Diagnostic criteria for premature ejaculation

Since a standardized definition has only recently been developed, we will include studies whether or not they used a standard definition (but recording all definitions used).

Intervention

• SSRI

Comparator

• Placebo/no treatment

Concomitant interventions will have to be the same in both the intervention and comparator groups to establish fair comparisons.

If a trial includes multiple arms, we will include any arm that meets the inclusion criteria in the review.

We will not consider agents classified as serotonin‐noradrenaline re‐uptake inhibitors such as duloxetine.

Minimum duration of intervention and follow‐up

• 4 weeks

We will define trial duration according to the number of weeks over which the interventions have been conducted and will only include trials in the analyses with interventions that lasted at least four weeks.

Exclusion criteria

• Males aged less than 18 years of age

• Men with known conditions thought to cause PE or in whom PE is thought to be secondary to other medications.

Primary outcomes

We will focus on outcomes of direct patient importance that are directly applicable to routine clinical practice using instruments that have undergone validation.

1. Participant perception of change with treatment

2. Participant satisfaction with intercourse

3. Study withdrawal due to adverse events

We will assess participant perception of change using the Clinical Global Impression of Change questionnaire, which is a validated instrument that is administered after treatment (Althof 2010). We will record the number of participants describing the change as 'better' or 'much better' after treatment. No minimal clinically important difference (MCID) has been reported; we will consider a 10% difference between groups as clinically meaningful. This is a participant self reported outcome.

We will assess participant satisfaction with intercourse using the Premature Ejaculation Profile (PEP) questionnaire (Patrick 2009), a validated instrument that addresses four domains. We will record the number of participants describing their satisfaction as 'good' or 'very good' before and after treatment (for satisfaction and control). For distress and relationship difficulties, we will record the number of participants describing their distress 'a little bit' or 'not at all.' No MCID has been reported; we will consider a 10% difference between groups as clinically meaningful. All of these are participant self reported outcomes.

We will record the number of participants withdrawing from the trial due to adverse events. We will consider a 5% difference between groups as clinically meaningful. This is an investigator‐assessed outcome.

Secondary outcomes

1. Perceived control over ejaculation

2. Participant distress about PE

3. Relationship difficulties

4. Adverse events

5. Intravaginal ejaculatory latency time (IELT)

6. Depression

We will also use the PEP questionnaire to assess participant satisfaction with control over ejaculation, distress about PE, and relationship difficulties (Patrick 2009). We will record the number of participants describing their satisfaction as 'good' or 'very good' before and after treatment (for satisfaction and control). For distress and relationship difficulties, we will record the number of participants describing their distress 'a little bit' or 'not at all.' No MCID has been reported; we will consider a 10% difference between groups as clinically meaningful. All of these are participant self reported outcomes.

We will further assess the cumulative number of adverse events. We will consider a 5% difference between groups as clinically meaningful. This is an investigator‐assessed outcome. We will also provide descriptive information on the most common adverse events contributing to this analysis.

We will assess IELT as measured using a stopwatch in minutes (McMahon 2010). Although this method of measurement is not routinely used in clinical practice, it represents the best current method for assessing the fundamental issue that defines PE. No MCID has been reported in the literature. We will therefore assume a one‐minute difference as the smallest difference between groups to be clinically meaningful. This will be based on the mean IELT; we will not use the geometric mean average IELT, which has been proposed as an alternative measure more robust to non‐normal distributions (Waldinger 2008).

We will record the incidence of new symptoms of depression in participants. Ideally, we would seek out information using validated instruments such as the Beck Depression Inventory questionnaire (Novaretti 2002), but will also record other types of information as collected by the investigators. No MCID has been reported; we will consider a 10% difference between groups as clinically meaningful. This may either be a participant self reported or investigator‐assessed outcome.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents, or multiple reports of a primary trial, we will maximize the information yield by collating all available data and use the most complete data set aggregated across all known publications. We will list duplicate publications, companion documents, multiple reports of a primary trial, and trial documents of included trials (such as trial registry information) as secondary references under the study ID of the included trial. Furthermore, we will also list duplicate publications, companion documents, multiple reports of a trial, and trial documents of excluded trials (such as trial registry information) as secondary references under the study ID of the excluded trial.

