RimabotulinumtoxinB in sialorrhea: systematic review of clinical trials

Objective The aim of this study was to examine the efficacy, safety and dosing practices of rimabotulinumtoxinB (BoNT-B) for the treatment of patients with sialorrhea based on a systematic review of clinical trials. Methods A systematic literature review was performed to identify randomized controlled trials and other comparative clinical studies of BoNT-B for the treatment of sialorrhea published in English between January 1999 and December 2015. Medical literature databases (PubMed, Cochrane Library, and EMBASE) were searched and a total of 41 records were identified. Of these, six primary publications that evaluated BoNT-B for the treatment of sialorrhea met criteria and were included in the final data report. Synthesis Total BoNT-B doses ranged from 1500 to 4000 units for sialorrhea. Most of the studies in sialorrhea showed statistically significant benefits of BoNT-B versus placebo (range 4–19.2 weeks). BoNT-B was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Adverse events considered potentially associated with BoNT-B included: dry mouth, change in saliva thickness, mild transient dysphagia, mild weakness of chewing and diarrhea. Conclusions BoNT-B significantly reduces sialorrhea at doses between 1500 and 4000 units. The relatively mild dose-dependent adverse events suggest both direct and remote toxin effects. Electronic supplementary material The online version of this article (doi:10.1186/s40734-017-0055-1) contains supplementary material, which is available to authorized users.


PROJECT OVERVIEW
The primary objective of this project is to produce comprehensive evidenced-based data report that elucidates dosing practices and associated outcomes for RimabotulinumtoxinB .
This systematic literature review focuses on identifying clinical trials, systematic reviews, and meta-analyses.

INCLUSION AND EXCLUSION CRITERIA
The inclusion and exclusion criteria are based on a strategy that will identify study types of interest within the population or disease condition of interest. The criteria listed in Table 35 and 36 will be applied to the 37 unique titles and abstracts identified by the medical literature search in Section 2. Systematic reviews and metaanalyses will not be included in their own right; they will be used for identification of additional primary studies. Systematic reviews and meta-analyses will not be included in their own right, but will be used for identification of primary studies.

Criteria Included Excluded
Criteria in Table 35 Only biochemical or immunologic endpoints will be excluded.  Table 35 Criteria in Table 35 No further restriction Interventions Criteria in Table 35 Criteria in Table 35 No further restriction For studies excluded at the level 2 selection process, the study citations will be tabulated and the reason for exclusion of individual studies will be recorded.
Included studies will be categorized as randomized controlled trials (RCTs), non-RCTs, comparative long-term follow-up clinical trials, and comparative prospective observational studies. Randomized controlled trials will be advanced to the formal data extraction and quality assessment process. If the number of RCTs identified is less than 25 studies, other study types (non-RCTs and observational studies) will be evaluated for formal data extraction and quality assessment.

A-18
At level 1 screening, titles and abstracts of the identified studies from the electronic databases and Internet searches will be scanned by two researchers independently to evaluate the potential study relevance using the criteria outlined in Table 35 and Table 36. If there is uncertainty regarding the relevance of the study, the two researchers will review and reconcile discrepancies to reach consensus. Bibliographic reference lists of systematic reviews identified during level 1 screening will be searched to identify any relevant studies that were not identified through the electronic database searches.
At level 2 screening, full texts of studies selected at level 1 will be reviewed, and the same inclusion and exclusion criteria will be applied.
The inclusion and exclusion processes will be thoroughly documented, including completion of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram (Moher et al., 2009) for studies included at the level 2 screening. For studies excluded at level 1, the reason for exclusion will be recorded and the number of studies excluded for each reason summarized. For studies excluded at level 2, the study citations will be tabulated and the reason for exclusion of individual studies will also be recorded.

DATA EXTRACTION AND REPORTING OF RESULTS
Data will be extracted for the outcomes of interest for all relevant time points for all RCTs. If fewer than 25 RCTs are identified, non-RCTs and other studies will be evaluated for data extraction.
The relevant data will be extracted into evidence tables in Microsoft Word. All data-extraction templates will be created and agreed upon by the project team before commencing data extraction.
Data will be extracted from full-text versions of studies where available (i.e., we will not use abstracts unless an abstract is the terminal source document). Quality-control procedures for

Evidence Table Templates
The data extraction outline will include all draft evidence table templates.

