Types of studies

We will include randomized controlled clinical trials (RCTs) that compare macrolides as first‐line therapy with any other antibiotic treatment or any other symptomatic treatment. We will also include RCTs that compare different macrolides regimens (by macrolide type) for the treatment of H. ducreyi infection. We will exclude quasi‐RCTs because this produces effect estimates that indicate more extreme benefits when they are compared with RCTs (Higgins 2011). We will also exclude crossover and cluster trials, because of the nature of the condition and intervention (Higgins 2011).

Finally, we will exclude RCTs that assess the effectiveness of trimethoprim/sulfamethoxazole because several H. ducreyi isolates with resistance to this medication have been reported worldwide (BASSH 2007; CDC 2015).

Types of participants

We will include men and non‐pregnant women over the age of 16 years who present with purulent genital ulcers that are clinically compatible with chancroid. We will use this diagnostic pathway because it reflects clinical practice and also because the World Health Organization (WHO) (WHO 2005), and other clinical practice guidelines (CDC 2015; Min Salud 2013), recommend the syndromic approach.

Types of interventions

Macrolides (any doses, frequency, duration and administration route) versus:

• any other antibiotic treatment (any doses, frequency, duration and administration route);

• any symptomatic treatment (e.g. buboes aspiration or analgesic treatment); or

• any other macrolide type (any doses, frequency, duration and administration route).

Types of outcome measures

Electronic searches

We will contact the Information Specialist of the Cochrane Sexually Transmitted Infections (STI) Group in order to implement a comprehensive search strategy to identify as many relevant RCTs as possible in electronic databases. We will use a combination of controlled vocabulary (Medical Subject Headings (MeSH), Emtree terms, DeCS, including exploded terms) and free‐text terms (considering spelling variants, synonyms, acronyms, and truncation) for “Haemophilus ducreyi infection” and “Macrolides”, with field labels, proximity operators, and boolean operators. We have listed our search strategies in Appendix 1.

We will search the following electronic databases:

• the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform: inception to present;

• MEDLINE, Ovid platform: inception to present;

• MEDLINE In‐Process & Other Non‐Indexed Citations, Ovid platform: inception to present;

• MEDLINE Daily Update, Ovid platform: inception to present;

• Embase: inception to present;

• LILACS, IAHx interface: inception to present.

For MEDLINE, we will use the Cochrane highly sensitive search strategy for identifying RCTs: sensitivity and precision maximizing version (2008 revision), Ovid format (Higgins 2011). We will combine the LILACS search strategy with a RCT filter of IAHx interface.

Searching other resources

We will search the following resources for additional trials:

• the Cochrane STI Group’s Specialized Register, which includes RCTs and controlled clinical trials, from 1944 to 2014, located through:

  • electronic searches of MEDLINE, EMBASE and CENTRAL;

  • online handsearching of journals not indexed in MEDLINE or EMBASE, according to the journals’ master list of the Cochrane STI Group;

• trials registers:

  • the WHO International Clinical Trials Registry Platform (ICTRP) portal (http://apps.who.int/trialsearch/): inception to present;

  • ClinicalTrials.gov (http://clinicaltrials.gov/): inception to present;

• the Web of Science®: inception to present.

Selection of studies

Three review authors (CH, LR, and CFG‐A) will independently screen all the titles and abstracts retrieved from the search strategy to determine which trials we should assess further. Three review authors will independently investigate the full‐text articles of all potentially relevant articles and we will resolve any disagreements through discussion. We will present a PRISMA flow diagram to show the process of trial selection. We will list all articles excluded after full‐text assessment and the reasons for exclusion in a 'Characteristics of excluded studies' table.

Data extraction and management

We will design a data extraction form, which we will pilot test before we use it to extract data from the included studies. For eligible studies, three review authors (CH, LR, and CFG‐A) will independently extract data using the agreed data extraction form. We will resolve any disagreements about extracted data through discussion until we reach a consensus.

We will extract data on the following:

• location of the study and setting;

• study design;

• power calculation performed;

• inclusion and exclusion criteria;

• baseline information of the participants in order to have comparable intervention groups at entry (number of women, number of men, age, prior treatment for ulcer, presence of buboes, site and number of lesions, HIV coinfection);

• total number of intervention groups;

• types of interventions: macrolide type, concentration, frequency, and duration of treatment;

• types of comparison: any other antibiotic treatment (any doses, frequency, duration and administration route) or any symptomatic treatment (e.g. buboes aspiration or analgesic treatment);

• methods used to generate random allocation and maintain allocation concealment;

• use of any method of blinding of the researchers or participants in order to evaluate outcomes;

• number of participants enrolled, randomized, excluded after randomization, and analyzed;

• adherence to the planned intervention and other interventions in the groups under evaluation;

• how the trial authors defined outcomes;

• time of follow‐up of participants to measure outcomes;

• use of intention‐to‐treat (ITT) analysis;

• funding sources, if reported;

• ethical issues: use of signed informed consent and ethics approval.

For eligible studies, two review authors (CH and LR) will enter data into Review Manager 5 (RevMan 5) (RevMan 2014), and will check them for accuracy. When information regarding any of the above is unclear, we will attempt to contact the authors of the original trial reports for further details. For a single RCT report, we will extract data directly into a data collection form; in cases of multiple reports, we will extract data from each report separately and then combine information across data collection forms.

Assessment of risk of bias in included studies

Two review authors (CH and CFG‐A) will independently assess the risk of bias for each included trial using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by consensus or by consulting a third review author (HGG). The review authors that will assess the risk of bias in the included studies will be theme and methodology experts.

Measures of treatment effect

For dichotomous data, we will present the results as risk ratios (RRs) with 95% confidence intervals (CIs). The RR is used as a relative effect measure, which works well with a low or high rate of events, and is easy to interpret and use in clinical practice.

Unit of analysis issues

Where we identify a clinical trial that randomized participants to several intervention groups, we will determine which intervention groups are relevant. To avoid confusion for the reader, we will include all intervention groups of the study in the 'Characteristics of included studies' table, and will provide a detailed description only of the intervention groups that are relevant to the review, and we will only use these groups in the analyses.

Finally, in order to overcome a unit‐of‐analysis error for a study that could contribute multiple, correlated comparisons, we will combine all relevant experimental intervention groups of the studies into a single group and also combine all relevant control intervention groups into a single control group, in order to create a single pairwise comparison (Higgins 2011).

Dealing with missing data

We will report the percentage of observations with missing data of each included trial. For all outcomes, we will perform analyses, as far as possible, on an ITT basis (i.e. we will attempt to include all participants randomized to each group in the analyses, and we will analyze all participants in the group to which they were allocated, regardless of whether or not they received the allocated intervention). In case that this could not be possible, the denominator for each outcome in each trial will be the number randomized minus any participants whose outcomes are missing. We will contact the study investigators in order to obtain the missing data.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta‐analysis using the Tau², I² statistic, and Chi² test values (Higgins 2011). We will regard heterogeneity as substantial if the I² statistic value is greater than 40% and if either the Tau² value is greater than zero or there is a low P value (less than 0.10) in the Chi² test for heterogeneity, which we will plot in a forest plot (RevMan 2014).

Assessment of reporting biases

If there are 10 or more studies in the meta‐analysis, we will investigate publication bias using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes we will use the test proposed by Egger 1997, and for dichotomous outcomes we will use the test proposed by Harbord 2006. If we detect asymmetry in any of these tests or it is suggested after visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will perform statistical analyses using RevMan 5 (RevMan 2014). We will use a fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect (i.e. where trials are examining the same intervention, and the trial populations and methods are judged sufficiently similar). If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if we detect substantial statistical heterogeneity, we will use a random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. We will treat the random‐effects summary as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful we will not combine trials.

If we use random‐effects analyses, we will present the results as the average treatment effect with 95% CIs, and the estimates of the Tau² and I² statistics.

Subgroup analysis and investigation of heterogeneity

We will explore the following potential sources of heterogeneity using subgroup analyses:

• by HIV status (positive versus negative participants).

• by disease clinical stage (ulcer versus ulcer plus inguinal buboes).

We will restrict subgroup analyses to the primary outcomes: microbiological and clinical cure, clinical improvement, and serious adverse events of interventions.

Sensitivity analysis

We plan to perform sensitivity analyses to identify aspects of the review that might have affected the results; for example, where there was risk of bias associated with the quality of some of the included trials (low versus unclear or high risk of bias). We also plan to undertake a sensitivity analysis to explore the effects of intervention restricted to participants with etiological confirm infection (according to cell culture, PCR test, or any other microbiological criteria).