Types of studies

Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were considered for inclusion.

Types of participants

Individuals of any age with bilateral benign masseter hypertrophy which has been self‐evaluated and confirmed by clinical and radiological examination were considered for inclusion. In view of the possible clinical diversity in presentation, we excluded studies involving participants with unilateral or compensatory contra lateral masseter hypertrophy resulting from head and neck radiotherapy from this review.

Types of interventions

Interventions included transcutaneous intra‐masseteric injections of botulinum toxin versus placebo or no treatment. We sought to include studies in which the intervention had been administered for cosmetic facial sculpting. We considered studies involving a single injection cycle in addition to studies in which all participants entered in to a trial had received repeat injections at similar time periods.

Types of outcome measures

Assessment was to include a follow‐up period of up to two years after the intervention.

Electronic searches

Databases searched

We extended and updated the searches for the following databases:

• MEDLINE (via Pubmed) (1950 to 19 April 2013). See Appendix 1

• EMBASE (via embase.com) (from 1980 to 19 April 2013). See Appendix 2

• Web of Science (from 1945 to 19 April 2013). See Appendix 3

• the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 4). See Appendix 4

• CINAHL (from 1982 to 19 April 2013). See Appendix 5

• Academic Search Premier (via EBSCOhost) (from 1897 to 19 April 2013). See Appendix 6

• ScienceDirect (from 1823 to 19 April 2013). See Appendix 7

• LILACS (via BIREME) (from 1982 to 19 April 2013). See Appendix 8

• PubMed Central (from 1809 to 19 April 2013). See Appendix 9

• Google Scholar (from 1700 to 19 April 2013). See Appendix 10

Although we did not search the Cochrane Movement Disorders Group Trials Register we clarified that it did not contain any relevant studies.

We updated our search of IndMED, a bibliographic database of Indian journals, available at (http://indmed.nic.in/) and a similar Iranian database, Iranmedex, available at (www.iranmedex.com), using free text terms appropriate for this review on 27 April 2013.

Searching other resources

We did not conduct any handsearching of journals but searched the reference lists of relevant articles in addition to the review authors' personal database of trial reports. We also contacted a number of investigators by electronic mail to ask for details of additional published and unpublished trials. There were no language restrictions on included studies and we arranged to translate any relevant non‐English papers.

Selection of studies

Two review authors (ZF and EvZ) independently assessed the abstracts of studies resulting from the searches. We obtained full copies of all relevant and potentially relevant studies, those appearing to meet the inclusion criteria, and those for which there were insufficient data in the title and abstract to make a clear decision.The two review authors independently assessed the full text papers and resolved any disagreement on the eligibility of included studies through discussion and consensus. We excluded all irrelevant records and noted details of the studies and the reasons for their exclusion in the 'Characteristics of excluded studies' table in RevMan 5.2 (RevMan 2012).

Data extraction and management

The following methods of data extraction and management will apply for subsequent updates, and when future studies are identified. We will enter study details into the 'Characteristics of included studies' table in RevMan 5.2. The review authors will collect outcome data using a pre‐determined form designed for this purpose. Two authors (ZF and EvZ) will enter extracted data into RevMan 5.2., data will only be included if there is an independently reached consensus.

We will extract the following details.

1. Trial methods: (a) method of allocation, (b) masking of participants, personnel and outcome assessors, (c) exclusion of participants after randomisation and proportion and reasons for losses at follow‐up.

2. Participants: (a) country of origin and location (i.e. private clinic or academic institute), (b) sample size, (c) age, (d) sex, (e) inclusion and exclusion criteria.

3. Intervention: (a) type, dosage, route of administration, (b) length of follow‐up.

4. Control: (a) type, dosage, route of administration, (b) length of follow‐up.

5. Outcomes: (a) primary and secondary outcomes pre‐specified 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.

Assessment of risk of bias in included studies

If studies are included in future updates each review author will grade the selected trials and assess every trial using a simple contingency form following the domain‐based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Higgins 2011). We will compare the evaluations and discuss and resolve any inconsistencies and disagreements.

The following domains will be rated separately for each of the included studies as 'low risk of bias', 'high risk of bias', and 'unclear' if the risk of bias was uncertain or unknown:

1. sequence generation;

2. allocation concealment;

3. blinding (of participants, personnel and outcome assessors);

4. incomplete outcome data;

5. selective outcome reporting;

6. other bias.

These assessments will be reported in the 'Risk of bias' table for each individual study in the 'Characteristics of included studies' section of the review.

We will also categorise and report the overall risk of bias of each of the included studies according to the following:

• low risk of bias (plausible bias unlikely to seriously alter the results) if all criteria were met;

• unclear risk of bias (plausible bias that raises some doubt about the results) if one or more criteria were assessed as unclear; or

• high risk of bias (plausible bias that seriously weakens confidence in the results) if one or more criteria were not met.

These assessments will be reported in the 'Risk of bias in included studies' section of this review.

Measures of treatment effect

If studies are included in future updates we will conduct analysis at the same level as the allocation. We will calculate risk ratios (RR) and corresponding 95% confidence interval (CI) for all dichotomous outcomes and the mean difference (MD) and 95% CI for continuous outcomes. We will use RevMan 5 for data analysis. Unless stated otherwise, we will use the Mantel‐Haenzel  method to calculate the RR for dichotomous outcomes and MD for continuous outcomes. As it is likely that the timing of outcome assessment will vary between studies we will consider grouping the data according to the following time‐points: six months, one year and two years.

Unit of analysis issues

We expect to include trials of participants with bilateral hypertrophy in which the masseter muscles of an individual participant were the units of randomisation and subsequent analysis. We will analyse these data based on the advice provided in sections 9.3.8 in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

If studies are included in future updates we will make attempts to retrieve missing data from the investigators of the included trials, and if unsuccessful or the discrepancies are significant, we will provide a narrative synthesis of the data as reported.

Assessment of heterogeneity

If studies are included in future updates we will assess clinical heterogeneity by examining the characteristics of the studies and the similarity between types of participants, interventions and outcomes. In view of the expectation of a degree of clinical heterogeneity between the studies we will use a random‐effects model for statistical analyses. Statistical heterogeneity will be assessed using the Chi² test and the I² statistic, where I² values over 50% indicate moderate to high heterogeneity (Higgins 2011).

Assessment of reporting biases

if future updates include studies we will follow the recommendations on testing for funnel plot asymmetry as described in section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Higgins 2011) to assess publication bias.

Data synthesis

If future updates include studies two review authors (ZF and EvZ) will analyse the data and report the results as specified in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (Higgins 2011). Where appropriate, we will calculate the pooled RR and 95% CI for dichotomous outcomes and the pooled MD and 95% CI for continuous outcomes. We will use the Mantel‐Haenzel method for combining results across studies using random‐effects models. 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

If studies are included in future updates we will perform subgroup analysis by dose (i.e. low dose of BtA compared to medium or high doses). We define a low dose of BtA as ≤ 150 U per muscle and a medium to high dose as > 150 U per muscle.

Sensitivity analysis

If future updates contain a sufficient number of included studies we plan to conduct sensitivity analyses to assess the robustness of our review results. We will do this by repeating the analyses excluding studies with unclear or inadequate allocation concealment, blinding of outcomes assessment and completeness of follow‐up.