Study design

A large number of pharmacological and non-pharmacological trials for the treatment of MD exist. We will conduct an umbrella SR of published randomised controlled trials (RCTs) of those interventions that have been systematically reviewed. From here we seek to evaluate the efficacy of therapy for MD. The current review has been registered at PROSPERO CRD42015024243. The steps throughout the conduct of the umbrella SR are shown in figure 1. This protocol is reported in line with PRISMA-P.12

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Figure 1

Flow chart of the umbrella systematic review. RCT, randomised controlled trial.

Eligibility criteria

Search strategy

In association with the UK Cochrane Centre, particularly the Ear, Nose and Throat Review Group, we will conduct a systematic search for all SRs for pharmacological and non-pharmacological interventions for MD. We will search the Database of Abstracts of Reviews of Effect (DARE), MEDLINE and EMBASE for SRs, and eligible RCTs will be extracted that examine the efficacy of pharmacological and non-pharmacological therapies in MD. In case several SRs investigate exactly the same treatment modality in the same population, we will extract the RCTs from the most recent published review. Since no current worldwide-recommended guidelines exist for the treatment of MD, we intend to include all systematically reviewed interventions. We will use Medical Subject Headings (MeSH) and key words in the search strategy containing ‘Menière’s disease’, ‘systematic review’, 'randomised controlled trial’ and ‘placebo controlled trial’. Details of the search strategy are shown in tables 1 and 2.

Two independent reviewers (BFvE and HJvdZ-L) will screen the title and abstract for potentially eligible SRs. These will be downloaded for full-text screening and further evaluation. Authors and journal names will be blinded. No restriction on language will be used. After identifying all interventions that were systematically reviewed, we will screen the title and abstract for potentially eligible RCTs that were published since the publications of these SRs. Similar to the selection of SRs, these RCTs will be screened on full text and evaluated. We will remove all duplicate RCTs after full-text screening and reference checking. The reviewers will examine and extract all data from the included RCTs into a data set.

Data extraction

After we selected eligible RCTs, the two reviewers (BFvE and HJvdZ-L) will independently extract information from the RCTs on predesigned data extraction forms. To begin with, we will extract the general information from each RCT covering the country, number of centres, number of participants, study design, the number of treatment arms, allocation ratio, and conflict of interest and funding. Then the study characteristics of the patients with MD will be extracted including sex, age, age at onset of disease, subclassification of MD types (diagnostic criteria defined by the AAO-HNS of 1995) and duration and frequency of vertigo attacks before start of treatment. Furthermore, details of the interventions will be extracted for the experimental and control groups. For the pharmacological interventions, we will record the drug category (eg, anticholamines, diuretics), generic name of the drug, dose per day, way of administration (eg, oral, intratympanic), additional treatments and period of treatment. In addition, for the non-pharmacological interventions, we will extract the type of intervention (eg, Meniett device, endolymphatic sac surgery) and any additional treatments (prestudy or during trial participation). Lastly, we will extract information of the effect on the primary and secondary outcome measures and record the incidence of adverse events and complications. We will extract the information from the intervention arm in pharmacological and non-pharmacological RCTs using a standard form (tables 3 and 4). In addition, tables 5 and 6 display the standard form that will be used to extract information from the placebo arm in pharmacological RCTs and the sham arm in non-pharmacological RCTs, respectively.

Outcome assessment

We aim to investigate the efficacy of treatment for MD in controlling vertigo attacks (primary outcome). As defined in the AAO-HNS guideline of 1995,13 the control of vertigo will be calculated and classified (class A, 100% control of vertigo, class B, 40% control of vertigo). Ideally, the primary outcome is again evaluated after 18 and 24 months following randomisation. However, it is unlikely that a placebo-controlled trial will last this long. Therefore, we will include papers that have assessed the efficacy of the therapy reflected by the primary outcome at 3–6 months of follow-up. We will ensure accurate assessment of the outcome measures as independent reviewers (BFvE and HJvdZ-L) extract the information from the selected RCTs and a third reviewer (TDB and/or PPGvB) will check the completeness and correctness of the extracted data.

