Criteria for considering studies for this review
Types of studies
Randomised controlled trials and quasi-randomised controlled trials.
Types of participants
Children and adults with confirmed diagnosis of CF by the presence of two disease causing mutations, or by a combination of positive sweat test and recognised clinical features of CF. Participants should also have either or both (post hoc change - see Differences between protocol and review) of the following:
a clinical diagnosis of influenza (temperature above 37.8 °C; at least two of the following symptoms: cough, headache, myalgia, sore throat or fatigue; and no clinical evidence of bacterial infection) made by a healthcare professional in a community in which there was an influenza outbreak;
laboratory or near-patient test confirmation of influenza.
Types of interventions
Interventions comparing NIs to placebo or other antiviral drugs for treating influenza in people with CF at any dose or regimen and each NI agent to be considered separately.
Types of outcome measures
Need for hospitalisation (directly related to influenza illness)
Time to alleviation of constitutional symptoms (fever and associated symptoms) (post hoc change - see Differences between protocol and review)
forced expiratory volume in one second (FEV1) as per cent of predicted for age, sex and height
forced vital capacity (FVC) as per cent of predicted for age, sex and height
Quality of life (as measured by a validated tool)
Acquistion of characteristic CF pathogens
Pulmonary exacerbation (protocol defined) or need for additional antibiotic treatment (oral or intravenous)
Need for ventilator support (hospital admission)
Development of flu-related complications
Clinical score (e.g. Schwachman score)
Treatment burden (using a validated measure such as Challenges of Living with Cystic Fibrosis (CLCF))
Time off school or work
body mass index (BMI)
Adverse events (relating to treatment)
mild (not needing additional treatment)
moderate (needing treatment or admission to hospital)
Search methods for identification of studies
Although there were no language restrictions on included studies we did not retrieve any relevant non-English papers. We will not apply any language restrictions on any studies identified for future updates of the review.
We searched the Group's Cystic Fibrosis Trials Register using the search terms: neuraminidase inhibitors AND cystic fibrosis.
The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals - Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group Module.
Date of last search of the Cystic Fibrosis Trials Register: 08 July 2013.
Searching other resources
We did not identify any relevant studies and were therefore unable to do any searching of the reference lists of relevant articles. We have contacted Roche UK (manufacturers of Tamiflu®) (last email sent September 2013) and GlaxoSmithKline (manufacturers of Relenza®) to request any unpublished information on any relevant ongoing or completed trials of their products. To date we have not received any response.
Data collection and analysis
Although no studies were identified for inclusion in this review the following methods of selection of studies, data extraction, assessment of risk of bias and data management will apply for subsequent updates, and when future studies are identified.
Selection of studies
Two review authors Vanitha Jagannath (VJ) and Zbys Fedorowicz (ZF) will independently assess the abstracts of studies resulting from the searches. We will obtain full copies of all relevant and potentially relevant studies, those appearing to meet the inclusion criteria, and those for which there are insufficient data in the title and abstract to make a clear decision.The two review authors will independently assess the full text papers and resolve any disagreement on the eligibility of included studies through discussion and consensus, or through a third party Jai Shanthini Singaram (JS). We will exclude all irrelevant records and note the details of the studies and the reasons for their exclusion in the 'Characteristics of excluded studies' table in RevMan 5 (RevMan 2008).
Data extraction and management
The authors will enter extracted study details into the 'Characteristics of included studies' table in RevMan 5 and will collect outcome data using a pre-determined form designed for this purpose. Both authors will compare extracted data to reach a consensus and one author (ZF) will enter the data into RevMan 5.
We will extract the following details.
method of allocation
masking of participants, trial investigators and outcome assessors
exclusion of participants after randomisation and proportion and reasons for losses at follow up
country of origin and location: private clinic or academic institute
inclusion and exclusion criteria
type, dosage, route of administration
length of time in follow up.
type, dosage, route of administration
length of time in follow up.
primary outcomes mentioned in the 'Types of outcome measures' section of this review
secondary outcomes mentioned in the 'Types of outcome measures' section of this review
If stated, we will record the sources of funding of any of the included studies.
The review authors will use this information to help them assess heterogeneity and the external validity of the trials.
