Background: In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response rate over sunitinib monotherapy for advanced renal cell carcinoma (RCC). Objective: To evaluate health-related quality of life (HRQoL) in KEYNOTE-426. Design, setting, and participants: A total of 861 patients were randomly assigned to receive pembrolizumab + axitinib (n = 432) or sunitinib (n = 429). HRQoL data were available for 429 patients treated with pembrolizumab + axitinib and 423 patients treated with sunitinib. Outcome measurements and statistical analysis: HRQoL end points were measured using the European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), EQ-5D visual analog rating scale (VAS), and Functional Assessment of Cancer Therapy Kidney Cancer Symptom IndexDisease-Related Symptoms (FKSI-DRS) questionnaires. Results and limitations: Better or not different overall improvement rates from baseline between pembrolizumab + axitinib and sunitinib were observed for the FKSI-DRS (-0.79% improvement vs sunitinib; 95% confidence interval [CI] -7.2 to 5.6), QLQ-C30 7.5% improvement vs sunitinib; 95% CI 1.0-14), and EQ-5D VAS (9.9% improvement vs sunitinib; 95% CI 3.2-17). For time to confirmed deterioration (TTcD) and time to first deterioration (TTfD), no differences were observed between arms for the QLQ-C30 (TTcD hazard ratio [HR] 1.0; 95% CI 0.82-1.3; TTfD HR 0.82; 95% CI 0.69-0.97) and EQ-5D VAS (TTcD HR 1.1; 95% CI 0.87-1.3; TTfD HR 0.98; 95% CI 0.83-1.2). TTfD was not different between treatment arms (HR 1.1; 95% CI 0.95-1.3) for the FKSI-DRS, but TTcD favored sunitinib (HR 1.4; 95% CI 1.1-1.7). Patients were assessed during the offtreatment period for sunitinib, which may have underestimated the negative impact of sunitinib on HRQoL. Conclusions: Overall, patient-reported outcome scales showed that results between the pembrolizumab + axitinib and sunitinib arms were not different, with the exception of TTcD by the FKSI-DRS. Patient summary: Compared with sunitinib, pembrolizumab + axitinib delays disease progression and extends survival, while HRQoL outcomes were not different between groups. (c) 2022 Published by Elsevier B.V. on behalf of European Association of Urology.

While randomized controlled trials (RCTs) are the gold-standard for establishing the efficacy and safety of a medical treatment, real-world evidence (RWE) generated from real-world data (RWD) has been vital in post-approval monitoring and is being promoted for the regulatory process of experimental therapies. An emerging source of RWD is electronic health records (EHRs), which contain detailed information on patient care in both structured (e. g., diagnosis codes) and unstructured (e. g., clinical notes, images) form. Despite the granularity of the data available in EHRs, critical variables required to reliably assess the relationship between a treatment and clinical outcome can be challenging to extract. We provide an integrated data curation and modeling pipeline leveraging recent advances in natural language processing, computational phenotyping, modeling techniques with noisy data to address this fundamental challenge and accelerate the reliable use of EHRs for RWE, as well as the creation of digital twins. The proposed pipeline is highly automated for the task and includes guidance for deployment. Examples are also drawn from existing literature on EHR emulation of RCT and accompanied by our own studies with Mass General Brigham (MGB) EHR.

Various oral interferon- and ribavirin-free regimens are becoming available to treat chronic hepatitis C virus (HCV) infection. This phase 3 trial evaluates the effectiveness and tolerability of a ...

