Study Design and Participants
ZIRCON (NCT02486406) is an ongoing, open-label, multinational study. It was designed to evaluate the pharmacokinetics, safety, and efficacy of individually formulated OBV, PTV, ritonavir, DSV mini-tablets with or without RBV oral solution (pediatric formulation) in children aged 3–11 years, who were infected with HCV GT1, treatment-naïve, and without cirrhosis. The study was designed to allow dose adjustments of OBV, PTV, ritonavir, and DSV to achieve optimal therapeutic exposure to the mini-tablet formulations.
The study enrolled chronic HCV-infected children aged 3–11 years who were treatment–naïve, weighing ≥ 15 kg, with HCV GT1 [positive anti-HCV antibody test and HCV ribonucleic acid (RNA) concentration ≥ 1000 IU/mL at screening] without cirrhosis in the United States between July 2017 and November 2017. At least 12 children aged 9–11 years (≥ 4 with a body weight 15–44 kg), and at least 12 children aged 3–8 years (≥ 2 children from each of the age groups 3–5 years and 6–8 years) were planned for enrollment. Absence of cirrhosis was based on liver biopsy (Metavir score ≤ 3, Ishak score ≤ 4) or a FibroScan™ (Echosens, Paris, France) result of < 14.6 kPa within the 24 months before screening. If neither biopsy nor FibroScan results were available, FibroTest™ (BioPredictive, Paris, France) was performed at screening and a score of < 0.75 confirmed absence of cirrhosis.
Key exclusion criteria included coinfection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV); current or past clinical evidence of Child–Pugh B or C classification (Child–Pugh score ≥ 7) or clinical history of liver decompensation; hepatocellular carcinoma; previous or current use of any investigational or commercially available anti-HCV drug; history of solid organ transplantation; or any of the following abnormal laboratory results: albumin < 2.8 g/dL, hemoglobin < 10 g/dL, platelets < 25,000 cells/mm3, or total bilirubin > 3.0 mg/dL. Full eligibility criteria are provided in S1.
Eligible children were allocated to receive 12 weeks of treatment with OBV, PTV, ritonavir, and DSV mini-tablet formulations, administered in a dosing vehicle of soft food with or without RBV solution, depending on the HCV GT1 subtype. All HCV GT1a-infected patients received weight-based RBV; dosing was in accordance to the US local label. Children aged 9–11 years were enrolled and treated first. Following acceptable efficacy, safety, and pharmacokinetic data in at least six children, children aged 3–8 years were enrolled and treated. All children received treatment based on body weight (Table
1).
Table 1Weight-based dosing regimen
15–29 | 10 | 50 | 35 | 100 | GT1a only |
30–44 | 15 | 100 | 70 | 150 | GT1a only |
≥ 45 | 25 | 150 | 100 | 250 | GT1a only |
All participants, irrespective of whether they prematurely discontinued study treatment, were followed up for an initial 24-week post-treatment period. The durability of response, emergence, and persistence of drug resistance, and the impact of study treatment on participants’ growth and development were assessed until post-treatment Week 144 in those who completed the post-treatment Week-24 visit.
Children with virologic failure during the treatment period were discontinued from study treatment per protocol. Virologic failure was defined as two consecutive HCV RNA measurements > 1 log 10 IU/mL above nadir at any time point or two consecutive HCV RNA measurements ≥ 100 IU/mL at any point after achieving HCV RNA less than the lower limit of quantification (LLOQ).
The study protocol and amendments were approved by the independent ethics committee or institutional review board for each study site. IRB/IEC approval was given to the study protocol by: Columbia University Medical Center; Boston Children’s Hospital; the Committees for Protection of Human Subjects at the Children’s Hospital of Philadelphia; the Western Institutional Review Board (WIRB) at the University of Florida; WIRB at Seattle Children’s Hospital; WIRB at Baylor College of Medicine; WIRB at the Children’s Hospital Colorado; the Indiana University Office of Research Administration, Human Subjects Office; the Human Research Protection Program IRB at the University of California, San Francisco. The study was designed and conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki. Parents or legal guardians provided written informed consent, and participants gave assent, as appropriate for their age and country. All authors had access to study data and reviewed and approved the final manuscript.
Efficacy Assessments
The primary efficacy endpoint was the percentage of children who achieved SVR12, defined as an HCV RNA concentration less than the LLOQ at post-treatment Week 12. Secondary efficacy endpoints were the percentages of children who achieved SVR12 by age group (9–11 years and 3–8 years) and by weight range and the percentages of children with normalization of alanine aminotransferase (ALT) concentrations during treatment [ALT ≤ central laboratory’s upper limit of normal (ULN); 34 U/L for females and 43 U/L for males] by age and weight group at the final treatment visit for children with ALT above ULN at baseline.
Blood samples were collected to determine HCV RNA concentrations at screening; on treatment Day 1; during treatment Weeks 2, 4, 8, and 12; and post-treatment Weeks 4, 12, 24, 36, 48, 96, and 144. HCV RNA concentrations were determined at a central laboratory (Covance® Central Laboratory Services) using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test (Roche, Basel, Switzerland), v2.0 (LLOQ and lower limit of detection: 15 IU/mL).
Safety Assessments
The following safety evaluations were undertaken at each visit during the 12-week treatment period: assessment of adverse events (AEs) and vital signs (up to post-treatment Week 44), and clinical laboratory findings (up to post-treatment Week 4), along with a symptom-directed physical examination when indicated. All AEs that occurred between the first dose of study treatment and 30 days after the last dose were recorded and coded according to the Medical Dictionary for Regulatory Activities (MedDRA MSSO, McLean, VA, USA) System Organ Class and preferred term (v.21.0). The relatedness of AEs to DAA or RBV treatment and the severity of AEs [according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) criteria] were assessed by the investigator.
The following growth and development endpoints were measured through post-treatment Week 24: growth rate at each post-baseline visit (defined as change in height divided by change in age from the previous visit), height z score, waist circumference, and Tanner staging.
Statistical Analysis
All data were analyzed using the SAS® software package (SAS Institute, Cary, NC, USA). For analysis of the primary and secondary efficacy endpoints, the percentages of children who achieved SVR12 were calculated with two-sided 95% confidence intervals (CIs) in the intention-to-treat (ITT) population, which comprised all patients who had received at least one dose of study treatment. The 95% CIs were calculated using the normal approximation to the binomial distribution if the rate was not 0% or 100%; otherwise, the Wilson’s score method was used. Backward imputation was used to impute missing data for SVR endpoints only. If there was no value in the window, but there was an HCV RNA value after the window, it was imputed into the SVR window; otherwise, participants were considered failures.
Safety was analyzed in all children who received at least one dose of study treatment (safety population) and summarized descriptively.
A planned sample size of 12 participants in each of the age groups 3–8 years and 9–11 years was considered adequate to characterize the pharmacokinetics of the mini-tablet formulations.