Safety and Tolerability of Elbasvir/Grazoprevir in Chronic Hepatitis C Virus Therapy

Integrated Analysis From Clinical Trials

Gayatri Nangia; John M. Vierling; Paul Kwo; Deborah D. Brown; Stephanie O. Klopfer; Michael N. Robertson; Barbara A. Haber; K. Rajender Reddy

Disclosures

J Viral Hepat. 2020;27(11):1222-1233. 

In This Article

Methods

Safety data from 12 EBR/GZR clinical trials were pooled (Table S1). The methods and primary outcomes of these clinical trials have previously been published (C-SCAPE[5] [Protocol 047/NCT01932762]; Japan Phase 2/3[6] [Protocol 058/NCT02203149]; C-SALT[13] [Protocol 059/NCT02115321]; C-EDGE Treatment-Naive[7] [Protocol 060/NCT02105467]; C-EDGE CO-INFECTION[8] [Protocol 061/NCT02105662]; C-CORAL[9,10] [Protocol 067/NCT02251990]; C-EDGE Treatment-Experienced[11] [Protocol 068/NCT02105701]; C-EDGE Head-2-Head[12] [Protocol 077/NCT02358044]; C-WORTHY[14,15] [Protocol 035/NCT01717326]; C-SURFER[16] [Protocol 052/NCT02092350]; C-EDGE CO-STAR[18] [Protocol 062/NCT02105688]; and C-EDGE Inherited Blood Disorders[17] [Protocol 065/NCT02252016]). All studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Independent institutional review boards or ethics committees reviewed and approved the protocols and applicable amendments for each institution (Table S2), and all participants gave written informed consent.

Participants

The studies included in this integrated analysis enrolled adult participants with HCV infection, most requiring participants to have a baseline viral load >10 000 IU/mL. Participants included in this analysis had HCV GT1, GT4 or GT6 infection, although the C-SCAPE study[5] also included participants with HCV GT2 and GT5 infection. Participants were treatment-naive or were previously treated with an interferon-containing regimen, and were noncirrhotic or had compensated, Child-Pugh A cirrhosis. Participants with human immunodeficiency virus (HIV) coinfection were also enrolled. Individuals who had received prior DAA therapy, those with hepatitis B virus coinfection, and those with signs or symptoms consistent with decompensated liver disease (presence or history of ascites, oesophageal or gastric variceal bleeding, hepatic encephalopathy, or other signs of advanced liver disease) were excluded.

Analyses

Safety data from these studies were analysed according to treatment duration, use of concomitant RBV and medical comorbidity. Analyses were based on three treatment populations: participants receiving EBR/GZR for 12 weeks; participants receiving EBR/GZR plus RBV for 16–18 weeks; and those with specific comorbidities (CKD 4/5, receiving opioid agonist therapy or with inherited blood disorders) receiving EBR/GZR for 12 weeks. Safety data from participants who received EBR/GZR for 12 weeks (without RBV) were pooled from eight clinical trials.[5–13] This group of participants included treatment-naive and treatment-experienced participants with HCV GT1, GT4 and GT6 infection, and included participants with compensated cirrhosis and those with HIV coinfection. The safety and tolerability of EBR/GZR for 12 weeks was also assessed separately in participants with HCV infection and CKD stage 4/5,[16] those receiving opioid agonist therapy[18] and those with inherited blood disorders[17] as unique study populations. In the original studies,[16–18] these participants were randomized to receive immediate treatment with EBR/GZR for 12 weeks or a matched placebo for 12 weeks followed by deferred active therapy with EBR/GZR. Thus, the initial 12-week treatment period in these studies allowed for a placebo-controlled comparison of safety events, enabling treatment-related safety events to be distinguished from the underlying disease-related comorbidity. Finally, the safety and tolerability of EBR/GZR administered for 16–18 weeks in combination with RBV was assessed using data from the C-EDGE Treatment-Experienced[11] and C-WORTHY[14,15] studies.

Safety Assessments

During each study, safety and tolerability were monitored by the investigator and sponsor in accordance with standard procedures. AE categories included any adverse event, a drug-related AE, a serious AE and discontinuation due to an AE. These data were integrated and summarized as the proportion of participants with adverse experiences or abnormal laboratory values (SAS Institute, v9.4; Cary, North Carolina).

For the analysis of laboratory values, the percentages of participants with abnormal haemoglobin (Hgb), ALT, total bilirubin and serum creatinine (sCr) levels were calculated. Hgb was divided into three grades: grade 2 (Hgb levels of 9.0–9.9 g/dL), grade 3, (Hgb levels of 7.0–8.9 g/dL) and grade 4 (Hgb levels <7.0 g/dL). ALT was characterized as grade 3 (5.1–10.0× ULN) or grade 4 (>10.0× ULN). Total bilirubin was categorized into grade 3 (2.6–5.0× ULN) or grade 4 (>5.0× ULN). sCr was categorized as grade 3 (1.9–3.4× ULN) or grade 4 (≥3.5× ULN). For the special populations (CKD, opioid agonist therapy, inherited blood disorders), the data were analysed according to placebo or EBR/GZR treatment groups.

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