Objectives: To assess the antiviral effect, clinical outcomes, and safety of the respiratory syncytial virus (RSV) fusion inhibitor rilematovir in non-hospitalized RSV-infected adults.Methods: This phase 2a, double-blind, multicentre study randomly assigned RSV-positive adult outpatients <= 5 days from symptom onset 1:1:1 to receive rilematovir 500 mg, 80 mg, or placebo once-daily for 7 days. Antiviral effect was assessed by RSV RNA viral load (VL), measured by quantitative RT-PCR, and Kaplan-Meier (KM) estimates of time to undetectable VL. Clinical course was assessed by KM estimates of median time to resolution of key RSV symptoms assessed through patient-reported outcomes.Results: RSV-positive patients (n = 72) were randomly assigned; 66 had confirmed RSV infection and received rilematovir 500 mg (n = 23), 80 mg (n = 21) or placebo (n = 22). Differences versus placebo in mean RSV RNA VL area under the curve (90% CI) through days 3, 5 and 8, respectively, were 0.09 (-0.837; 1.011), -0.10 (-2.171; 1.963), and -1.03 (-4.746; 2.682) log(10) copies.day/mL for rilematovir 500 mg, and 1.25 (0.291; 2.204), 2.53 (0.430; 4.634), and 3.85 (0.097; 7.599) log(10) copies.day/mL for rilematovir 80 mg. KM estimates of median (90% CI) time-to-first confirmed undetectable VL were 5.9 (3.85; 6.90), 8.0 (6.86; 12.80) and 7.0 (6.62; 10.88) days and 5.7 (2.93; 7.01), 8.1 (6.74; 12.80) and 7.9 (6.62; 11.74) days in patients with symptom onset <= 3 days, for rilematovir 500 mg, 80 mg, and placebo, respectively. KM estimates of median (90% CI) time to resolution of key RSV symptoms were 7.1 (5.03; 11.43), 7.6 (5.93; 8.32), and 9.6 (5.95; 14.00) days for rilematovir 500 mg, 80 mg, and placebo, respectively; and in patients with symptom onset <= 3 days, median 8.0, 7.6, and 11.8 days, respectively.Discussion: Rilematovir use, initiated early, suggests a potential clinical benefit in RSV-infected adults, with data supporting development of RSV therapeutic options.

Background The Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) is a patient-reported outcome measure designed to assess symptoms and impacts of respiratory syncytial virus (RSV) infection. This study evaluated the construct validity, reliability, and responsiveness of the RiiQ™ Respiratory and Systemic Symptoms Scale scores. Methods Prospective data were analyzed from a total of 1795 participants, including from non-hospitalized patients with acute respiratory infection (ARI) and no coinfections enrolled in a Phase 2b RSV vaccine study (RSV-positive: n = 60; RSV-negative: n = 1615), and two observational studies of patients hospitalized with RSV (n = 20; n = 100). Descriptive statistics, confirmatory factor analysis (CFA), test–retest intraclass correlation coefficients (ICCs), construct validity correlations (between a clinician-assessed clinical questionnaire and the RiiQ™ symptoms scale), known-groups validity, and responsiveness (correlations of change scores) were evaluated. Results Mean patient age ranged from 66.5 to 71.5 years and the majority of patients were female. Initial assessments in the vaccine trial (ARI Day 1) were suggestive of less severe illness than in the observational studies with hospitalized patients. CFA loadings (> 0.40) supported summary scores. ICCs exceeding the recommended threshold of 0.70 supported test–retest reliability for Respiratory and Systemic Symptoms, except in the small observational study. At the scale level, correlations were moderate to strong (| r | ≥ 0.3) and positive between the Respiratory Symptoms Scale and the related clinical questionnaire scores, reflecting measurement of similar symptoms in support of convergent validity. Correlations with change in Patient Global Impression of Severity > 0.30 supported responsiveness. Conclusions Psychometric tests applied to the RiiQ™ Symptoms scales provide evidence of its reliability, construct validity, discriminating ability, and responsiveness for use in clinical studies to assess the onset and severity of RSV symptoms.

