Study design
CERTAIN-1 (NCT02707952) is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in Japanese patients with HCV infection. The study was composed of two substudies; in Substudy 1, DAA-naïve patients with GT1 HCV infection without cirrhosis and without the Y93H polymorphism were randomized to 8 weeks of treatment with G/P (Arm A) or 12 weeks of treatment with OBV/PTV/r (Arm B). The randomization was stratified by prior IFN-experience (naïve versus experienced) and HCV RNA viral load (< or ≥ 6 million IU/ml). Patients without the NS5A Y93H polymorphism were randomized 2:1 to Arms A or B, while patients with the Y93H polymorphism were assigned to Arm A only. In Substudy 2, DAA-naïve patients with GT1 HCV infection with compensated cirrhosis were assigned to 12 weeks of G/P (300/120 mg) once daily. All patients reported here were required to have an eGFR ≥ 30 ml/min/1.73 m2. Substudy 2 also enrolled cohorts of patients other than those with GT1 infection and cirrhosis, including those with eGFR < 30 m/min/1.73 m2 and results will be reported elsewhere. All patients were followed for 24 weeks after the last dose of study drug. Figure 1 shows the study design. The treatment duration of G/P for patients without cirrhosis and with compensated cirrhosis was based on both the results from the global Phase 2 SURVEYOR-I and SURVEYOR-II studies [17, 18], and the clinical exposure-response simulation predicted range (data not shown).
All patients provided written, informed consent to participate and the study was conducted consistent with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines. The study was approved by an institutional review board of each study site prior to the initiation of any screening or study-specific procedures. Supporting Fig. 1 shows patient disposition.
Patients
Patients were screened from February 22, 2016 to June 1, 2016 at 62 study sites in Japan. Adults ≥ 18 years of age with GT1 HCV infection without cirrhosis were eligible for enrollment in CERTAIN-1 Substudy 1 and those with GT1 HCV infection and compensated cirrhosis were eligible for enrollment in CERTAIN-1 Substudy 2. Patients were required to be either HCV treatment-naïve or to have failed prior IFN/pegIFN ± RBV therapy, be DAA-naïve, test positive for anti-HCV Ab, have a plasma HCV RNA load ≥ 1000 IU/ml at the time of screening and have a laboratory result indicating HCV infection with GT1 only. HCV NS5A population sequencing was performed by a central laboratory at the screening visit for Substudy 1 patients to detect the presence or absence of the Y93H polymorphism (approximately 15% detection threshold for Y93H).
In Substudy 1, patients were required to demonstrate absence of cirrhosis with one of the following criteria: a liver biopsy demonstrating absence of cirrhosis (e.g., Metavir score of ≤ 3 or an Ishak score of ≤ 4), a Fibroscan score < 12.5 kPa, or FibroTest score ≤ 0.72 and aspartate aminotransferase to Platelet Ratio Index ≤ 2. Patients with compensated cirrhosis enrolled in Substudy 2 were required to have one of the following: a liver biopsy with a METAVIR (or equivalent) fibrosis score > 3 or Ishak fibrosis score > 4, a FibroTest score ≥ 0.73 with an aminotransferase to Platelet Ratio Index > 2, a FibroScan score ≥ 14.6 kPa or screening Discriminant Score (z) greater than zero. Absence of HCC was confirmed with a negative ultrasound, computed tomography scan or magnetic resonance imaging scan within 3 months prior to screening or a negative ultrasound at screening. HCV genotype was assessed with the Versant® HCV Genotype Inno LiPA Assay, version 2.0 or higher; if the assay failed to yield a result, a Sanger sequencing assay of the NS5B region was used.
Patients were excluded from this study if they had a positive test result for hepatitis B surface antigen, or anti-human immunodeficiency virus antibody, any current or past clinical evidence of Child–Pugh B or C classification or clinical history of decompensated liver disease such as ascites, hepatic encephalopathy or variceal bleeding, any cause of liver disease other than HCV infection, any clinically significant abnormalities or co-morbidities that make the patient an unsuitable candidate for this study in the opinion of the investigator, or abnormal screening laboratory results as listed in Table 1.
Table 1 Abnormal laboratory results exclusion criteria for patients without cirrhosis and with compensated cirrhosis
Study assessments
Virologic response was assessed using serum HCV RNA concentration with a lower limit of quantitation of 15 IU/ml. Samples were collected at the screening visit, day 1 visit and treatment weeks 1, 2, 4, 8 (and week 12 for Arm B patients and patients with compensated cirrhosis) and post treatment weeks 2, 4, 8, 12, and 24. The primary efficacy endpoint for GT1 HCV-infected patients without cirrhosis was to demonstrate non-inferiority of 8 weeks of G/P compared to 12 weeks of OBV/PTV/r in achieving SVR12 among patients in the intent-to-treat (ITT) population, defined as those who received at least one dose of study drug, excluding those with the NS5A Y93H baseline polymorphism (ITT–PS). A secondary endpoint is the percentage of all patients receiving 8 weeks of G/P achieving SVR12 including those with the Y93H polymorphism (ITT population). For GT1-infected patients with compensated cirrhosis, the primary efficacy endpoint was the percentage of patients achieving SVR12 in the ITT population. The secondary endpoints for all cohorts in this study were the percentage of patients with virologic failure during treatment and virologic relapse post treatment. Next-generation sequencing was conducted on HCV NS3 and NS5A genes from samples collected from all patients at baseline, and presence of HCV baseline polymorphisms was evaluated using a 15% detection threshold.
Blood samples for pharmacokinetic assessment of the study drugs were collected from patients during each study visit (G/P: N = 129 for patients without cirrhosis and N = 38 for patients with compensated cirrhosis; OBV/PTV/r: N = 52 patients without cirrhosis). Patients consenting to intensive pharmacokinetic sampling had samples drawn at the study day 1 (at hour 2, 4, and 6 h post-dose) and at week 4 visit at hour 0 (before study drug administration) and 2 and 4 h post-dose. Plasma concentrations for GLE, PIB, and OBV/PTV/r were summarized as steady-state trough levels (Ctrough) based on binning of pharmacokinetic samples using time of sample collection after dosing, such that concentrations that fall in the interval of 22–26 h after dosing were considered as Ctrough for once daily dosing. Plasma concentrations were determined using a validated liquid chromatography assay.
Adverse events and laboratory tests were assessed and relationship to study drugs were determined by the clinical investigator throughout the treatment period and 24 weeks post-treatment for safety evaluations. Treatment emergent adverse events (TEAEs)/serious-TEAEs were collected from the time of study drug administration until 30 days following discontinuation of study treatment. After 30 days following completion of study treatment and throughout the post-treatment period, only SAEs were collected. All adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Statistical analyses
The primary analysis was conducted after all enrolled patients had completed the post-treatment week 12 visit or prematurely discontinued from the study. Efficacy, safety, and demographic analyses were performed on the ITT population. For Substudy 1, the primary efficacy endpoint was conducted on the ITT–PS population. The difference in SVR12 rate between the two arms (Arm A minus Arm B) of Substudy 1 was computed as well as the two-sided 95% confidence interval using the normal approximation to the binomial distribution. Non-inferiority of Arm A versus Arm B was considered established if the lower bound of this confidence interval was above −10%. Efficacy was also assessed in the modified ITT (mITT) population, which excluded patients who did not achieve SVR12 due to reasons other than virologic failure. Safety analyses compared the rate of adverse events and laboratory abnormalities between treatment groups (Arm A vs. Arm B) with the use of Fisher’s exact test.