Risk of bias assessment

We will assess the methodological quality of the RCTs by use of the Cochrane Collaboration's risk of bias tool14 within Review Manager V.5.3 software (Review Manager (Revman) V.5.3 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). The tool is based on the following eight potential sources of bias: random sequence generation; allocation concealment; blinding of the participants; blinding of the outcome assessors; incomplete outcome data; missing data and selective outcome reporting, other bias (eg, improper statistical analysis). Two independent reviewers (BFvE and HJvdZ-L) will independently evaluate the quality of the RCTs. Each aspect will be graded with ‘yes’, ‘no’ or ‘unclear’, which will reflect a high risk of bias, low risk of bias and unclear risk of bias, respectively. For each study, all eight domains will be evaluated and displayed in a table (see table 7). If there is any disagreement on inclusion or exclusion, this will be settled by discussion, if necessary in the presence of a third reviewer (TDB and/or PPGvB). In addition, we will grade the diagnostic validity of studies on the basis of the robustness of the methods used to diagnose the disorder (homogeneity of the types of participants). This grading will form the basis to assess the risk of bias and perform sensitivity analyses. We will grade papers that used the AAO-HNS 1995 criteria for ‘definite’ and ‘certain’ MD as ‘I’. We will grade studies in which less clear but rigorous criteria were used as ‘II’. Studies in which no or less clear diagnostic criteria were used will be graded as ‘III’.

Data analysis

Data will be entered into Review Manager (V.5.3). For each treatment modality, we aim to perform a statistical analysis for the primary outcome comparing the interventional arm to the control group (placebo or sham). In addition, for studies that report the vertigo attack frequency as a continuous outcome, we intend to calculate the effect size using the mean difference (MD) or the standardised MD. The same applies for the loss of hearing. Where appropriate, data will be categorised or dichotomised for control of vertigo, severity of vertigo attacks, severity of tinnitus, perception of aural fullness, quality of life, complications and adverse events.

The included studies will be explored on methodological and statistical heterogeneity. The latter will be quantified by the I² statistic. An I² value >50% is considered to indicate substantial heterogeneity (Handbook 2011, The Cochrane Collaboration).15 If the data are sufficiently homogeneous, we will pool outcome data. It is expected that the data will carry a certain amount of heterogeneity and a random-effects model will be used. Forest plots will be shown for each intervention. If the data turn out to be too heterogeneous for pooling based on methodological heterogeneity and statistical heterogeneity, we will perform a descriptive review and summarise the available evidence for this intervention. The strength of the evidence will be evaluated by use of the GRADE method as generated by the Cochrane Collaboration. Table 8 shows the summary of findings per intervention based on the GRADE method.

Dealing with missing data

We expect missing data in the selected trials for the SR. All corresponding authors will be contacted and asked for the original data. If only a per protocol analysis has been carried out, corresponding authors will be contacted for the original data on the intention-to-treat analysis.

Subgroup analysis

We will perform subgroup analysis to investigate heterogeneity and inconsistency in the selected trials. Subgroup analysis will be performed with regard to subtype of MD (‘certain’, ‘definite’, ‘probable’ or ‘possible’ MD in accordance with the AAO-HNS 1995 criteria13), stage of disease (as defined by the AAO-HNS 1995 criteria13) and duration of treatment. Since the primary outcome is a patient-reported outcome, blinding can be of influence. Therefore, we will consider the method of blinding the most important subgroup analysis.

Sensitivity analysis

We will perform a sensitivity analysis to address whether the eight potential sources of bias played a relevant role in the robustness of our study findings. Studies with a high risk of bias will be analysed separately to evaluate if the efficacy of the intervention is not solely based on these trials and if trial results are robust.

Publication bias

Publication bias will be explored by performing funnel plots if sufficient data are available (10 or more studies).