Coblopasvir and sofosbuvir for treatment of chronic hepatitis C virus infection in China: A single‐arm, open‐label, phase 3 trial

Abstract Background & Aim An affordable, pangenotypic regimen remains as an unmet medical need for chronic hepatitis C patients in China. This single‐arm, open‐label, multicenter, phase 3 trial evaluated the efficacy and safety of coblopasvir, a pangenotypic non‐structural protein 5A (NS5A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic hepatitis C virus (HCV) infection. Methods Treatment‐naïve and interferon‐experienced adult patients, including those with advanced fibrosis (F3) or compensated cirrhosis (F4), were treated with a universal, combinational regimen of coblopasvir 60 mg and sofosbuvir 400 mg, once daily, for 12 weeks. The primary efficacy endpoint was sustained virological response at post‐treatment week 12 (SVR12). Results Overall, 371 patients (men, 51%; age, 47 ± 11 years; genotype 1a < 1%, 1b 48%, 2a 26%, 3a 6%, 3b 7% and 6 12%) were enrolled from 19 sites. Fifty‐one patients (14%) had F3, 39 patients (11%) had F4 and 39 patients (11%) were interferon experienced. The overall SVR12 was 97% (95% CI, [94%, 98%]) for the full analysis set and was equal to or above 90% for all predefined subsets. Ten patients (3%) experienced virological relapse and two patients did not complete follow‐up. No adverse events (AEs) occurred at a frequency ≥5%, and the most often reported AEs (≥1%) were neutropenia and fatigue. The majority of AEs were mild to moderate and transient without specific medical intervention. Conclusions The universal, pangenotypic combo of coblopasvir plus sofosbuvir is an efficacious and safe treatment for Chinese patients monoinfected with HCV of genotype 1, 2, 3 and 6, including those with compensated cirrhosis. Lay summary The regimen of coblopasvir and sofosbuvir is a safe and effective treatment for Chinese patients with genotype 1, 2, 3 and 6 HCV infection, including those with compensated cirrhosis. Therefore, this regimen would be a novel choice of treatment for this patient population.

confounding effects of HCV genotype, liver fibrosis and interferon experience on SVR.

| Study protocol and participants
This single-arm, open-label, phase 3 study was conducted at 19 clinical sites across China. The study protocol was approved by the Institutional Review Board or Independent Ethics Committee at each participating site, and the study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice and other applicable national regulations. All participants volunteered to provide informed consent in writing before any study procedures.
The eligibility criteria were as follows: men and non-pregnant and non-lactating women aged 18-70 years (inclusive); with documented chronic HCV monoinfection of genotypes 1-6 or any other (sub) types, including mixed and indeterminate types; with a central laboratory confirmed plasma HCV RNA titre ≥10 000 IU/mL on screening; without cirrhosis or with evidenced compensated cirrhosis on precedent liver biopsy (F4 on Ishak, Metavir or GS scoring system) and/or liver transient elastography (FibroScan liver stiffness modulus [LSM] ≥14.6 kPa). Patients who had been previously exposed to interferons at least 6 months before screening could be enrolled, but those previously exposed to DAAs of any sources were excluded.
Patients with unstable or uncontrolled medical conditions or co-infected with hepatitis B virus (HBV) or human immunodeficient virus (HIV) were also excluded. Detailed inclusion and exclusion criteria are shown in Table S1 and the definitions of liver fibrosis are shown in Table S2.

| Procedures
Patients were instructed to self-administer coblopasvir capsules 60 mg and sofosbuvir tablets 400 mg (Kawin Technology Share-Holding Co., Ltd., Beijing, China) with or without meal, once daily for 12 successive weeks. No dose modification was allowed throughout the treatment period.
Efficacy and safety were continuously monitored at treatment

| Outcome measures
Efficacy and safety were assessed in all patients receiving at least one dose of the study drug. The primary efficacy endpoint was SVR12,  Table S3.

| Sample size estimation and statistical analysis
The sample size was estimated based on a superiority hypothesis test. For the FAS, the overall SVR12 for patients receiving coblopasvir plus sofosbuvir was conservatively estimated at 90% and that for a historical control was set at 85% 3 in communication with the regulatory agency. A sample size of 324 patients would provide a statistical power of 85% at a one-sided significance level of 0.025. In consideration of enrolling an adequate number of patients with genotypes 3 and 6, the sample size was set at 360 patients; genotype distribution was also set as follows to represent the real-world HCV genotype profile in China 2 : genotype 1 and others at 50%, genotype 2 at 25%, genotype 3 at 12.5% and genotype 6 at 12.5%. The proportion of patients with advanced fibrosis (F3) or compensated cirrhosis (F4) was capped at 20%, and that of interferon-experienced patients was also capped at 10%.
Point estimates and two-sided 95% confidence intervals (95% CIs) were calculated using the Clopper-Pearson method for primary and secondary efficacy endpoints. Missing HCV RNA data for any reason were counted as treatment failure for the full analysis set (FAS) using the intention-to-treat principle. Exploratory efficacy endpoints and safety endpoints were descriptively summarized. The SVR of patient subsets and the potential effects of genotype, liver fibrosis and interferon experience on SVR (expressed as odds ratio [OR] and 95% CI) were analysed in a post hoc manner using the logistic regression model with bootstrapping. All statistical summaries and analyses were performed using the SAS software package ver- This trial is registered with ClinicalTrials.gov, number NCT03995485, and with ChinaDrugTrials.org.cn, number CTR20171654. . Thirty-nine patients (n = 39, 11%) had been previously exposed to interferons, most of whom had virological relapse or intolerance.