The Pediatric Respiratory Syncytial Virus Electronic Severity and Outcome Rating System (PRESORS) was developed to assess the severity of respiratory syncytial virus (RSV) infection in children. Because young children cannot report how they feel or function, ratings are based on observations by the child's caregiver (Observer‐Reported Outcome questionnaire [ObsRO]) and clinician (Clinician‐Reported Outcome questionnaire [ClinRO]). This prospective study aimed to evaluate the psychometric properties of the PRESORS.

The cover image is based on the Original Article by Ann R. Falsey et al., https://doi.org/10.1111/irv.12903.

Background: The hospitalized acute respiratory tract infection (HARTI) study used the Respiratory Intensity and Impact Questionnaire (RiiQ (TM)) Symptom Scale, derived from FluiiQ (TM), to assess and compare the burden of respiratory infection symptoms for patients with influenza, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) infection, with or without core risk factors (CRF) (age >= 65; chronic heart, renal, obstructive pulmonary disease; asthma). Methods: This was a prospective cohort study in adult patients hospitalized with acute respiratory tract infection (40 centers, 12 countries) during two consecutive influenza/RSV/hMPV seasons (2017-2019). The RiiQ (TM) Symptom Scale and EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) were assessed by interview at two timepoints during hospitalization and at 1, 2, and 3 months post-discharge. Results: Mean lower respiratory tract (LRT) symptom scores were higher for RSV and hMPV participants compared to influenza at 48 h after enrollment/early discharge (p = 0.001) and 3 months post-discharge (p = 0.007). This was driven by LRT symptoms, including shortness of breath (SOB) (p < 0.01) and wheezing (p < 0.01) during hospitalization, and SOB (p < 0.05) and cough (p < 0.05) post-discharge. Participants with CRF reported more moderate-to-severe SOB (p < 0.05) and wheezing (p < 0.05) compared to CRF(-) participants post-discharge. EQ-5D-5L scores were moderately associated with RiiQ (TM) LRT and systemic symptoms domains. Conclusions: Results from the HARTI study suggest that in the study population, LRT symptoms were more severe for RSV and hMPV groups and for patients with CRF. RiiQ (TM) Symptom Scale scores shows a moderate association with EQ-5D-5L indicating that the RiiQ (TM) may provide useful insights and offer advantages over other measures for use in interventional RSV adult clinical studies.

IMPORTANCE Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. OBJECTIVE To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. EVIDENCE REVIEW The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. FINDINGS Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. CONCLUSIONS AND RELEVANCE The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

Abstract Background Respiratory Syncytial Virus (RSV) is a leading cause of hospitalization and serious respiratory illness in infants/young children. The objectives of this study were to (1) identify important RSV-related signs of illness in infants that were observed by the parent/caregiver of the child and (2) assess content validity and usability of the Pediatric RSV Electronic Severity and Outcomes Rating System (PRESORS) to monitor signs of RSV-related illness. Methods Review of medical literature identified signs of pediatric RSV-related illness in PRESORS. Semi-structured interviews with caregivers of infants (0–24 months of age) hospitalized with laboratory-confirmed RSV infection (in the two months prior to recruitment) were conducted to spontaneously elicit signs and impacts of the infant’s illness from caregiver observations. Caregivers completed PRESORS using a “think-aloud” protocol to confirm comprehension, relevance, and usability of the smartphone application. Verbatim transcripts were analyzed using thematic analysis methods and Atlas.ti software. Results Interviews with 21 caregivers confirmed PRESORS captured 23/26 signs caregivers spontaneously reported. Cough, difficulty breathing, problems sleeping, and reduced feeding/drinking were the most worrying signs of severe RSV-related illness described. Cognitive debriefing indicated that caregivers: understood the wording of all PRESORS items and response options (except how to count heartbeats), recall periods were appropriate, and the PRESORS smartphone application was easy to use. Minor changes to enhance content validity were identified. Conclusions In-depth interviews confirmed content validity and usability of the PRESORS by caregivers of infants with RSV. Next steps are to assess the revised PRESORS in clinical studies and evaluate its measurement properties.

