A phase 2 randomized, double-blind, placebo-controlled trial of MHAA4549A, a monoclonal antibody, plus oseltamivir in patients hospitalized with severe influenza a virus infection
(2020) In Antimicrobial Agents and Chemotherapy 64(7).- Abstract
For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical... (More)
For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO2) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.).
(Less)
- author
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Antiviral agents, Influenza A virus, MHAA4549A, Monoclonal antibody
- in
- Antimicrobial Agents and Chemotherapy
- volume
- 64
- issue
- 7
- article number
- e00352-20
- publisher
- American Society for Microbiology
- external identifiers
-
- scopus:85087095282
- pmid:32393496
- ISSN
- 0066-4804
- DOI
- 10.1128/AAC.00352-20
- language
- English
- LU publication?
- yes
- id
- bbb6bcb6-a722-42df-b3c5-0d5bbbabccf0
- date added to LUP
- 2020-07-07 12:28:49
- date last changed
- 2024-06-12 16:56:01
@article{bbb6bcb6-a722-42df-b3c5-0d5bbbabccf0,
abstract = {{<p>For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO<sub>2</sub>) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.).</p>}},
author = {{Lim, Jeremy J. and Nilsson, Anna C. and Silverman, Michael and Assy, Nimer and Kulkarni, Priya and McBride, Jacqueline M. and Deng, Rong and Li, Chloe and Yang, Xiaoying and Nguyen, Allen and Horn, Priscilla and Maia, Mauricio and Castro, Aide and Peck, Melicent C. and Galanter, Joshua and Chu, Tom and Newton, Elizabeth M. and Tavel, Jorge A.}},
issn = {{0066-4804}},
keywords = {{Antiviral agents; Influenza A virus; MHAA4549A; Monoclonal antibody}},
language = {{eng}},
number = {{7}},
publisher = {{American Society for Microbiology}},
series = {{Antimicrobial Agents and Chemotherapy}},
title = {{A phase 2 randomized, double-blind, placebo-controlled trial of MHAA4549A, a monoclonal antibody, plus oseltamivir in patients hospitalized with severe influenza a virus infection}},
url = {{http://dx.doi.org/10.1128/AAC.00352-20}},
doi = {{10.1128/AAC.00352-20}},
volume = {{64}},
year = {{2020}},
}