Reporting of Results
In lieu of a formal final study report, the research team will prepare a final data extraction summary of tables.
The final data extraction outline will present table templates and elements for extraction.

Random sequence generation.
Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.

Allocation concealment.
Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
Performance bias.

Blinding of participants and personnel Assessments should be made for each main outcome (or class of outcomes).
Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.

Blinding of outcome assessment Assessments should be made for each main outcome (or class of outcomes).
Describe all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.
Detection bias due to knowledge of the allocated interventions by outcome assessors.

A-23
Domain Support for Judgment (Study specific information entered here)

Author's Judgment on 'Risk of Bias'
High, Low, Unclear Incomplete outcome data Assessments should be made for each main outcome (or class of outcomes).
Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any reinclusions in analyses performed by the review authors.
Attrition bias due to amount, nature or handling of incomplete outcome data.

Selective reporting.
State how the possibility of selective outcome reporting was examined by the review authors, and what was found.
Reporting bias due to selective outcome reporting.

Other bias
Other sources of bias.
State any important concerns about bias not addressed in the other domains in the tool. If particular questions/entries were pre-specified in the review's protocol, responses should be provided for each question/entry.
Bias due to problems not *See  Minimization*.
*Minimization may be implemented without a random element, and this is considered to be equivalent to being random. Criteria for the judgment of 'High risk' of bias.
The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example:  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.
Other non-random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of nonrandom categorization of participants, for example:  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; Allocation by availability of the intervention. Criteria for the judgment of 'Unclear risk' of bias.
Insufficient information to permit judgement of 'Low risk' or 'High risk'. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgementfor example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.
Criteria for a judgment of 'Low risk' of bias.
Any one of the following:  No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. Criteria for the judgment of 'High risk' of bias.
Any one of the following:  No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding. Criteria for the judgment of 'Unclear risk' of bias.
Any one of the following:  Insufficient information to permit judgment of 'Low risk' or 'High risk'; The study did not address this outcome.

A-1 INCOMPLETE OUTCOME DATA
Attrition bias due to amount, nature or handling of incomplete outcome data.
Criteria for a judgment of 'Low risk' of bias.
Any one of the following:  No missing outcome data;  Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing 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 not enough to have a clinically relevant impact on the intervention effect estimate;  For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; Missing data have been imputed using appropriate methods. Criteria for the judgment of 'High risk' of bias.
Any one of the following:  Reason for missing outcome data 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 (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size;  'As-treated' analysis done with substantial departure of the intervention received from that assigned at randomization; Potentially inappropriate application of simple imputation. Criteria for the judgment of 'Unclear risk' of bias.
Any one of the following:  Insufficient reporting of attrition/exclusions to permit judgment of 'Low risk' or 'High risk' (e.g. number randomized not stated, no reasons for missing data provided); The study did not address this outcome.

A-1 SELECTIVE REPORTING
Reporting bias due to selective outcome reporting.
Criteria for a judgment of 'Low risk' of bias.
Any of the following:  The study protocol is available and all of the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way; The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon). Criteria for the judgment of 'High risk' of bias.
Any one of the following:  Not all of the study's pre-specified primary outcomes have been reported;  One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified;  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 review are reported incompletely so that they cannot be entered in a meta-analysis; The study report fails to include results for a key outcome that would be expected to have been reported for such a study. Criteria for the judgment of 'Unclear risk' of bias.
Insufficient information to permit judgment of 'Low risk' or 'High risk'. It is likely that the majority of studies will fall into this category.

OTHER BIAS
Bias due to problems not covered elsewhere in the table.
Criteria for a judgment of 'Low risk' of bias.
The study appears to be free of other sources of bias.
Criteria for the judgment of 'High risk' of bias.
There is at least one important risk of bias. For example, the study:  Had a potential source of bias related to the specific study design used; or  Has been claimed to have been fraudulent; or Had some other problem. Criteria for the judgment of 'Unclear risk' of bias.
There may be a risk of bias, but there is either:  Insufficient information to assess whether an important risk of bias exists; or Insufficient rationale or evidence that an identified problem will introduce bias.