The Respiratory Infection Intensity and Impact Questionnaire Version 2 (RiiQ™v2) is a patient-reported outcome tool to measure symptoms (respiratory and systemic) and impacts of respiratory syncytial virus (RSV) infection. This study evaluated the reliability, validity, and responsiveness of two key RiiQ™v2 symptom scores: lower respiratory tract symptom score (LRT-SS; cough, wheeze, phlegm, short of breath) and upper respiratory tract symptom score (URT-SS; sore throat, nasal congestion) to support their use as clinical trial endpoints. Data were collected in patients with acute respiratory infection (ARI) from a Phase 2b study in 60 confirmed RSV-positive and 1,615 RSV-negative non-hospitalized individuals with no coinfections, and two observational studies in hospitalized RSV patients (n=20; n=100). Descriptive statistics, confirmatory factor analysis (CFA), test-retest intraclass correlation coefficients (ICCs), construct validity correlations (with clinician-reported signs/symptoms scores [CSS] and patient global impression of severity [PGIS]), known-groups validity (based on comorbidities and PGIS), and responsiveness (correlations of change scores) were evaluated. At ARI onset, higher proportions of RSV-positive patients had moderate-to-severe respiratory symptoms (≥3 on a 1 to 4 scale) than RSV-negative patients (cough: 60%/35%; phlegm: 28%/12%; nasal congestion: 56%/49%; sore throat: 28%/21%). CFA loadings (>0.40) along with several adequate goodness-of-fit indices supported planned summary scores. LRT and URT ICCs supported test-retest reliability. Moderate-to-strong correlations between LRT-SS, the CSS and PGIS support construct validity and consistency between clinician and patient ratings; correlations with URT-SS were moderate among RSV-negative patients but small among RSV-positive patients. Correlations with change in PGIS >0.30 supported responsiveness. The LRT domain showed stronger psychometric properties than the URT domain, possibly resulting from higher variability in the distribution of URT scores. Results show initial support for the reliability, validity, and responsiveness of the RiiQ™v2 for use in clinical studies.

Patient-reported outcomes (PROs) are used in clinical trials to provide valuable evidence on the impact of disease and treatment on patients’ symptoms, function and quality of life. High-quality PRO data from trials can inform shared decision-making, regulatory and economic analyses and health policy. Recent evidence suggests the PRO content of past trial protocols was often incomplete or unclear, leading to research waste. To address this issue, international, consensus-based, PRO-specific guidelines were developed: the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-PRO Extension. The SPIRIT-PRO Extension is a 16-item checklist which aims to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection to minimise research waste, and ultimately better inform patient-centred care. This SPIRIT-PRO explanation and elaboration (E&E) paper provides information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template. For each SPIRIT-PRO item, we provide a detailed description, one or more examples from existing trial protocols and supporting empirical evidence of the item’s importance. We recommend this paper and protocol template be used alongside the SPIRIT 2013 and SPIRIT-PRO Extension paper to optimise the transparent development and review of trial protocols with PROs.

PURPOSE:PRESORS ClinRO completed by clinicians and ObsRO completed by caregivers were developed to characterize the clinical course of respiratory syncytial virus (RSV) infection. This study describes preliminary analysis of PRESORS' measurement properties using clinical trial data.PATIENTS AND METHODS:PRESORS ClinRO and ObsRO data were collected in a 28-day randomized, double-blind, Phase 1b trial of JNJ-53718678 or placebo in infants and children ≤24 months of age treated for RSV infection in hospitals. PRESORS data were scored and key psychometric properties of scores were evaluated, including ability to discriminate between known groups and to detect change over time. Time to resolution of RSV signs was explored using two responder definitions.RESULTS:Daily completion rates for PRESORS ClinRO and ObsRO were high for the 44 children in the study (median: 100% and 93%, respectively). Large floor effects were observed at baseline for signs of severe RSV infection that were either absent (cyanosis, fever, apnea) or rarely reported (reduced urination/dehydration, vomiting). Implausible ObsRO ratings suggested some caregivers could not accurately measure heart rate. Known-group validity was confirmed: children in poor health based on baseline ClinRO had mean baseline composite scores that were significantly worse for both ObsRO (p=0.001) and ClinRO (p<0.001) compared to those with better overall health. ObsRO (p=0.009) and ClinRO (p<0.001) composite scores were responsive to change in overall health status from baseline to Day 3. Mean scores for RSV sign dimensions decreased rapidly from baseline to Day 7 except for coughing and sleep ratings by caregivers. Time to recovery varied greatly depending on definitions used.CONCLUSION:PRESORS ClinRO and ObsRO can inform endpoints and enable monitoring the clinical course of RSV in pediatric trials. Improved alignment between ClinRO and ObsRO and revisions ensuring caregivers can assess all signs will be addressed in revised PRESORS.

infectious) than the initial disease from the first encounter with the virus 10,11 .All these observations support the proposal of careful clinical observation of the disease that may eventually affect vaccinated patients, including monitoring selected at-risk people for asymptomatic infection and infectivity.Ultimately, the most information about immune escape is learned in the clinic, when there is a variant-specific drop-off of efficacy, along with a propensity for reinfection as a function of particular variants.The in vitro assays are expected to correlate with the clinical findings, as surrogate metrics to indicate what will be expected to manifest in patients.Finally, should SARS-CoV-2 be able to perfectly escape vaccine-induced immunity, rapid modification of mRNA vaccines could provide an immunity boost likely to provide protection against the new viral strains as well.However, it is important to be aware of the existence of and the sequence of such variants in the shortest possible time frame in order to mitigate risk and control the consequences.The Italian word for concern is 'preoccupazione' , which comes from 'occupazione' ('take care') and 'pre' ('in advance').Simply put, this is what needs to be done.Concern about SARS-CoV-2 variants should not cause panic but instead should prompt efforts to ensure that all the necessary steps for mitigating variant impact are taken in advance through the development of tools that detect and characterize these new strains in a timely and standard manner.

Background: Hepatitis C virus (HCV) infection and its treatments are associated with significant symptoms, side effects and impact on patients functioning. The Hepatitis C Symptom and Impact Questionnaire version 4 (HCV-SIQv4) was developed according to FDA Patient Reported Outcomes (PRO) Guidance, for evaluating chronic HCV infection and its treatment. Objectives: This study evaluated the psychometric properties and clinically important change (CIC) thresholds of the measure. Methods: PRO data were pooled from three Phase IIb and III trials evaluating interferon-free simeprevircontaining regimens for treatment of chronic HCV infection. Scale range adequacy, reliability, validity, responsiveness and CIC thresholds were assessed incorporating knowledge of the appropriate measurement model. Results: Data from 437 patients were analyzed. Stage of liver disease was associated with symptom severity and functioning at baseline. Reliability was acceptable (test-retest ICC ≥0.7) for most scores except the Gastrointestinal and Integumentary domains. Convergent validity was observed between HCV-SIQv4 scores and concurrent measures of conceptual similarity. Greater symptom severity and worse impact scores were associated with liver cirrhosis, depression, severe fatigue and health limitations. Patients who achieved SVR12 had better outcomes than those failing to. HCV-SIQv4 symptom and domain scores were responsive to changes in health state (effect sizes ≥0.5). Exploratory thresholds for change in scores indicating a clinically important improvement and worsening were HCV-SIQv4 Overall Body System Score (BSS), 8 and 8; Constitutional BSS, 10 and 10; Gastrointestinal BSS, 5 and 5; Psychiatric BSS, 8 and 8; Neurocognitive BSS, 8 and 8; and Integumentary BSS, 5 and 5. Conclusions: The HCV-SIQv4 offers reliable, responsive assessments within HCV clinical development. CIC thresholds are now available to aid score interpretation.

Influenza virus and Respiratory Syncytial Virus (RSV) cause acute respiratory tract infections that present with similar symptoms. Although no PRO measures have been developed to monitor the severity of RSV symptoms in adults, influenza symptom PRO measures may be useful for RSV severity assessment. This study was conducted to evaluate the content validity of RSV adaptations of the FLU-PRO™ and Flu-iiQ™ (RI-PRO™ and R-iiQ™, respectively) for research in inpatients and outpatients with RSV infection.

