VEL 200/50 mg and placebo tablets |
||
31 Aug 2017 |
• Added clinical pharmacology data and safety results from Cohort 1 from the PK lead-in phase supporting the dose for subjects 12 to < 18 years old (Group 1) in the treatment phase and dose determination for Cohort 2 (6 to < 12 years old) in the PK lead-in phase
• Added an optional intensive PK substudy for adolescent subjects 12 to < 18 years old enrolled in the treatment phase at Weeks 4 or 8 to support development of the population PK model
• Added additional time points to the intensive PK assessment for Cohort 3 (subjects 3 to < 6 years old) to support characterization of PK of all analytes in the youngest age group
• Added clarification of the sparse PK sample at Weeks 1, 4, 8, and 12
• Added a second sparse PK sample at Weeks 4 and 8 for all enrolled subjects
• Clarified that the non-tablet formulation information would be included in a future protocol amendment once it was available and would be submitted for approval prior to dosing of subjects
• Added biomarker testing to align with the Gilead Sciences (Gilead) protocol template
• Updated the dosing instructions in the case of vomiting to align with the SOF/VEL label
• Updated the background information to include Studies GS-US-342-1553 and GS US 342 1146 since both of these studies were not included in the SOF/VEL investigator’s brochure (IB) |
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15 Jun 2018 |
• Added clinical pharmacology data from Cohort 2 from the PK lead-in phase supporting the dose for subjects 3 to < 6 years old (Cohort 3) in the PK lead-in phase
• Added dosing instructions for subjects 3 to < 6 years old
• Added information on the oral granule formulation, including the dose for each age group and dosing instructions
• Added subject dosing diary for subjects who were administered oral granules
• Clarified dosing instructions for subjects 6 to < 12 years old
• Clarified collection of parental height
• Clarified requirements for the complete and symptom-directed physical examinations
• Updated the disallowed and concomitant medication table to align with the table in the SOF/VEL FDC IB (Edition 5.0; dated 12 December 2017)
• Updated the list of PK parameters to align with regulatory commitments
• Updated the schedule of assessments for consistency |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |