DOI: 10.5061/dryad.77471
title: Data from: Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

description: PLEASE NOTE, THESE DATA ARE ALSO REFERRED TO IN TWO OTHER ARTICLES. PLEASE
 SEE http://dx.doi.org/10.1136/bmj.g2547 AND
 http://dx.doi.org/10.1136/bmj.g2545 FOR MORE INFORMATION. Background:
 Neuraminidase inhibitors (NIs) are stockpiled and recommended by public
 health agencies for treating and preventing seasonal and pandemic
 influenza. They are used clinically worldwide. Objectives: To describe the
 potential benefits and harms of NIs for influenza in all age groups by
 reviewing all clinical study reports of published and unpublished
 randomised, placebo-controlled trials and regulatory comments. Search
 methods: We searched trial registries, electronic databases (to 22 July
 2013) and regulatory archives, and corresponded with manufacturers to
 identify all trials. We also requested clinical study reports. We focused
 on the primary data sources of manufacturers but we checked that there
 were no published randomised controlled trials (RCTs) from
 non-manufacturer sources by running electronic searches in the following
 databases: the Cochrane Central Register of Controlled Trials (CENTRAL),
 MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the
 Database of Reviews of Effects, the NHS Economic Evaluation Database and
 the Health Economic Evaluations Database. Selection criteria: Randomised,
 placebo-controlled trials on adults and children with confirmed or
 suspected exposure to naturally occurring influenza. Data collection and
 analysis: We extracted clinical study reports and assessed risk of bias
 using purpose-built instruments. We analysed the effects of zanamivir and
 oseltamivir on time to first alleviation of symptoms, influenza outcomes,
 complications, hospitalisations and adverse events in the
 intention-to-treat (ITT) population. All trials were sponsored by the
 manufacturers. Main results: We obtained 107 clinical study reports from
 the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We
 accessed comments by the US Food and Drug Administration (FDA), EMA and
 Japanese regulator. We included 53 trials in Stage 1 (a judgement of
 appropriate study design) and 46 in Stage 2 (formal analysis), including
 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628
 participants). Inadequate reporting put most of the zanamivir studies and
 half of the oseltamivir studies at a high risk of selection bias. There
 were inadequate measures in place to protect 11 studies of oseltamivir
 from performance bias due to non-identical presentation of placebo.
 Attrition bias was high across the oseltamivir studies and there was also
 evidence of selective reporting for both the zanamivir and oseltamivir
 studies. The placebo interventions in both sets of trials may have
 contained active substances. Time to first symptom alleviation. For the
 treatment of adults, oseltamivir reduced the time to first alleviation of
 symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P
 &lt; 0.0001). This represents a reduction in the time to first
 alleviation of symptoms from 7 to 6.3 days. There was no effect in
 asthmatic children, but in otherwise healthy children there was (reduction
 by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001).
 Zanamivir reduced the time to first alleviation of symptoms in adults by
 0.60 days (95% CI 0.39 to 0.81 days, P &lt; 0.00001), equating to a
 reduction in the mean duration of symptoms from 6.6 to 6.0 days. The
 effect in children was not significant. In subgroup analysis we found no
 evidence of a difference in treatment effect for zanamivir on time to
 first alleviation of symptoms in adults in the influenza-infected and
 non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment
 of adults with oseltamivir had no significant effect on hospitalisations:
 risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no
 significant effect in children or in prophylaxis. Zanamivir
 hospitalisation data were unreported. Serious influenza complications or
 those leading to study withdrawal. In adult treatment trials, oseltamivir
 did not significantly reduce those complications classified as serious or
 those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor
 in child treatment trials; neither did zanamivir in the treatment of
 adults or in prophylaxis. There were insufficient events to compare this
 outcome for oseltamivir in prophylaxis or zanamivir in the treatment of
 children. Pneumonia. Oseltamivir significantly reduced self reported,
 investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to
 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451)
 in the treated population. The effect was not significant in the five
 trials that used a more detailed diagnostic form for pneumonia. There were
 no definitions of pneumonia (or other complications) in any trial. No
 oseltamivir treatment studies reported effects on radiologically confirmed
 pneumonia. There was no significant effect on unverified pneumonia in
 children. There was no significant effect of zanamivir on either self
 reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir
 significantly reduced the risk of self reported, investigator-mediated,
 unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311
 (95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and
 otitis media. Zanamivir significantly reduced the risk of bronchitis in
 adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to
 155), but not oseltamivir. Neither NI significantly reduced the risk of
 otitis media and sinusitis in both adults and children. Harms of
 treatment. Oseltamivir in the treatment of adults increased the risk of
 nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm
 (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to
 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold
 increases in antibody titre was significantly lower in the treated group
 compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I2 statistic
 = 0%) (5% absolute difference between arms). Oseltamivir significantly
 decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43
 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB
 = 148 (101 to 2509) compared to placebo during the on-treatment period.
 There was a dose-response effect on psychiatric events in the two
 oseltamivir “pivotal” treatment trials, WV15670 and WV15671, at 150 mg
 (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment
 of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to
 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower
 proportion of children on oseltamivir with a four-fold increase in
 antibodies (RR 0.90, 95% CI 0.80 to 1.00, I2 = 0%). Prophylaxis. In
 prophylaxis trials, oseltamivir and zanamivir reduced the risk of
 symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83
 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54);
 NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI
 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to
 16.55); NNTB = 7 (7 to 9)). There was no significant effect on
 asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33);
 zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like
 illness could not be assessed due to data not being fully reported. In
 oseltamivir prophylaxis studies, psychiatric adverse events were increased
 in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to
 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population.
 Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%,
 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on
 treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB
 &gt; 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to
 9.51); NNTH = 25 (95% CI 11 to 116). Authors’ conclusions: Oseltamivir and
 zanamivir have small, non-specific effects on reducing the time to
 alleviation of influenza symptoms in adults, but not in asthmatic
 children. Using either drug as prophylaxis reduces the risk of developing
 symptomatic influenza. Treatment trials with oseltamivir or zanamivir do
 not settle the question of whether the complications of influenza (such as
 pneumonia) are reduced, because of a lack of diagnostic definitions. The
 use of oseltamivir increases the risk of adverse effects, such as nausea,
 vomiting, psychiatric effects and renal events in adults and vomiting in
 children. The lower bioavailability may explain the lower toxicity of
 zanamivir compared to oseltamivir. The balance between benefits and harms
 should be considered when making decisions about use of both NIs for
 either the prophylaxis or treatment of influenza. The influenza
 virus-specific mechanism of action proposed by the producers does not fit
 the clinical evidence.
description: Relenza (Zanamivir)
 Clinical Study ReportsFull set of clinical
 study reports for the neuraminidase inhibitor Relenza (Zanamivir) produced
 by GlaxoSmithKline and made available to the Cochrane collaboration for
 the production of their meta-analysis of neuraminidase inhibitors for
 preventing and treating influenza in healthy adults and
 childrenRelenza.zipTamiflu (oseltamivir) clinical study reportsFull set of clinical study reports for the neuraminidase inhibitor Tamiflu (Oseltamivir) produced by Roche and made available to the Cochrane collaboration for the production of their meta-analysis of neuraminidase inhibitors for preventing and treating influenza in healthy adults and childrenTamiflu.zip