We plan to report outcomes at up to one week, between one and two weeks, more than two weeks to three weeks, more than three weeks to four weeks. We will also consider additional follow-up data recorded at other time periods. The above time points were chosen to comprehensively evaluate the effect of intervention:
on the viral influenza infection in CF which would be immediate;
on the secondary complications of Influenza like bacterial infections pneumonia or acute suppurative otis media (ASOM), which would last for a few days to weeks; and
the impact of flu and its secondary complications on the CF disease course which could last for weeks to months.
Assessment of risk of bias in included studies
Each review author will grade the risk of bias in the selected trials using a simple contingency form following the domain-based evaluation described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0 (Higgins 2008). They will compare the evaluations and any disagreements between the review authors will be discussed and resolved.
The following domains will be assessed as 'Yes' (i.e. low risk of bias), 'Unclear' (uncertain risk of bias) or 'No' (i.e. high risk of bias):
blinding (of participants, personnel and outcome assessors);
incomplete outcome data;
selective outcome reporting.
These assessments will be reported for each individual study in the 'Risk of bias in included studies' table.
Measures of treatment effect
We will report risk ratios (RR) and their associated 95% confidence intervals (CIs) for dichotomous outcomes, and odds ratios (OR) with 95% CIs for adverse events.
For continuous outcomes, we will report the mean relative change from baseline or the mean post-intervention value as well as the difference in means between treatment groups and their associated 95% CIs. We will also record the standard deviations (SDs); if standard errors (SEs) are provided, these will be converted to SDs.
Time-to-resolution data will be reported as hazard ratio (HR) with 95% CIs.
Unit of analysis issues
We expect to include trials in which the individual participants were the units of randomisation and subsequent analysis. If cluster-randomised trials are included in the analyses, we will adjust their sample sizes using an estimate of the intra-cluster correlation co-efficient (ICC) derived from the trial or another source (Higgins 2008).
We do not plan to include any cross-over trials as the interventions are not appropriate for this review.
Dealing with missing data
We will make attempts to retrieve missing data from the investigators for any of the included trials, and if unsuccessful or the discrepancies are significant, we will provide a narrative synthesis of the data as reported. We have contacted the manufacturers of the two currently commercially available drugs (Tamiflu® and Relenza®) for any unpublished trial information.
Assessment of heterogeneity
We will assess clinical heterogeneity by examining the characteristics of the studies, the similarity between the types of participants, the interventions and the outcomes as specified in the criteria for included studies. Statistical heterogeneity will be assessed using a chi2 test and the I2 statistic (Higgins 2003). Using chi2, we will consider a P value of less than 0.10 as evidence of heterogeneity. We will evaluate the I2 statistic as follows:
0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.
Assessment of reporting biases
To assess publication bias we will follow the recommendations on testing for funnel plot asymmetry (with at least 10 studies) as described in section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0 (Higgins 2008), and we will explore these in the Discussion section if appropriate. We will also attempt to assess outcome reporting bias as stated above by comparing the protocols of included trials to the final published papers to establish that all outcomes measured are reported. If the protocols of trials are not available, we will compare the 'Methods' and the 'Results' sections of the final published papers. We will also use clinical knowledge to identify the measures usually reported for specific outcomes.
We will seek statistical support from the Cochrane Cystic Fibrosis and Genetic Disorders Group. Two review authors Zbys Fedorowicz (ZF) and Vanitha Jagannath (VJ) will analyse the data and report them as specified in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0 (Higgins 2008). We will report the different types of NIs separately. In view of the expectation of a degree of clinical heterogeneity between the studies we intend using the random-effects model with studies grouped together by mode of drug activity. In the event that there are insufficient clinically homogeneous trials for any specific intervention or insufficient study data that can be pooled, we will present a narrative synthesis.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses if we identify moderate, substantial or considerable heterogeneity (as defined above) and if we are able to include at least 10 studies.
age (under 16 years; 16 years and older)
severity of CF (Schwachman score: severe - under 40; moderate - 41 to 55; mild - 56 to 70; good - 71 to 85; excellent - over 85)
influenza immunisation status (influenza immunisation within last 12 months)
If there are sufficient included studies (n = 10) we plan to conduct sensitivity analyses to assess the robustness of our review results by repeating the analysis with the following adjustments: exclusion of quasi-randomised studies; of studies with unclear or inadequate allocation concealment; of studies with unclear or inadequate blinding of outcomes assessment and completeness of follow up; exclusion of cluster-randomised studies.