Types of studies

We will include randomised and cluster‐randomised controlled trials (RCTs). We will also include cross‐over studies but, to overcome potential carry‐over effects from the first phase (e.g. antibiotic resistance), we will only use data from the first pre‐cross‐over phase. We will include studies reported in full text, those only published as abstracts, and unpublished data.

Types of participants

We will include adults and children (< 18 years) with a clinical diagnosis of bronchiectasis confirmed by high resolution computed tomography (HRCT), plain film chest radiograph, or bronchography and a documented history of recurrent chest infections. We will exclude studies where participants received high dose antibiotics immediately prior to enrolment or those with a diagnosis of allergic bronchopulmonary aspergillosis (ABPA), hypogammaglobulinaemia, cystic fibrosis (CF), sarcoidosis, or a primary diagnosis of COPD. We will also exclude studies where participants receive short courses of antibiotics for an acute exacerbation. We will only include studies with mixed populations (different respiratory conditions), if there is a separate subgroup analysis for participants with bronchiectasis. Data on children and adults will be analysed separately.

Types of interventions

We will include studies comparing the following:

• Prophylactic intermittent antibiotics versus placebo.

• Prophylactic intermittent antibiotics versus usual care. Usual care may include bronchodilators, anti‐inflammatories, mucolytics, inhaled hyperosmolar agents, or chest physiotherapy.

• Prophylactic intermittent antibiotics using regimen X versus regimen Y, e.g. 14 days of antibiotics followed by 14 days of none versus 28 days of antibiotics followed by 28 days of none.

These different comparisons will be reported separately. Intermittent prophylactic administration is defined as repeated courses of antibiotics with predefined on‐treatment duration of at least 14 days and off‐treatment intervals of at least 14 days, for a study duration of at least three months. The method of administration may be oral or inhaled, but should be the same in all study groups in order to isolate the effect of the antibiotic rather than the delivery device. We will exclude studies that compare continuously administered prophylactic antibiotics with those administered intermittently as this has been addressed in a separate review (Donovan 2018).

Types of outcome measures

We will use exacerbation and hospitalisation rates as reported by study authors. We will collect outcome data at a range of follow‐up points that best reflect available evidence from included studies (e.g. end of study, end of follow‐up, change from baseline).

Electronic searches

We will identify studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group. The Cochrane Airways Trials Register contains studies identified from several sources:

1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL), through the Cochrane Register of Studies Online (crso.cochrane.org);

2. weekly searches of MEDLINE Ovid SP 1946 to date;

3. weekly searches of Embase Ovid SP 1974 to date;

4. monthly searches of PsycINFO Ovid SP 1967 to date;

5. monthly searches of CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature) 1937 to date;

6. monthly searches of AMED EBSCO (Allied and Complementary Medicine);

7. handsearches of the proceedings of major respiratory conferences.

Studies contained in the Trials Register are identified through search strategies based on the scope of Cochrane Airways. Details of these strategies, as well as a list of handsearched conference proceedings are in Appendix 1. See Appendix 2 for search terms used to identify studies for this review.

We will search the following trials registries:

1. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);

2. World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch).

We will search the Cochrane Airways Trials Register and additional sources from inception to present, with no restriction on language of publication.

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references and search relevant manufacturers' websites for study information.

We will also search for errata or retractions from included studies published in full text on PubMed and report the date of the search in the review.

Selection of studies

Two review authors (TD and MMD) will screen the titles and abstracts of the search results independently and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports of all potentially eligible studies and two review authors (TD and MMD) will independently screen them for inclusion, recording the reasons for exclusion of ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person/review author (SS). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection using a PRISMA flow diagram and 'Characteristics of excluded studies' table (Moher 2009).

Data extraction and management

We will use a data collection form for study characteristics and outcome data, which has been piloted on at least one study in the review. One review author (AT) will extract the following study characteristics from included studies:

1. Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and location, study setting, withdrawals, and date of study.

2. Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria.

3. Interventions: intervention, comparison, concomitant medications, and excluded medications.

4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

5. Notes: funding for studies and notable conflicts of interest of trial authors.

We will summarise the interventions in included studies (study, adults or children, number of participants, type of antibiotic, dose, frequency, regimen, delivery mode, comparator) using a study characteristics table.

Two review authors (AT and GP) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person/review author (SS). One review author (AT) will transfer data into the Review Manager file (RevMan 2014). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (GP) will spot‐check study characteristics for accuracy against the study report.

Assessment of risk of bias in included studies

Two review authors (SS and TD) will assess risk of bias independently for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (MMD). We will assess the risk of bias according to the following domains:

1. random sequence generation;

2. allocation concealment;

3. blinding of participants and personnel;

4. blinding of outcome assessment;

5. incomplete outcome data;

6. selective outcome reporting;

7. other bias.

We will judge each potential source of bias as high, low, or unclear and provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We will summarise the 'risk of bias' judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes, where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Measures of treatment effect

We will analyse dichotomous data as odds ratios (OR) and continuous data as the mean difference (MD) or standardised mean difference (SMD). If data from rating scales are combined in a meta‐analysis, we will ensure they are entered with a consistent direction of effect (e.g. lower scores always indicate improvement).

We will undertake meta‐analyses only where this is meaningful; that is, if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.

We will describe skewed data narratively (for example, as medians and interquartile ranges for each group).

Where multiple trial arms are reported in a single study, we will include only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta‐analysis, we will either combine the active arms or halve the control group to avoid double‐counting.

We will use adjusted date as first choice if it is available (e.g. rate ratios from Poisson regression models, mean differences from ANOVAs or results from cluster‐RCTs adjusted for the effects of clustering), followed by change scores and endpoint scores.

We will use intention‐to‐treat (ITT) analyses where they are reported instead of completer or per protocol analyses.

Unit of analysis issues

For dichotomous outcomes, we will use participants, rather than events, as the unit of analysis (i.e. number of people admitted to hospital, rather than number of admissions per person). However, if exacerbations and hospitalisations are reported as rate ratios (number of events experienced by a participant) in a study, we will analyse them on this basis.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data, where possible (e.g. when a study is identified as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will take this into consideration in the GRADE rating for affected outcomes.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity among the studies in each analysis. If we identify substantial heterogeneity (> 50%) we will report it and explore the possible causes by prespecified subgroup analysis. 

Assessment of reporting biases

If we are able to pool more than 10 studies, we will create and examine a funnel plot to explore possible small study and publication biases.

Data synthesis

We will use a random‐effects model, reported with 95% confidence intervals (CI) and perform a sensitivity analysis with a fixed‐effect model. We will synthesise and report dichotomous and continuous data separately for each outcome, e.g. hospitalisation/no hospitalisation or duration of hospitalisation. Data on adults and children will be reported separately. Odds ratios will also be analysed and reported separately. For a given outcome measure, we will combine effect estimates, such as differences at endpoint and change from baseline, providing that there are no reported baseline differences between groups, When outcomes are measured using different scales, e.g. health‐related quality of life, we will use standardised mean differences (SMD) in the analyses. We will use the baseline standard deviation (SD) for the SMD analyses.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses:

1. Colonisation with P aeruginosa at study enrolment versus no colonisation;

2. Method of administration (oral versus IV versus inhaled).

We will use the following outcomes in subgroup analyses:

1. Exacerbation frequency;

2. Serious adverse events.

We will use the formal test for subgroup interactions in Review Manager (RevMan 2014).

Sensitivity analysis

We plan to carry out sensitivity analyses by comparing results before and after removing studies at high risk of bias from:

1. Random sequence generation;

2. Allocation concealment.

We will also compare the results from a fixed‐effect model with results from the random‐effects model.