Types of studies

Randomised or quasi‐randomised controlled studies.

Types of participants

Individuals with CF following lung transplantation (including lobe, single‐lung, and bilateral transplants) or heart‐lung transplantation. 

Types of interventions

We planned to include studies of comparisons of individual drugs (e.g. cyclosporine (CsA), tacrolimus (Tac), sirolimus (rapamycin), mycophenolate mofetil (MMF)) or combinations of individual drugs to placebo or other individual drugs or combinations of other individual drugs. We also planned to include comparisons of two drugs within the same class (e.g. daclizumab versus basiliximab).

Types of outcome measures

We planned to assess the following outcome measures.

Electronic searches

We identified relevant studies from the Group's Cystic Fibrosis Trials Register using the terms: transplantation AND lung AND immunosuppressant.

The CF Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), weekly 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 Unpublished work is identified by searching the abstract books of three major CF conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis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 Cochrane Cystic Fibrosis and Genetic Disorders Group website.

Date of search: 30 May 2018.

We also searched the www.clinicaltrials.gov registry and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/) on May 29, 2018 to obtain information on unpublished and ongoing studies.

Searching other resources

If we identify eligible studies for updates of the review, we will search the reference lists of included articles and other relevant studies and reviews to identify additional studies. We will also contact the authors of the included articles. We also handsearched the Journal of Heart and Lung Transplantation (for the years 2012, 2013, and 2014), which is the official publication of the International Society for Heart and Lung Transplantation (ISHLT).

Selection of studies

We used a two‐tier screening process to identify relevant articles. Initially, we screened the titles and abstracts of articles identified through searching and obtained the full text versions of those considered potentially relevant. We then screened the full text articles to identify those studies which should be included in the review and are eligible for data abstraction. Two review authors (IJS, OA) independently screened each article. We resolved any disagreements by consensus.

We planned to include studies which either included people with CF exclusively or which included at least some people with CF. However, this second kind of study would only be included provided we were able to abstract from the article, or obtain from its authors, specific data on outcomes related to those with CF.

Data extraction and management

We imported search results into a reference management software (Procite, Thomson Reuters, New York, NY). We then screened citations and tracked results of the screening using the reference management software. We designed custom data abstraction forms to abstract information from eligible review articles and planned for one author (IJS) to abstract data and a second author (OA) to review the abstracted data for completeness and accuracy. We intended to resolve any disagreements through consensus or consultation with a third reviewer (KAR). One author (IJS) would then have entered the data into RevMan (RevMan 2014).

We planned to group eligible studies together based on time of outcome assessment. We planned to consider outcomes as immediate if up to one week duration; short term if more than one week and up to one month duration; medium term if more than one month and up to six months duration; and long term if more than six months duration. If studies reported data at multiple time points within an interval, we planned to analyse these separately if appropriate.

Assessment of risk of bias in included studies

We planned to assess the risk of bias in included studies through assessment of random sequence generation; allocation concealment; blinding of the study participants and personnel, blinding of outcome assessors; incomplete outcome data; selective reporting; and other sources of bias (compliance assessment; washout reporting; intention‐to‐treat analysis; and loss to follow up). We would have assessed studies using each of these criteria as having high, low, or unclear risk of bias. Two review authors (IJS, OA) would have independently applied the methods for evaluating the risk of bias described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We intended to resolve any disagreements through consensus or consultation with a third review author (KAR).

Measures of treatment effect

We planned to analyse continuous outcomes using the mean difference (MD) (or we would have calculated the standardised mean difference (SMD) if different scales of measurement have been used) and dichotomous outcomes using the risk ratio (RR). We planned to present all outcomes with associated 95% confidence intervals (CIs).

Unit of analysis issues

When conducting analyses, we planned to take into consideration the level at which randomisation occurred (Sterne 2011). Randomised controlled studies with parallel group designs are studies where individuals are independently randomised to intervention groups. In cross‐over studies, individuals are randomised to more than one intervention. However, this design is not suitable for most immunosuppressive drug studies because the clinical outcomes of transplant recipients or graft survival may be highly dependent on the initial anti‐rejection therapy (Leonard 2001). We therefore only planned to include first‐arm data from cross‐over studies.

Dealing with missing data

In the event of missing, incomplete, or unclear data, we intended to contact the original investigators. This includes unreported outcomes, missing participants, and missing statistics (such as standard deviations). Where the necessary data for analysis was not available, we planned to provide a narrative summary of the studies.

Assessment of heterogeneity

We intended to assess clinical heterogeneity by considering variability in the participants, interventions, and comparisons in the included studies. We also intended to assess statistical heterogeneity within each outcome between the comparisons using the Chi² test and I² statistic (Higgins 2003). Under the null hypothesis of homogeneity, we would have considered a P value of less than 0.10 to indicate the presence of heterogeneity in the Chi² test (Sterne 2011). We would have interpreted the results with care since the test could have low or high power. Low power is common when studies have a small sample size or there are a small number of studies, which may result in the lack of detection of heterogeneity when it is present. High power is common when there are many studies being analysed, resulting in the detection of heterogeneity that may be insignificant. The I² statistic measures the proportion of inconsistency in individual studies that cannot be explained by sampling error. In this test the degree of heterogeneity is quantified. The values of I² lie between 0 and 100%. We planned to consider I² results less than 40% to indicate that heterogeneity might not be important; between 30% and 60% to indicate that heterogeneity may be moderate; between 50% and 90% to indicate that heterogeneity may be substantial; and between 75% and 100% to indicate considerable heterogeneity (Deeks 2011).

Assessment of reporting biases

If we had included more than 10 studies, we planned to assess reporting bias among the studies using the funnel plot method discussed in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). If asymmetry had been present, we would have explored possible causes including publication bias, risk of bias, outcome reporting bias, and true heterogeneity. Outcome reporting bias can occur when studies measure outcomes, but do not publish all of them. This can lead to misleading results (Kirkham 2010). We planned to compare the 'Methods' section of the paper to the 'Results' section to ensure all outcomes are reported. If we had suspected outcome reporting bias, we would have contacted study authors for the data.

Data synthesis

We planned to enter data abstracted from included studies into RevMan 5.3 (RevMan 2014). If heterogeneity was low, as indicated by an I² result less than 30%, we planned to use a fixed‐effect model to synthesise the results. If heterogeneity was moderate, substantial, or considerable, as indicated by an I² of 30% or higher, we planned to use a random‐effects model to synthesise the results. We aimed to synthesise results by combining studies of individual drugs as well as combining studies of drugs within the same class of immunosuppressants. If we had found it inappropriate to conduct meta‐analysis, we would have provided a narrative synthesis of the available data.

Subgroup analysis and investigation of heterogeneity

If the review had included at least 10 studies, we planned to investigate any heterogeneity through the following subgroup analyses:

1. age (children (up to 18 years old) versus adults);

2. type of donor (among the deceased donors, DBD donors versus DCD donors);

3. extent of tissue being transplanted (lobe, single lung, and bilateral lung transplants);

4. pre‐transplant lung function (FEV₁% predicted over 60%, 41% to 59%, 21% to 40%, under 20%);

5. pre‐transplant ventilator status (on versus off ventilation).

Sensitivity analysis

We planned to perform sensitivity analyses to identify the effects of unpublished studies, study size (stratified by sample size), study design (cross‐over versus parallel studies), allocation concealment (high risk of bias versus low risk of bias), participant blinding (high risk of bias versus low risk of bias), assessor blinding (high risk of bias versus low risk of bias), and loss to follow up (high risk of bias versus low risk of bias) on the results.

Summary of findings and assessment of the certainty of the evidence

If we had been able to include eligible studies in this systematic review, we planned to develop a summary of findings table for each comparison presented in the review in accordance with GRADE guidelines. In that event, we intended to include the following seven outcomes in the summary of findings table:

1. Hyperacute rejection

2. Acute rejection

3. Chronic rejection (BOS)

4. Mortality

5. QoL

6. Opportunistic infections

7. Adverse events