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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.

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 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.).

SUBMITTER: Lim JJ

PROVIDER: S-EPMC7318030 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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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.

Lim Jeremy J JJ Nilsson Anna C AC Silverman Michael M Assy Nimer N Kulkarni Priya P McBride Jacqueline M JM Deng Rong R Li Chloe C Yang Xiaoying X Nguyen Allen A Horn Priscilla P Maia Mauricio M Castro Aide A Peck Melicent C MC Galanter Joshua J Chu Tom T Newton Elizabeth M EM Tavel Jorge A JA

Antimicrobial agents and chemotherapy 20200623 7

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-contro ...[more]

PMID: 32393496

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Project description:BACKGROUND:VIS410, a broadly neutralizing monoclonal antibody that binds the hemagglutinin stem of influenza A viruses, was safe and efficacious in a human H1N1 virus challenge study. This study evaluated the safety and tolerability of VIS410 in non-hospitalized adult patients with uncomplicated influenza A. METHODS:Patients 18 to 65?years of age with symptom onset within 72?h were randomized 1:1:1 to receive a single intravenous infusion of VIS410 4000?mg, 2000?mg, or placebo. Neuraminidase inhibitor therapy was prohibited. Treatment-emergent adverse events (TEAEs) were evaluated up to 100?days post-infusion. Influenza symptoms were assessed daily for 10?days using the FLU-PRO tool. Nasopharyngeal virus shedding was assessed by quantitative reverse-transcription PCR (qRT-PCR) and viral culture through Day 7. FINDINGS:Of the 150 patients randomized, 148 received study drug, and 138 were confirmed influenza A positive. Median age was 42?years; median time from symptom onset to treatment was 42?h; 93% had influenza A subtype H3N2. SAFETY:TEAEs, most commonly diarrhea of mild severity, were dose-related, occurring in 55%, 35%, and 24% of the 4000?mg, 2000?mg, and placebo patients, respectively. Two serious adverse events occurred, both in placebo patients. SYMPTOM ANALYSES:Baseline FLU-PRO symptom scores were balanced among groups. Mean scores were lower by Days 3 and 4 in the pooled VIS410 treatment group versus placebo (p?<?0.023), with a tendency toward faster resolution by Kaplan-Meier analysis. VIROLOGY ANALYSES:VIS410 was associated with reduced median nasopharyngeal viral load TCID50 AUCDay7 (days?×?log10 TCID50/mL) (3.66 pooled VIS410 vs 4.78 placebo, p?=?0.08) and in the subset of patients with baseline hemagglutination inhibition (HAI) titer ?40 (overall, 74% of patients) was significantly reduced vs placebo (4.218 pooled VIS410 vs 6.152 placebo, p?=?0.009). Kaplan-Meier estimated time to resolution of viral shedding was reduced (1.9 vs 3.6?days, p?=?0.03) in VIS410 treated patients. There was a trend toward greater proportion of culture-negative patients by Day 3 (66.7% vs 51.1%, p?=?0.11); when this analysis was limited to the subset of patients with positive baseline cultures, this difference became more pronounced (63.2% vs 42.5%, p?=?0.053). No differences were observed in nasopharyngeal influenza qRT-PCR profiles, which represent both live and neutralized virus. INTERPRETATION:VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication. TRIAL REGISTRATION:Clinical Trials: NCT02989194. FUNDING:This project was funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201500018C.

Project description:BackgroundInfluenza continues to have a substantial socioeconomic and health impact despite a long established vaccination programme and approved antivirals. Preclinical data suggest that combining antivirals might be more effective than administering oseltamivir alone in the treatment of influenza.MethodsWe did a randomised, double-blind, multicentre phase 2 trial of a combination of oseltamivir, amantadine, and ribavirin versus oseltamivir monotherapy with matching placebo for the treatment of influenza in 50 sites, consisting of academic medical centre clinics, emergency rooms, and private physician offices in the USA, Thailand, Mexico, Argentina, and Australia. Participants who were aged at least 18 years with influenza and were at increased risk of complications were randomly assigned (1:1) by an online computer-generated randomisation system to receive either oseltamivir (75 mg), amantadine (100 mg), and ribavirin (600 mg) combination therapy or oseltamivir monotherapy twice daily for 5 days, given orally, and participants were followed up for 28 days. Blinded treatment kits were used to achieve masking of patients and staff. The primary endpoint was the percentage of participants with virus detectable by PCR in nasopharyngeal swab at day 3, and was assessed in participants who were randomised, had influenza infection confirmed by the central laboratory on a baseline nasopharyngeal sample, and had received at least one dose of study drug. Safety assessment was done in all patients in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01227967.FindingsBetween March 1, 2011, and April 29, 2016, 633 participants were randomly assigned to receive combination antiviral therapy (n=316) or monotherapy (n=317). Seven participants were excluded from analysis: three were not properly randomised, three withdrew from the study, and one was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 (40·0%) of 200 participants in the combination group had detectable virus at day 3 compared with 97 (50·0%) of 194 (mean difference 10·0, 95% CI 0·2-19·8, p=0·046) in the monotherapy group. The most common adverse events were gastrointestinal-related disorders, primarily nausea (65 [12%] of 556 reported adverse events in the combination group vs 63 [11%] of 585 reported adverse events in the monotherapy group), diarrhoea (56 [10%] of 556 vs 64 [11%] of 585), and vomiting (39 [7%] of 556 vs 23 [4%] of 585). There was no benefit in multiple clinical secondary endpoints, such as median duration of symptoms (4·5 days in the combination group vs 4·0 days in the monotherapy group; p=0·21). One death occurred in the study in an elderly participant in the monotherapy group who died of cardiovascular failure 13 days after randomisation, judged by the site investigator as not related to study intervention.InterpretationAlthough combination treatment showed a significant decrease in viral shedding at day 3 relative to monotherapy, this difference was not associated with improved clinical benefit. More work is needed to understand why there was no clinical benefit when a difference in virological outcome was identified.FundingNational Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

Project description:BackgroundAntiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy.MethodsFor this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086.Findings1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6-3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8-4·7; hazard ratio [HR] 0·63, 95% CI 0·41-0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90-4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21-0·86] and 0·43 [0·20-0·96]; for positive tests 0·86 [0·37-2·00] and 0·55 [0·26-1·24], respectively).InterpretationWithout a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status.FundingDepartment of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).

Dataset Information

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.

Publications

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.

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