| Patient characteristics
None of the patients had a serum creatinine clearance below 50 ml/ min (using the Cockcroft-Gault formula) per the eligibility criteria. The most often reported concomitant medical conditions were non-alcoholic fatty liver disease and essential hypertension.

| Virological responses
All compliant patients achieved a virological response by treatment week 8. Detailed on-treatment virological responses are shown in Table S4. Among the 371 patients enrolled, 359 patients (97%; 95% CI [95%, 99%]) achieved the primary efficacy endpoint of SVR12 (Table 2). This high SVR12 was significantly greater than the prespecified 85% performance goal (P < .001), meeting the primary efficacy endpoint for this study. Per protocol set analysis also showed a similar result (358/368, 97%; 95% CI [96%, 99%], P < .001). Three hundred and fifty-one patients (n = 351) who achieved SVR12 completed the post-treatment week 24 visit, all of whom achieved SVR24 with the exception of one patient, representing a consistence of >99% between SVR24 and SVR12.
Subset analysis by genotype (
One compliant patient of genotype 3b with F3 experienced virological breakthrough at treatment week 2 (87 IU/mL) from <15 IU/ mL at treatment week 1 but achieved SVR12. One patient (genotype 3b with F0-2) prematurely withdrew from the study after completing 2-week treatment for unknown reasons, and one patient (genotype 3a with F0-2) was lost to follow-up as a result of institutionalization at post-treatment week 12.
All of these patients achieved virological response at the time of treatment completion, withdrawal or the last visit before they were lost to follow-up. A detailed description of virological failure is shown in Table S7.  Table S7.   Figure S1D). Isolated, elevated creatinine was reported for three patients (n = 3) and assessed to be not clinically significant.

| Safety data
Of two patients (n = 2) with increased alfa-fetal protein, one patient with genotype 1b and with F4 relapsed at post-treatment week 12 (HCV RNA titre approximating 100 IU/mL) and was further diagnosed with hepatocellular carcinoma on increased serum alfa-fetal protein combined with contrast liver imaging. One patient had a prolonged QT interval on treatment, which resolved without medical intervention 1 month later.

| D ISCUSS I ON
Our study population was highly representative of Chinese realworld patients infected with HCV 2 and comparable to that reported for the China phase 3 study of velpatasvir-sofosbuvir in terms of age, gender, genotype (also no genotype 4 or 5 detected), HCV titre, fibrosis and previous treatment history. 3  Two patients (n = 2) with genotypes 6e and 6n experienced post-treatment relapse. These two less common subtypes were not evaluated in the China phase 3 study of velpatasvir-sofosbuvir, 3 but is relatively more common in Thai patients (predominance accounting for 1% and 22% of genotype 6, respectively) 8 and was also detected in Chinese injection drug users (predominance accounting for 9% and 3% of injection drug users respectively). 9 The treatment efficacy of coblopasvir, along with other pangenotypic NS5A inhibitors, plus sofosbuvir warrants further evaluation in this special population infected with HCV of profound genetic diversity.
Owing to the small number (n = 5) of patients with genotype 1b The beneficial effect of DAA regimens is evident from the reduced occurrence of HCC but liver malignancy should be monitored, especially for cirrhotic patients. 15 The proportions of HCV genotype, liver fibrosis and previous interferon exposure were capped from the regulatory perspective, although the study population maximally represented the real-world population of HCV-infected patients in China. Therefore, the generalization of the results of this study should be further validated in post-marketing studies and observations in Chinese patients with highly diversified baseline characteristics, especially for these special populations.
In conclusion, the ribavirin-free, all-oral, pangenotypic combo regimen of coblopasvir plus sofosbuvir demonstrates a high SVR and a favourable safety profile for Chinese adult patients chronically monoinfected with HCV, including those with compensated cirrhosis. This regimen requires no pretreatment assessment of HCV genotype or liver fibrosis, and the treatment duration is fixed at 12 weeks for all patients regardless of the baseline characteristics. These clinical benefits and the affordability of this combo regimen address the 'unmet medical needs' for chronic hepatitis C in China and facilitate the goal of a 'No HepC' China by the year 2030.

ACK N OWLED G EM ENTS
Kawin Technology sponsored this study and oversaw trial management, data collection, statistical analyses, quality audit and preparation and review of this manuscript. All authors had access to study data and reviewed and approved the final manuscript. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication in consen- Junqi Niu https://orcid.org/0000-0002-9857-6520