Evaluation of Efficacy Endpoints for a Phase IIb Study of a Respiratory Syncytial Virus Vaccine in Older Adults Using Patient-Reported Outcomes With Laboratory Confirmation

Abstract

Objectives: There are no approved vaccines for respiratory syncytial virus (RSV), and consensus on methods to assess RSV vaccine efficacy has not been established. In this study of an adjuvanted RSV vaccine, we evaluated an RSV disease endpoint using a patient-reported outcome instrument (the inFLUenza Patient-Reported Outcome instrument [FLU-PRO]) and molecular testing for virologic confirmation. Methods: In a randomized, blinded efficacy study (NCT02508194), 1900 adult participants aged $60 years who had any respiratory symptom lasting $24 hours recorded symptoms in a FLU-PRO-based workbook for 21 days, self-collected nasal swabs on illness days 2 to 4, and had a site-collected swab obtained on (approximately) day 4. The endpoint, acute RSVassociated respiratory illness (ARA-RI), required specific symptoms with virologic confirmation. Results: The FLU-PRO demonstrated reliability, ability to detect change, and validity and had high participant adherence and acceptable patient burden in the setting of an RSV prevention trial. The ARA-RI endpoint definition captured all 33 virologically confirmed RSV illnesses for which symptom data were provided, and in 32 of these, at least 1 lower respiratory symptom was reported. Sensitivity analysis with an endpoint requiring $2 lower respiratory symptoms captured greater symptom severity but fewer cases. Results of self-and site-collected swabs were highly correlated. Selfswabbing detected 9 additional cases that would have been missed by site swabbing only. Conclusions: These results demonstrated the reliability and validity of the ARA-RI definition and of the FLU-PRO for use in RSV studies. Self-swabbing improved RSV detection.

Comparative assessment of reported symptoms of influenza, respiratory syncytial virus, and human metapneumovirus infection during hospitalization and post‐discharge assessed by Respiratory Intensity and Impact Questionnaire

“…The few well‐tested PRO measures available to evaluate the symptoms of influenza include the Influenza Intensity and Impact Questionnaire (FluiiQ™) Symptom Scale and the inFLUenza Patient‐Reported Outcome instrument (FLU‐PRO). 1 , 2 Respiratory syncytial virus (RSV) causes acute respiratory tract infection (ARTI) that presents with similar symptoms to influenza and results in substantial morbidity and mortality, particularly among older adults aged ≥ 65 years; however, there is limited evidence of symptom burden associated with RSV in adults. 3 , 4 , 5 PROs that are designed for influenza are often used or adapted for patients with RSV and other ARTIs.…”

“… 3 , 4 , 5 PROs that are designed for influenza are often used or adapted for patients with RSV and other ARTIs. 2 , 6 , 7 A comprehensive symptom assessment that robustly measures the burden of RSV infection in both inpatient and outpatient settings would be an important tool for clinical research in RSV.…”

Patient-reported outcomes in vaccines research: relevance for decision-making

“…31 Table 1 provides an overview of examples where PROs have been utilized, including as inclusion or exclusion criterion or as a case definition within a clinical trial. 19 , 32 When a PRO is assessed electronically (i.e. ePRO) the identification of a case can trigger other events such as a telephone call, site visit or the completion of other assessments to be performed according to the study protocol.…”

“…The GOLD classification is widely used to define the study population within COPD trials and as inclusion/exclusion criteria. In the case definition 19 An ARI case identification was triggered using the FLU-PRO. If subjects experienced 1 day of any respiratory symptom from a pre-defined list of respiratory symptoms (e.g.…”

“…PROs have served as a primary endpoint in pivotal phase III clinical trials when developing a vaccine, as seen in the Merck Shingles Prevention Study, but have also emerged as important vaccine secondary and/or exploratory endpoints for regulators, HTA bodies, payers, policy experts, healthcare providers and patients. 18 , 19 …”