Background: Typical management for renal cell carcinoma (RCC) is nephrectomy. However, patients with intermediate- to high-risk advanced disease can experience relapse. Upregulation of the programmed death 1 (PD-1) pathway is associated with poor prognosis in RCC, and drugs to target the PD-1 pathway have shown efficacy and reasonable safety in metastatic RCC. Therefore, the PD-1 pathway may represent a novel target to prevent disease recurrence in the adjuvant setting. The randomized, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial (ClinicalTrials.gov identifier, NCT03142334) is designed to evaluate the efficacy and safety of pembrolizumab in the adjuvant treatment of RCC after nephrectomy. Trial Design: Patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks by intravenous infusion. Treatment will continue until disease recurrence, treatment discontinuation, or the completion of 17 cycles. Randomization will be stratified by metastasis stage (M0 vs M1 NED). Randomization within the M0 group will be further stratified by Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 and region (US vs rest of world). Imaging will be performed every 12 weeks after randomization, every 12 weeks for the first year of follow-up, every 16 weeks during years 2 to 4 of follow-up, and every 24 weeks thereafter. Key inclusion criteria are age ≥18 years; histologically confirmed clear cell RCC of intermediate-high risk (pT2, grade 4 or sarcomatoid, N0 M0; pT3, any grade, N0 M0), high risk (pT4, any grade, N0 M0; pT any stage, any grade, N+ M0), or M1 NED; no prior systemic therapy for advanced RCC; partial nephroprotective or radical complete nephrectomy with negative surgical margins; disease free after partial or radical complete nephrectomy validated by either computed tomography or magnetic resonance imaging; ECOG PS 0 or 1; and adequate and available tumor sample for biomarker analyses. Primary end point is disease-free survival (DFS) per investigator assessment. Secondary end point is overall survival (OS). Additional secondary analyses are safety and tolerability, pharmacokinetic parameters, antidrug antibodies, patient-reported outcomes, and DFS and OS per PD-L1 expression status. Biomarkers associated with response will be evaluated as an exploratory objective. KEYNOTE-564 is underway in 19 countries in Asia, Australia, Europe, North America, and South America, and recruitment will continue until ~950 patients are enrolled. Citation Format: Toni K. Choueiri, David I. Quinn, Tian Zhang, Howard Gurney, Gurjyot K. Doshi, Patrick Wayne Cobb, Francis Parnis, Jae-Lyun Lee, Se Hoon Park, Andrey Semenov, Antoine Thiery-Vuillemin, Piotr Sawrycki, Piotr Tomczak, Boris Alekseev, Adel Izmailov, Wayne Yen-Hwa Chang, Shuyan M. Wan, Christian Heinrich Poehlein, Jaqueline Willemann-Rogerio, Thomas Powles. Pembrolizumab monotherapy for the adjuvant treatment of renal cell carcinoma post-nephrectomy: Randomized, double-blind, Phase III KEYNOTE-564 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT162.

In longitudinal clinical trials with daily patient-reported outcomes, the analysis endpoints are often defined as the averaged daily diary outcomes in a treatment cycle (such as a month or a week). Conventional methods often deal with missing data at the cycle level by imputing the average, and the cycle average is treated as missing if the number of days with available outcomes in the treatment cycle is less than a certain number. This was the method used for a case study of a phase 3 clinical trial evaluating a treatment for insomnia with daily patient-reported outcomes. Such methods may introduce bias. Motivated by this, we propose methods to impute missing daily outcomes in this paper. Specifically, we define a two-level missing pattern for clinical trials with daily patient-reported outcomes, and propose two-level methods to impute missing data at daily base. Other than the standard methods by multiple imputations, we derive analytic formulas for the proposed two-level methods to reduce computational intensity and improve the estimates of variances. The proposed two-level methods provide more powerful approaches to estimate the treatment difference compared to the conventional cycle-level methods, which are evaluated by theoretical development and simulation studies. In addition, the methods are applied to the motivating phase 3 trial evaluating a treatment for insomnia with daily patient-reported outcomes.

4500 Background: In KEYNOTE-426, pembro + axi significantly improved OS (HR 0.53, P < .0001), PFS (HR 0.69, P = .0001), and ORR (59.3% vs 35.7%, P < .0001) vs sunitinib and had manageable toxicity as first-line therapy for mRCC (NCT02853331). The pembro + axi benefit was observed across all IMDC risk groups and regardless of PD-L1 expression. We present data for the combined intermediate/poor risk group and for patients (pts) with sarcomatoid features. Methods: 861 eligible pts with clear-cell mRCC, no prior systemic therapy for mRCC, and KPS ≥70 were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID (N = 432) or sunitinib 50 mg orally QD (4-wk on/2-wk off) (N = 429). Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR (RECIST v1.1 by BICR) was the key secondary endpoint. The intermediate/poor risk group was prespecified; the sarcomatoid group was exploratory. HRs and their 95% CIs were calculated with a Cox proportional hazards model. None of the analyses were multiplicity-controlled. Results: 592 (68.8%) of all randomized pts were of IMDC intermediate/poor risk — 294 in the pembro + axi arm, 298 in the sunitinib arm. Pembro + axi improved OS (HR 0.52, 95% CI 0.37-0.74; 12-mo rate 87.3% vs 71.3%), PFS (HR 0.67, 95% CI 0.53-0.85; median 12.6 vs 8.2 mo), and ORR (55.8% [95% CI 49.9-61.5] vs 29.5% [24.4-35.1]) in pts with intermediate/poor risk; CR rates were 4.8% (95% CI 2.6-7.9) vs 0.7% (0.1-2.4). Of the 578 pts with known status, 105 (18.2%) had sarcomatoid features — 51 in the pembro + axi arm, 54 in the sunitinib arm. Pembro + axi improved OS (HR 0.58, 95% CI 0.21-1.59; 12-mo rate 83.4% vs 79.5%), PFS (HR 0.54, 95% CI 0.29-1.00; median not reached vs 8.4 mo), and ORR (58.8% [95% CI 44.2-72.4] vs 31.5% [19.5-45.6]) in pts with sarcomatoid features; CR rates were 11.8% (95% CI 4.4-23.9) vs 0% (0.0-6.6). Conclusions: Pembro + axi provides benefit in the combined population of pts with IMDC intermediate or poor risk and in pts whose tumors had sarcomatoid features. The observed benefits were consistent with those seen in the total population. Clinical trial information: NCT02853331.

