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Hospitalized influenza clinical studies: benchmarking and refinement of clinical endpoints

Hospitalized influenza clinical studies - benchmarking and refinement of clinical endpoints

Kimberly Armstrong

Biomedical Advanced Research and Development Authority (BARDA)Office of the Assistant Secretary for Preparedness and Response (ASPR)Department of Health and Human Services (HHS)

3 May 2019

Treatment options for the severely ill, hospitalized influenza-infected population are limited. Several studies investigating new therapeutic candidates have failed in phase 2 and phase 3 clinical studies, including the study in this data request. There are several challenges for conducting influenza clinical trials. The clinical endpoint for severe influenza infections has not been established. Different studies have used different endpoints such as the time to clinical response defined as the resolution of vital signs or hospital discharge. Another endpoint is the time to return to respiratory baseline status, and the ordinal scale has also been used as an endpoint for hospital studies. The ordinal scale has been used in different ways, but here the categories will be discharged from the hospital, in the hospital, in the intensive care unit, on mechanical ventilation or death. These endpoints have not been compared for their sensitivity using the same data, largely due to the failure of the candidate drugs. In this proposal, we will be assessing the timing of treatment as the surrogate for efficacy because it is known that neuraminidase inhibitors are most effective when given early in the course of disease (Murtheri 2014 Lancet Respir Med. 2:395). Using the timing of neuraminidase inhibitor treatment, the sensitivity of different endpoints will be assessed using several statistical methods.Another challenge of hospitalized influenza studies is identifying the appropriate population to enroll. The severely ill population is heterogeneous, which may be hampering the ability to detect a difference in treatment effect. The data from this study will be used to assess patients with different comorbidities and underlying risk factors to identify a more homogeneous target population for future study enrollment.Neuraminidase inhibitor treatment is considered the standard of care for the hospitalized influenza-infected population in the United States. All patients in this study were given a neuraminidase inhibitor allowing for a determination of baseline characteristics for future studies.The goal of this research is to inform future clinical study design by defining a target population enrollment, finding a sensitive endpoint and determining the baseline characteristics of the target population as a whole.

[{ "PostingID": 4740, "Title": "GSK-NAI114373", "Description": "A Phase III international, randomized, double-blind, double-dummy study to evaluate the efficacy and safety of 300 mg or 600 mg of intravenous zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily in the treatment of hospitalized adults and adolescents with influenza" }]

Statistical Analysis Plan