Data from clinical trial registers

If data of included trials are available as study results in clinical trial registers such as ClinicalTrials.gov or similar sources, we will make full use of this information and extract the data. If there is also a full publication of the trial, we will collate and critically appraise all available data. If an included trial is marked as a completed study in a clinical trial register but no additional information is available, we will add this trial to the 'Characteristics of studies awaiting classification' table.

Random sequence generation (selection bias due to inadequate generation of a randomized sequence) ‐ assessment at trial level

For each included trial we will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

• Low risk of bias: the trial authors achieved sequence generation using computer‐generated random numbers or a random numbers table. Drawing of lots, tossing a coin, shuffling cards or envelopes, and throwing dice are adequate if an independent person performed this who was not otherwise involved in the trial. We will consider the use of the minimization technique as equivalent to being random.

• Unclear risk of bias: insufficient information about the sequence generation process.

• High risk of bias: the sequence generation method was non‐random or quasi‐random (e.g. sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number; allocation by judgement of the clinician; allocation by preference of the participant; allocation based on the results of a laboratory test or a series of tests; or allocation by availability of the intervention).

Allocation concealment (selection bias due to inadequate concealment of allocation prior to assignment) ‐ assessment at trial level

We will describe for each included trial the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of or during recruitment, or changed after assignment.

• Low risk of bias: central allocation (including telephone, interactive voice‐recorder, web‐based and pharmacy‐controlled randomization); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes.

• Unclear risk of bias: insufficient information about the allocation concealment.

• High risk of bias: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards; alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

We will also evaluate trial baseline data to incorporate assessment of baseline imbalance into the 'Risk of bias' judgement for selection bias (Corbett 2014). Chance imbalances may also affect judgements on the risk of attrition bias. In case of unadjusted analyses, we will distinguish between studies we rate as at low risk of bias on the basis of both randomization methods and baseline similarity, and studies we rate as low risk of bias on the basis of baseline similarity alone (Corbett 2014). We will re‐classify judgements of unclear, low, or high risk of selection bias.

Blinding of participants and study personnel (performance bias due to knowledge of the allocated interventions by participants and personnel during the trial) ‐ assessment at outcome level

We will evaluate the risk of detection bias separately for each outcome (Hróbjartsson 2013). We will note whether endpoints were self reported, investigator assessed, or adjudicated outcome measures (see below).

• Low risk of bias: blinding of participants and key study personnel is ensured, and it is unlikely that the blinding could have been broken; no blinding or incomplete blinding, but we judge that the outcome is unlikely to have been influenced by lack of blinding.

• Unclear risk of bias: insufficient information about the blinding of participants and study personnel; the trial does not address this outcome.

• High risk of bias: no blinding or incomplete blinding, and the outcome is likely to have been influenced by lack of blinding; blinding of trial participants and key personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias due to knowledge of the allocated interventions by outcome assessors) ‐ assessment at outcome level

We will evaluate the risk of detection bias separately for each outcome (Hróbjartsson 2013). We will note whether endpoints were self reported, investigator assessed, or adjudicated outcome measures (see below).

• Low risk of bias: blinding of outcome assessment is ensured, and it is unlikely that the blinding could have been broken; no blinding of outcome assessment, but we judge that the outcome measurement is unlikely to have been influenced by lack of blinding.

• Unclear risk of bias: insufficient information about the blinding of outcome assessors; the trial did not address this outcome.

• High risk of bias: no blinding of outcome assessment, and the outcome measurement is likely to have been influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias due to amount, nature, or handling of incomplete outcome data) ‐ assessment at outcome level

For each included trial for each outcome, we will describe the completeness of data, including attrition and exclusions from the analyses. We will state whether the trial reported attrition and exclusions, and the number of participants included in the analysis at each stage (compared with the number of randomized participants per intervention/comparator groups). We will also note if the trial reported the reasons for attrition or exclusion and whether missing data were balanced across groups or were related to outcomes. We will consider the implications of missing outcome data per outcome such as high dropout rates (e.g. above 15%) or disparate attrition rates (e.g. difference of 10% or more between trial arms).

• Low risk of bias: no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to introduce bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardized mean difference) among missing outcomes is not enough to have a clinically relevant impact on observed effect size; appropriate methods such as multiple imputation were used to handle missing data.

• Unclear risk of bias: insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to introduce bias; the trial did not address this outcome.

• High risk of bias: reason for missing outcome data is likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardized mean difference) among missing outcomes enough to induce clinically relevant bias in observed effect size; 'as‐treated' or similar analysis done with substantial departure of the intervention received from that assigned at randomization; potentially inappropriate application of simple imputation.

Selective reporting (reporting bias due to selective outcome reporting) ‐ assessment at trial level

We will assess outcome reporting bias by integrating the results of the appendix 'Matrix of trial endpoints (publications and trial documents)' (Boutron 2014; Jones 2015; Mathieu 2009), with those of the appendix 'High risk of outcome reporting bias according to ORBIT classification' (Kirkham 2010). This analysis will form the basis for the judgement of selective reporting.

• Low risk of bias: the trial protocol is available and all of the trial's prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way; the study protocol is unavailable, but it is clear that the published reports include all expected outcomes (Outcome Reporting Bias in Trials (ORBIT) classification).

• Unclear risk of bias: insufficient information about selective reporting.

• High risk of bias: not all of the trial's prespecified primary outcomes are reported; one or more primary outcomes are reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the Cochrane Review are reported incompletely so that we cannot enter them in a meta‐analysis; the trial report fails to include results for a key outcome that would have been expected to have been reported for such a trial (ORBIT classification).

Other bias (bias due to problems not covered elsewhere) ‐ assessment at trial level

• Low risk of bias: the trial appears to be free of other sources of bias.

• Unclear risk of bias: there is insufficient information to assess whether an important risk of bias existed; insufficient rationale or evidence that an identified problem introduced bias.

• High risk of bias: the trial has a potential source of bias related to the specific trial design used; the trial has been claimed to have been fraudulent; or the trial had some other serious problem.

We will present a 'Risk of bias' graph and a 'Risk of bias' summary figure.

We will distinguish between self reported, investigator assessed, and adjudicated outcome measures.

We will accept the following outcomes as self reported.

• Participant perception of change with treatment

• Participant satisfaction with intercourse

• Perceived control over ejaculation

• Participant distress about PE

• Relationship difficulty

• Depression

We will require the following outcomes as investigator assessed.

• IELT

• Study withdrawal due to adverse events

• Adverse events

We do not anticipate encountering any adjudicated outcome measures.

Summary assessment of risk of bias

Quality of evidence

We will present the overall quality of the evidence for each outcome according to the GRADE approach, which takes into account issues related not only to internal validity (risk of bias, inconsistency, imprecision, publication bias) but also to external validity, such as directness of results. Two review authors (RM, PD) will independently rate the quality of evidence for each outcome.

We will present a summary of the evidence in a 'Summary of findings' table, which will provide key information about the best estimate of the magnitude of the effect, in relative terms and as absolute differences, for each relevant comparison of alternative management strategies, numbers of participants and trials addressing each important outcome, and rating of overall confidence in effect estimates for each outcome. We will create the 'Summary of findings' table based on the methods described in the Cochrane Handbook for Systematic Reviews of Interventions by means of the table editor in Review Manager 5 (Review Manager 2014). We will include an appendix titled 'Checklist to aid consistency and reproducibility of GRADE assessments' to help with standardization of the 'Summary of findings' tables (Higgins 2011a; Meader 2014). Alternatively, we will use GRADEpro GDT software and present evidence profile tables as an appendix (GRADEpro GDT 2015). We will present results for the outcomes as described in the Types of outcome measures section. If meta‐analysis is not possible, we will present the results in a narrative format in a 'Summary of findings' table. We will justify all decisions to downgrade the quality of studies using footnotes, and we will make comments to aid the reader's understanding of the Cochrane Review where necessary.