TPS712 Background: Most patients with intermediate- to high-risk advanced renal cell carcinoma (RCC) will progress within 3 years following nephrectomy. Novel treatments in the adjuvant setting are needed to prevent disease recurrence in these higher-risk patients. Upregulation of the programmed death 1 (PD-1) pathway is associated with more aggressive disease and poor prognosis. PD-1 inhibitors have demonstrated activity in metastatic RCC, and PD-1 may represent a novel therapeutic target in the adjuvant setting. Pembrolizumab, a PD-1 inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Methods: KEYNOTE-564 (NCT03142334) is a randomized, double-blind, placebo-controlled phase 3 trial designed to evaluate the efficacy and safety of pembrolizumab as adjuvant therapy in patients with RCC. Eligibility criteria include age ≥18 years; intermediate- to high-risk (T2 grade 4, T3), high-risk (T4, T), or M1 NED RCC with a clear cell component; no prior systemic therapy for advanced RCC; disease free following complete or partial nephrectomy (and metastasectomy in patients with M1 NED) with negative surgical margins; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1; and provision of a tumor sample for biomarker analyses. Patients will be randomly assigned (1:1) to pembrolizumab 200 mg administered intravenously every 3 weeks or placebo. Randomization will be stratified by metastasis stage (M0 vs M1 NED); within the M0 group, randomization will be further stratified by ECOG PS (0 vs 1) and region (US vs rest of world). Treatment will continue until disease recurrence, unacceptable toxicity, or the completion of 17 cycles (~1 year). Imaging will be performed every 12 weeks. The primary end point is disease-free survival (DFS) per investigator assessment. The key secondary end point is overall survival (OS). Other secondary objectives include safety, disease recurrence-specific survival, DFS and OS according to PD-L1 expression status, and patient-reported outcomes. Biomarkers that may be associated with response will be evaluated as an exploratory objective. Enrollment is ongoing and will continue until ~950 patients are enrolled. Clinical trial information: NCT03142334.

TPS4599Background: The typical management for renal cell carcinoma (RCC) is nephrectomy. Despite this, patients with intermediate- to high-risk advanced disease can experience relapse with metastat...

Background There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. Methods Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1-6 (HCV RNA >= 10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [<15 IU/mL]). The trials are registered at ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 676 participants were randomly assigned between Feb 18, 2015, and Aug 16, 2016. In all 675 participants who received at least one dose of study drug (full analysis set), SVR12 for the 8-week regimen of grazoprevir, ruzasvir, and uprifosbuvir with and without ribavirin was achieved in 39 (93% [95% CI 81-99]) of 42 participants with genotype 1a, 45 (98% [88-100]) of 46 with genotype 1b, 54 (86% [75-93]) of 63 with genotype 2, 98 (95% [89-98]) of 103 with genotype 3, and seven (100% [59-100]) of seven participants with genotype 4. SVR12 for the 12-week regimen with and without ribavirin was achieved in 87 (99% [95% CI 94-100]) of 88 participants with genotype 1, 61 (98% [91-100]) of 62 with genotype 2, and four (100% [40-100]) of four with genotype 6. Among participants with cirrhosis who were infected with genotype 3, SVR12 for the 12-week regimen with and without ribavirin was achieved in 28 (97% [95% CI 82-100]) of 29 of those who were treatment-naive and 29 (100% [88-100]) of 29 who were treatment-experienced. SVR12 for the 16-week regimen with and without ribavirin was achieved in 26 (100% [95% CI 87-100]) of 26 participants with genotype 2 infection and 72 (96% [89-99]) of 75 participants with genotype 3 infection. The most common adverse events were headache (143 [22%] of 664), fatigue (129 [19%] of 664), and nausea (83 [13%] of 664). 16 (2%) of 664 participants had serious adverse events. Interpretation The combined regimen of grazoprevir (100 mg/day), ruzasvir (60 mg/day), and uprifosbuvir (450 mg/day) has the potential to provide a simplified treatment for HCV that is effective and well tolerated in most individuals infected with HCV, as well as a shorter duration of treatment in many individuals.

Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [ 91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [ 94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. Interpretation These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection.

Background: Effective adjuvant therapies for patients (pts) with RCC at risk of recurrence after nephrectomy are lacking. Programmed death ligand 1 (PD-L1) and 2 (PD-L2) expression predicts poor prognosis in RCC. Programmed death 1 (PD-1) inhibitors have demonstrated activity in metastatic RCC, and PD-1 may represent a novel therapeutic target in the adjuvant setting. Pembrolizumab is a PD-1 inhibitor that directly blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This randomized, double-blind, placebo-controlled phase 3 trial will evaluate the efficacy and tolerability of pembrolizumab as adjuvant therapy in pts with RCC who have T2 grade 4, T3, T4, N (+), or stage M1 with no evidence of disease (M1 NED) following nephrectomy and/or metastasectomy (NCT03142334). Trial design: Key inclusion criteria are: age ≥18 years; histologically confirmed RCC with a clear cell component; intermediate-high or high risk of recurrence, or M1 NED; no prior systemic therapy for advanced RCC; disease-free following complete or partial nephrectomy (and metastasectomy in M1 NED pts) with negative surgical margins; and Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Approximately 950 pts will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg every 3 weeks by intravenous infusion, or placebo, continued for up to 17 cycles (∼1 year) or until disease recurrence or treatment discontinuation. Randomization will be stratified by metastasis stage (M0 vs M1 NED); within the M0 group, randomization will be further stratified by ECOG performance status (0 vs 1) and region (US vs rest of world). The primary end point is investigator-assessed disease-free survival (DFS). Radiographic imaging will be performed every 12 weeks. Secondary objectives include overall survival (OS), safety, disease recurrence-specific survival, DFS and OS according to PD-L1 expression status, pharmacokinetics, antidrug antibodies, and patient-reported outcomes. Molecular biomarkers that may be associated with response, safety, pharmacodynamic activity, or mechanism of action will be evaluated as exploratory objectives. Clinical trial identification: NCT03142334; May 3, 2017 Legal entity responsible for the study: Merck & Co., Inc. Funding: Merck & Co., Inc. Disclosure: T.K. Choueiri: Ad Board and/or funding: AstraZeneca Bayer Bristol-Myers Squib Cerulean Eisai, Foundation Medicine Inc Genetech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs Inc, Roche, Eisai Exelixis GSK Merck, Tracon. T. Powles: Research Funding/Honoraria/Travel: Pfizer, Merck, AstraZeneca, Roche, Novartis T. Zhang: Owns stock in Capio Biosciences and have received research funding from Janssen, Pfizer, and Acerta. D.I. Quinn: Ad board/funding/honoraria: Pfizer, Bristol-Myers Squib, Merck, EMD Serono, AstraZeneca, Genentech, Exelixis. J.E. Gschwend: Ad board/Honoraria/Travel Expenses: Bayer, Bristol-Myers Squib, Janssen, Novartis, Pfizer, Roche. S.S. Wan: Employment and stock ownership: Merck & Co., Inc. C. Poehlein: Employment: Merck & Co/MSD.

Background: Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection.Objective: To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients.Design: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467)Setting: 60 centers in the United States, Europe, Australia, Scandinavia, and Asia.Patients: Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection.Intervention: Oral, once-daily, fixed-dose grazoprevir 100 mg/ elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy.Measurements: Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups.Results: Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% Cl, 92% to 97%[) achieved SVR12, including 144 of 157 (92% [Cl, 86% to 96%]) with genotype 1a, 129 of 131 (99% [Cl, 95% to 100%)) with genotype 1b, 18 of 18(100% [Cl, 82% to 100%]) with genotype 4, 8 of 10(80% [Cl, 44% to 98%]) with genotype 6, 68 of 70 (97% [Cl, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [Cl, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9(2.8%) and 3(2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point (Cl, -5.4 to 3.1 percentage points)); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%).Limitation: The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections.Conclusion: Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection.

Background Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease.Methods In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0.0 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350.Findings 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95.3-100.0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis.Interpretation Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease.