Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial

Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.

METHODS:

We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.

FINDINGS:

Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group.

INTERPRETATION:

Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner.

FUNDING:

European Commission's Seventh Framework Programme.

Author/s:

Butler, CC, van der Velden, AW, Bongard, E, Saville, BR, Holmes, J, Coenen, S, Cook, J, Francis, NA, Lewis, RJ, Godycki-Cwirko, M, Llor, C, Chlabicz, S, Lionis, C, Seifert, B, Sundvall, PD, Colliers, A, Aabenhus, R, Bjerrum, L, Jonassen Harbin, N, Lindbæk M, Glinz, D, Bucher, HC, Kovacs, B, Radzeviciene Jurgute, R, Touboul Lundgren, P, Little, P, Murphy, AW, De Sutter, A, Openshaw, P, de Jong, MD, Connor, JT, Matheeussen, V, Ieven, M, Goossens, H, Verheij, TJ

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Tracy Ashby — Mon, 03 Dec 2018 06:00:00 +0000

Date Added:

October 30, 2019

Journal/Publication:

The New England Journal of Medicine

Publisher:

Massachusetts Medical Society

Publication Date:

September 6, 2018

Issue:

Volume:

379

Pages:

913-923

URL:

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1056/NEJMoa1716197

Keywords

baloxavir marboxil

oseltamivir

influenza

PMID (1):

30184455

MeSH

adolescent

Adult

Antiviral Agents/administration & dosage

Antiviral Agents/adverse effects

Antiviral Agents/therapeutic use

child

double-blind method

Endonucleases/antagonists & inhibitors

Intention to Treat Analysis

Kaplan-Meier Estimate

male

Middle Aged

oseltamivir/therapeutic use

Oxazines/administration & dosage

Oxazines/adverse effects

Pyridines/administration & dosage

Pyridines/adverse effects

Thiepins/admistration & dosage

Thiepins/adverse effects

Triazines/administration & dosage

Triazines/adverse effects

viral load

Virus Replication/drug effects

Young Adult

These RCTs of the new anti-viral agent, baloxavir marboxil (Zofluza), found that, when given within 48 hours of onset of symptoms, it relieves symptoms one day sooner than placebo (same as Tamiflu). Viral shedding is reduced more effectively though. Resistance appears to develop quickly. The single-dose treatment costs about $150. James W. Mold, MD, MPH

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BACKGROUND:

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

METHODS:

We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

RESULTS:

In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.

CONCLUSIONS:

Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).

Author/s:

Hayden, Frederick G., Sugaya, Norio, Hirotsu, Nobuo, Lee, Nelson, de Jong, Menno D., Hurt, Aeron C., Ishida, Tadashi, Sekino, Hisakuni, Yamada, Kota, Portsmouth, Simon, Kawaguchi, Keiko, Shishido, Takao, Arai, Masatsugu, Tsuchiya, Kenji, Uehara, Takeki, Watanabe, Akira, Baloxavir Marboxil Investigators Group