Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children With Chronic HCV-Infection

Study Overview
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Brief Summary
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The primary objective of the PK Lead-in Phase of the study is to evaluate the steady state pharmacokinetics (PK) and confirm the dose of ledipasvir/sofosbuvir (LDV/SOF) fixed dose combination (FDC) in hepatitis C virus (HCV)-infected pediatric participants. The PK Lead-in Phase will also evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of LDV/SOF FDC in HCV-infected pediatric participants. The Treatment Phase will be initiated by age cohort after confirmation of age-appropriate LDV/SOF FDC dosage levels. Participants from the PK Lead-in Phase will immediately rollover into the Treatment Phase with no interruption of study drug administration. The primary objective of the Treatment Phase is to evaluate the antiviral efficacy, safety, and tolerability of LDV/SOF FDC +/- ribavirin (RBV) for 12 or 24 weeks in pediatric participants with HCV. During screening, participants will receive placebo to match LDV/SOF FDC to assess ability to swallow tablets.

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

Conditions
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Hepatitis C Virus Infection

Intervention / Treatment
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* Drug: LDV/SOF
* Drug: RBV


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Consent of parent or legal guardian required Chronic HCV infection Screening laboratory values within defined thresholds Key Exclusion Criteria: History of clinically significant illness or any other medical disorder that may interfere with individual's treatment, assessment or compliance with the protocol. Co-infection with HIV, acute hepatitis A virus, or hepatitis B virus Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage) Pregnant or nursing females Known hypersensitivity to study medication Use of any prohibited concomitant medications as within 28 days of the Day 1 visit Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 12 to < 18 Years Old<br>Participants between 12 to < 18 years of age weighing ≥ 45 kg will receive LDV/SOF FDC (90/400 mg tablet or 4 x 22.5 mg/100 mg tablets or 8 x 11.25/50 mg granules based on swallowability assessment during screening). Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment. United Kingdom: HCV genotypes (GT) 1, 4, 5, or 6 treatment-naive (TN) with or without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 treatment-experienced (TE) without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks United States/Australia/New Zealand: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks | Drug: LDV/SOF<br>* LDV/SOF FDC administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* Ribavirin (RBV) oral solution or capsules will be administered orally in a divided daily dose based on weight<br>* Other names: REBETOL®;|
| Experimental: 6 to < 12 Years Old<br>Participants between 6 to < 12 years of age weighing ≥ 17 kg and < 45 kg will receive LDV/SOF FDC (45/200 mg as 2 x 22.5/100 mg tablets or 4 x 11.25/50 mg granules based on swallowability assessment during screening). Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment. United Kingdom: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks United States/Australia/New Zealand: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks | Drug: LDV/SOF<br>* LDV/SOF FDC administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* Ribavirin (RBV) oral solution or capsules will be administered orally in a divided daily dose based on weight<br>* Other names: REBETOL®;|
| Experimental: 3 to < 6 Years Old<br>Participants between 3 to < 6 years of age weighing ≥ 17 kg will receive LDV/SOF FDC (45/200 mg granules as 4 x 11.25/50 mg packets) and participants weighing < 17 kg will receive LDV/SOF FDC (33.75/150 mg oral granules as 3 x 11.25/50 mg packets). Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment. United Kingdom: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks United States/Australia/New Zealand: HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks | Drug: LDV/SOF<br>* LDV/SOF FDC administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* Ribavirin (RBV) oral solution or capsules will be administered orally in a divided daily dose based on weight<br>* Other names: REBETOL®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Participants in the PK Lead-in Phase, Pharmacokinetic (PK) Parameter: AUCtau of GS-331007 (Metabolite of SOF), LDV, and SOF | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Cohorts 1 and 2 (6 to < 18 years of age): predose, 0.5, 1, 2, 3, 4, 5, 8, and 12 hours postdose on Day 10; Cohort 3 (3 to < 6 years of age): predose, 0.5, 2, 4, 8, and 12 hours postdose on Day 10 | 
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event During the PK Lead-in Phase or the Treatment Phase |  | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Participants in the PK Lead-in Phase, Change From Baseline in HCV RNA |  | Baseline; Weeks 1, 2, 4, 8, and 12 | 
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event During the PK Lead-in Phase |  | Up to Day 10 | 
| For the Treatment Phase, Percentage of Participants With Sustained Virologic Response (SVR) at 4 Weeks After Discontinuation of Therapy (SVR4) | SVR4 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 4 weeks after stopping study treatment. | Posttreatment Week 4 | 
| For the Treatment Phase, Percentage of Participants With SVR at 12 Weeks After Discontinuation of Therapy (SVR12) | SVR12 was defined as HCV RNA < LLOQ at 12 weeks after stopping study treatment. | Posttreatment Week 12 | 
| For the Treatment Phase, Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) | SVR24 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment. | Posttreatment Week 24 | 
| For the Treatment Phase, Percentage of Participants Experiencing Viral Breakthrough | Viral breakthrough was defined as having confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment. | Up to 24 weeks | 
| For the Treatment Phase, Percentage of Participants Experiencing Viral Relapse | Viral relapse was defined as having confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit. | Up to Posttreatment Week 24 | 
| For the Treatment Phase, Change From Baseline in HCV RNA |  | Baseline; Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only) | 
| For the Treatment Phase, Percentage of Participants With HCV RNA < LLOQ While On Treatment |  | Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only) | 
| For the Treatment Phase, Percentage of Participants With Alanine Aminotransferase (ALT) Normalization | ALT normalization was defined as ALT > the upper limit of normal (ULN) at baseline and ALT ≤ ULN at each visit. | Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only), and Posttreatment Week 4 | 
| For the Treatment Phase, Change From Baseline in Height |  | Baseline; Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only), and Posttreatment Weeks 4, 12, and 24 | 
| For the Treatment Phase, Change From Baseline in Weight |  | Baseline; Weeks 1, 2, 4, 8, 12, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only), and Posttreatment Weeks 4, 12, and 24 | 
| For the Treatment Phase, Number of Male Participants With a Change From Baseline in Tanner Stage for Pubic Hair | Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented. | Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24 | 
| For the Treatment Phase, Number of Male Participants With a Change From Baseline in Tanner Stage for Genitalia Development | Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented. | Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24 | 
| For the Treatment Phase, Number of Female Participants With a Change From Baseline in Tanner Stage for Pubic Hair | Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented. | Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24 | 
| For the Treatment Phase, Number of Female Participants With a Change From Baseline in Tanner Stage for Breast Development | Tanner Stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Any shifts (increase or decrease) in Tanner Stage from Baseline were analyzed and presented. | Baseline; End of Treatment (either Week 12 or 24), Posttreatment Week 12, and Posttreatment Week 24 | 
| Acceptability of LDV/SOF Tablets as Measured by the Percentage of Participants Able/Unable to Swallow Placebo Tablet at Day 1 | Participants who were able/unable to swallow placebo tablets were assessed. Participants 12 to < 18 years old were first asked to perform the swallowability assessment using the 90/400 mg placebo tablet. If they were unable to swallow this, they were then asked to perform the swallowability assessment with 22.5/100 mg placebo tablets. Participants 6 to < 12 years old were to be assessed with the 22.5/100 mg placebo tablets. However, 8 participants were mistakenly assessed using the 90/400 mg placebo tablet. | Day 1 | 
| Acceptability of LDV/SOF Granules as Measured by Palatability at Day 1 | Participants who were dosed with granules were asked if they tasted the study drug. If they tasted it, then they were asked to provide a number from 0 to 100 to rate the taste of the study drug, with higher scores indicating better taste. Data was then summarized as percentage of participants choosing the following palatability categories: 1) Did not taste the study drug, 2) Tasted drug with score > 60 to 100, 3) Tasted drug with score 40 to 60, and 4) Tasted drug with score of 0 to < 40. | Day 1 |