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Using zanamivir trial data to evaluate baseline characteristics and disease progression by various subgroups to inform clinical development of novel therapies in hospitalized patients with influenza

Using zanamivir trial data to evaluate baseline characteristics and disease progression by various subgroups to inform clinical development of novel therapies in hospitalized patients with influenza

Lesley Butler

Genentech, Inc., A member of the Roche Group

The proposed research study will be internally funded by Roche/Genentech per FTE support for the Research Team (see Section B).

An employee of Roche/Genentech and involved in the clinical development of a novel monoclonal antibody for treatment of severe influenza.

29 August 2017

Illness due to severe influenza represents a tremendous burden to patients and health care systems worldwide. This is due in part to the relatively high hospitalization rates, as well as the morbidity and mortality associated with severe influenza. The lack of novel therapies being developed for severe influenza is partly due to challenges, such as a heterogeneous patient population and the lack of a validated endpoint (EMA Concept Paper, 2017; FDA Guidance, 2011). The proposed research study will diminish barriers to designing effective and safe novel therapies for patients with severe influenza by using the zanamivir trial data to address these challenges.

Severe influenza causes 140,000 to 710,000 hospitalizations per year, with an average annual rate of 95.9/100,000 (Rolfes, 2016; Thompson, 2004). Mortality exceeds 12% amongst patients that are admitted to the ICU. Worldwide, the number of deaths due to severe influenza range from 250,000 to 500,000 annually (WHO, Influenza Factsheet, 2016). The proposed research study will inform the design of clinical trials to test the efficacy of novel treatments in patients hospitalized with influenza.

The research objectives of the proposed study are:
1.   To identify subgroups of patients meeting selected demographic and clinical characteristics at baseline.
2.   To quantify proportions of patients from identified subgroups meeting clinically defined disease-related outcomes.

The proposed research will be led by a cross-functional team at Roche-Genentech. The project lead and statistician will review interim results on a weekly basis, and the team will meet via teleconference on a bimonthly basis to communicate interim results, align on interpretation and discuss next steps. Once the requested zanamivir trial data are made available for analyses, the entire project period from data acquisition to submitting a manuscript for peer review will be accomplished within 18 months.

The focus of this research study is on descriptive analyses of the GSK-114373 phase 3 trial data to evaluate the extent of patient heterogeneity by indicators of disease severity and its impact on clinical outcomes. The main analyses will be done by combining the two zanamivir treatment arms and the standard-of-care oseltamivir arm. The rationale for this approach is that intravenous zanamivir was not found to be superior to oseltamivir, as reported by Marty, et al. (2017).

Findings from descriptive analyses will be interpreted based on overall distributions and trends, the direction of difference between subgroups, and the degree of overlap of the 95% confidence intervals between the subgroups being compared. Where statistical tests are performed, P values less than 0.05 will be interpreted as statistically significant. The findings from this research project will be communicated through forums, such as infectious disease- or epidemiology-focused congresses, as well as in research publications.

[{ "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

Medicine: zanamivir, Condition: Influenza, Human, Phase: 3, Clinical Study ID: NAI114373, Sponsor: GSK" }]

Statistical Analysis Plan

The publication citation will be added after the research is published.