Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children With Genotype 2 or 3 Chronic HCV Infection

Study Overview
=================
Brief Summary
-----------------
This study will have two parts as follows: The PK Lead-in Phase of the study will evaluate the steady state pharmacokinetics (PK) and confirm the dose of sofosbuvir (SOF) in hepatitis C virus (HCV)-infected pediatric participants. The PK Lead-in Phase will also evaluate the safety and tolerability of 7 days of dosing of SOF+ribavirin (RBV) in HCV-infected pediatric participants. The Treatment Phase will be initiated by age cohort after confirmation of age-appropriate SOF dosage levels. Participants from the PK Lead-in Phase will immediately rollover into the Treatment Phase with no interruption of study drug administration. The Treatment Phase will evaluate the antiviral efficacy, safety, and tolerability of SOF+RBV for 12 or 24 weeks in pediatric participants with genotype 2 or 3 HCV infection, respectively.

Official Title
-----------------
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm Study to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children With Genotype 2 or 3 Chronic HCV Infection

Conditions
-----------------
Hepatitis C Virus Infection

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Consent of parent or legal guardian required Chronic HCV infection genotype 2 or 3 Screening laboratory values within defined thresholds PK Lead-in only: all individuals must be treatment naive 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 HIV, acute hepatitis A virus, or hepatitis B virus Clinical hepatic decompensation (ie, 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
-----------------
Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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, SOF+RBV 12 Weeks (GT 2)<br>Participants between 12 to < 18 years of age with genotype (GT) 2 HCV infection weighing ≥ 45 kg will receive SOF (1 x 400 mg tablet, 4 x 100 mg tablets, or 8 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 12 weeks. | Drug: SOF<br>* SOF administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* RBV oral solution or capsules will be administered orally in a divided daily dose based on weight<br>* Other names: REBETOL®;|
| Experimental: 12 to < 18 Years Old, SOF+RBV 24 Weeks (GT 3)<br>Participants between 12 to < 18 years of age with genotype 3 HCV infection weighing ≥ 45 kg will receive SOF (1 x 400 mg tablet, 4 x 100 mg tablets, or 8 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 24 weeks. | Drug: SOF<br>* SOF administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* 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, SOF+RBV 12 Weeks (GT 2)<br>Participants between 6 to < 12 years of age with genotype 2 HCV infection weighing ≥ 17 kg and < 45 kg will receive SOF (2 x 100 mg tablets or 4 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 12 weeks. | Drug: SOF<br>* SOF administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* 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, SOF+RBV 24 Weeks (GT 3)<br>Participants between 6 to < 12 years of age with genotype 3 HCV infection weighing ≥ 17 kg and < 45 kg will receive SOF (2 x 100 mg tablets or 4 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 24 weeks. | Drug: SOF<br>* SOF administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* 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, SOF+RBV 12 Weeks (GT 2)<br>Participants between 3 to < 6 years of age with genotype 2 HCV infection weighing ≥ 17kg will receive SOF (4 x 50 mg oral granules) plus RBV (up to 1400 mg) for 12 weeks and those weighing < 17 kg will receive SOF (3 x 50 mg oral granules) + RBV (up to 1400 mg) for 12 weeks. | Drug: SOF<br>* SOF administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* 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, SOF+RBV 24 Weeks (GT 3)<br>Participants between 3 to < 6 years of age with genotype 2 HCV infection weighing ≥ 17kg will receive SOF (4 x 50 mg oral granules) plus RBV (up to 1400 mg) for 24 weeks and those weighing < 17 kg will receive SOF (3 x 50 mg oral granules) + RBV (up to 1400 mg) for 24 weeks. | Drug: SOF<br>* SOF administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* 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?
-----------------
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) | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | 6 to < 18 years of age: predose, 0.5, 1, 2, 3, 4, 8, and 12 hours postdose on Day 7; 3 to < 6 years of age: predose, 2, 4, 8, and 12 hours postdose on Day 7 | 
| 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 | 
| For the Treatment Phase, Percentage of Participants With SVR at 12 Weeks After Discontinuation of Therapy (SVR12) | SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 12 weeks after stopping study treatment. | Posttreatment Week 12 | 

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, 16 (24 Week groups only), 20 (24 Week groups only), and 24 (24 Week groups only) | 
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event During the PK Lead-in Phase |  | Up to Day 7 | 
| 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 < LLOQ at 4 weeks after stopping study treatment. | Posttreatment Week 4 | 
| 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. One participant in the 3 to < 6 Years Old 12 Weeks group had ALT > ULN at Baseline, but had no other available data. | 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 | 
| For the Treatment Phase, Palatability of SOF Granules at Day 1 as Assessed by the Percentage of Participants Able/Unable to Taste the SOF Oral Granules | Participants were asked if they were able to taste the SOF oral granules. | Day 1 |