This study aimed to evaluate the content validity of the Chronic Liver Disease Questionnaire (CLDQ) and EQ-5D-5L in a chronic hepatitis B (CHB) patient population. Patients receiving treatment for CHB in the United Kingdom were asked to complete the measures using a 'think aloud' cognitive debriefing technique, sharing their thoughts on each question and response option. Framework analysis of interview transcripts using ATLAS.ti v7.5. explored conceptual relevance, understanding of item wording, and suitability of response scale/options and recall period. To identify missing concepts, CLDQ content was compared with a CHB conceptual model developed from qualitative literature and multinational concept elicitation interviews with 84 patients with CHB. Twenty-three patients completed the CLDQ (74% male; aged 18-55; 39% Asian, 35% Black, 22% White, 4% other ethnicity). Patients generally found the CLDQ response options and recall period appropriate. Patients collectively endorsed each CLDQ item as relevant, with fatigue, pain, and emotional wellbeing (e.g., worry) the most common concerns. Some concepts (e.g., shortness of breath) were less common amongst the sample. Some terminology (e.g., 'abdominal') was difficult for patients to understand. Comparison with the CHB conceptual model highlighted that the CLDQ does not assess several important concepts for patients with CHB related to emotional and psychological wellbeing, lifestyle limitations, and impact on relationships. Patients understood the EQ-5D-5L but many did not find items assessing mobility and self-care relevant. The CLDQ provides comprehensive assessment of fatigue and pain-related symptoms experienced by patients with CHB, and of some aspects of emotional wellbeing. The CLDQ does not assess stigmatization and impact on self-esteem which are important concepts for many patients with CHB. Revised wording is recommended to ensure the CLDQ is easy for CHB patients to understand. EQ-5D-5L items assessing self-care and mobility may be less relevant for CHB patients.

Hepatitis C virus (HCV)–infected patients with cirrhosis are historically a difficult‐to‐treat population and are at risk of hepatic decompensation. In the phase 2 COSMOS study that evaluated simeprevir (HCV NS3/4A protease inhibitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) ± ribavirin for 12 or 24 weeks in HCV genotype (GT)1–infected patients, high rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were achieved, including in patients with cirrhosis (METAVIR score F4). This phase 3, open‐label, single‐arm study (OPTIMIST‐2 [NCT02114151]) evaluated the efficacy and safety of 12 weeks of simeprevir + sofosbuvir in HCV GT1–infected treatment‐naive or treatment‐experienced patients with cirrhosis. Patients (aged 18‐70 years) with chronic HCV GT1 infection and documented presence of cirrhosis received oral simeprevir 150 mg once daily + sofosbuvir 400 mg once daily for 12 weeks. The primary efficacy endpoint of the study was the proportion of patients achieving SVR12 versus a composite historical control (SVR12 rate of 70%). Safety and patient‐reported outcomes were assessed. Overall, 103 patients received treatment. SVR12 with simeprevir + sofosbuvir (83%, 95% confidence interval 76%‐91%) met the primary objective of superiority versus the historical control (70%). SVR12 rates for treatment‐naive and treatment‐experienced patients were 88% (44/50) and 79% (42/53), respectively. Adverse events occurred in 72 (70%) patients, with most (64%) being grade 1 or 2. Serious adverse events (none considered related to study treatment) occurred in five (5%) patients, and three (3%) patients discontinued all study treatment due to adverse events. Patient‐reported outcomes improved from baseline to follow‐up week 12. Conclusion: Simeprevir + sofosbuvir for 12 weeks achieved superiority in SVR12 rates versus the historical control in treatment‐naive and treatment‐experienced HCV GT1‐infected patients with cirrhosis and was generally safe and well tolerated. (Hepatology 2016;64:360‐369)

Background Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12. Methods In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression. Results Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen. Conclusions Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen. Trial Registration ClinicalTrials.gov NCT01846832

Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)‐infected patients. The phase 2 COSMOS study reported high SVR rates in treatment‐naive and prior null‐responder HCV genotype (GT) 1‐infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST‐1 (NCT02114177) was a multicenter, randomized, open‐label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1‐infected treatment‐naive and treatment‐experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non‐CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%‐100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76‐89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12‐week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8‐week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12‐week arm) and three (2%, 8‐week arm) patients experienced a serious adverse event (all unrelated to study treatment). Conclusion: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1‐infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370‐380)