Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

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Heneghan CJ, et al. "Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments". British Medical Journal. 2014. 348:.
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Clinical Question

In patients with confirmed or suspected exposure to natural influenza, will the use of zanamivir compared with usual care for prophylaxis and treatment, reduce the time to alleviation of symptoms and reduce the risk of symptomatic influenza?

Bottom Line

Due to the time to improve symptoms only being half a day, and no evidence being found on the reduction of risk of complications or the risk of admission to the hospital or death, zanamivir therapy is not supported for the prophylaxis or treatment of influenza.

Major Points

This study was a systematic review that attempts to answer the clinical question, “In patients with confirmed or suspected exposure to natural influenza, will the use of zanamivir compared with usual care for prophylaxis and treatment, reduce the time to alleviation of symptoms and reduce the risk of symptomatic influenza”? The study consisted of 26 trials (16 treatment and 10 prophylaxis) and a total of 14,628 participants. The studies included were randomized placebo controlled trials and included both adults and children.

Other studies have been completed regarding zanamivir, but they were found to have publication bias, missing data, and limitations in the design of the studies. This review on zanamivir uses full CSRs obtained from various sources without the need for a contract or as a result of litigation and with no need to access a controlled environment such as a company website. Randomized controlled trials testing the effects of zanamivir for prophylaxis, postexposure prophylaxis (PEP), and treatment of influenza were included in the study.

The primary outcome of this study was the time to alleviation of symptoms of influenza-like illness. For adults, the alleviation of symptoms was by 0.60 days (p<0.001). Several other secondary outcomes studied include the reduced risk of symptomatic influenza through prophylactic treatment, the risk of asymptomatic influenza through prophylaxis, and the risk of complications associated with influenza. The study also analyzed if zanamivir was associated with adverse events. When analyzing internal criticism, all parts of the clinical study reports were consistent. In terms of external criticism, all reports, documents, and references were cross-checked to maintain consistency of data. After careful analysis of the data, the conclusion is that zanamivir is not supported for prophylaxis or treatment of influenza.

Guidelines

CDC guidelines state that zanamivir is a licensed prescription antiviral agent recommended by the FDA for treatment or prevention of influenza during influenza season. Zanamivir is a neuraminidase inhibitor and is effective against both influenza A and B. Inhaled zanamivir is FDA approved for treatments of adults with uncomplicated acute illness caused by influenza A or B virus, as well as for chemoprophylaxis for influenza A and B in adults. It is administered via an inhaler device using 5 mg blister packs, 2 inhalations twice daily. Chemoprophylaxis dosage is 10mg (2 inhalations) once a day. Zanamivir is also FDA approved for the treatment of influenza in children older than 7, and for chemoprophylaxis in children older than 5. The dosing frequency is the same in children as it is for adults.

Design

  • N= 26 trials
  • Experimental trials n=16 trials (14 on treatment in adults, 2 on treatment in children)
  • Prophylactic Trials n=10 trials
  • Setting: Unabridged clinical study reports (CSRs) of randomized controlled studies.
  • Enrollment: 1995-2001
  • Mean follow-up:
    • Experimental Trials: 24 days
    • Prophylactic Trials: 23 days
  • Analysis: Intention to treat (ITT)
  • Primary outcome: Reduced alleviation time of symptoms of influenza-like illness

Population

Inclusion Criteria

  • Trials testing the effects of zanamivir for prophylaxis and treatment
  • Randomized controlled trials
  • Trials with unabridged clinical study reports
  • Those exposed to naturally occurring influenza with or without symptoms
  • Previously healthy children and adults
  • Zanamivir administered by any any route compared to placebo
  • Intention to treat and safety populations

Exclusion Criteria

  • Open label and post marketing studies
  • Trials that included patients with illnesses such as malignancy or HIV

Baseline Characteristics

  • Randomized placebo controlled trials
  • Adults and children who had confirmed or suspected exposure

Interventions

This study evaluated multiple trials that looked at the use of zanamivir for treatment and prevention of influenza. After evaluating the exclusion criteria, 26 zanamivir trials were finally included in the meta-analysis. Fourteen of the trials looked at treatment of adults, two of the trials were on treatment in children, and ten of the trials studied prophylaxis of zanamivir in healthy patients.

Outcomes

Primary Outcome

For treatment of adults, zanamivir reduced alleviation time of symptoms of influenza-like illness by 0.60 days (95% confidence interval 0.39 to 0.81, p<0.001, I2=9%).

Secondary Outcomes

In prophylaxis treatment of individuals, zanamivir significantly reduced the risk of symptomatic influenza(RR 0.39, 95% confidence interval 0.22 to 0.70, I2=45%; RD=1.98%, 0.98% to 2.54%; NNT=51). Risk of symptomatic influenza was also significantly reduced in postexposure prophylaxis of households (RR 0.33, 0.18 to 0.58, I2=40%; RD 14.84%, 12.18% to 16.55%, NNT 7). On the contrary, zanamivir did not significantly affect the risk of asymptomatic influenza in prophylaxis as well as post exposure in households. In adults, zanamivir decreased the risk of bronchitis(RR 0.75, I2=3%; RD 1.80%, NNT 56) but no other complications such as otitis media,(RR 0.81, I2=0%) and sinusitis(1.12, I2=30%).

Subgroup analysis

A subgroup analysis on treatment effects for time to first symptoms in adults found that there was no difference between patients with influenza and in patients without influenza. A subgroup analysis was also completed on the difference between adults and children in this aspect and it was not significant with the overall effect being 0.66 days’ reduction in time to first alleviation of symptoms.

Adverse Events

No evidence was found that zanamivir was associated with an increased risk of adverse events in adults treatment trials. In trials involving children, data on harms was sparse and increased risk of adverse events did not exist. Nausea and vomiting was less frequent in the zanamivir treatment arm however, considerable variability of outcomes were found.

Criticisms

  • All parts (for example, denominators) of the same clinical study reports/unpublished reports were consistent.
  • Access to full clinical study reports allowed us to follow consistency across chapters and appendices, creating a need for far more interaction with the text.
  • The parts of a clinical study report we checked for consistency included the core report, the pre-study documents,study methods, individual subject listings of demographic and efficacy data, and individual listings of safety data, as well as the statistical analysis plan and the serious adverse events.
  • Consistency of data as reported in regulatory documents, other versions of the same clinical study reports/unpublished reports, and other references were established by cross checking.

Funding

This study was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in the Health Technology Assessment journal series.

Further reading