BMJ Open...16 Apeldoorn Dizziness Centre, Gelre Hospital, Albert Schweitzerlaan 31, 7334 DZ...

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Interventions for Menière’s disease: protocol for an umbrella systematic review and a network meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2015-010269

Article Type: Protocol

Date Submitted by the Author: 15-Oct-2015

Complete List of Authors: van Esch, Babette; Gelre Hospital Apeldoorn, Apeldoorn Dizziness Centre; University Medical Centre Utrecht, Otorhinolaryngology - Head and Neck Surgery van der Zaag-Loonen, Hester; Gelre Hospital Apeldoorn, Apeldoorn Dizziness Centre Bruintjes, Tjasse; Gelre Hospital Apeldoorn, Apeldoorn Dizziness Centre van Benthem, Peter Paul; University Medical Centre Leiden, Departement of Otorhinolaryngology

<b>Primary Subject Heading</b>:

Ear, nose and throat/otolaryngology

Secondary Subject Heading: Patient-centred medicine, Evidence based practice, Medical management, Qualitative research

Keywords:

Risk management < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Rationing < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Adult otolaryngology < OTOLARYNGOLOGY, Quality in health care < HEALTH SERVICES ADMINISTRATION & MANAGEMENT

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Interventions for Menière’s disease: protocol Interventions for Menière’s disease: protocol Interventions for Menière’s disease: protocol Interventions for Menière’s disease: protocol for for for for an an an an 1

umbrella systematic review and umbrella systematic review and umbrella systematic review and umbrella systematic review and a a a a network metanetwork metanetwork metanetwork meta----analysisanalysisanalysisanalysis 2

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Babette F. van Esch, MD, Hester J. van der Zaag-Loonen, MD, PhD, Tjasse D. Bruintjes, MD, PhD, Peter 4

Paul G. van Benthem, MD, PhD

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Apeldoorn Dizziness Centre, Gelre Hospital, Apeldoorn, The Netherlands 7

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Addresses authorsAddresses authorsAddresses authorsAddresses authors 9

Apeldoorn Dizziness Centre, Gelre Hospital, Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, The 10

Netherlands, Babette F. van Esch PhD Candidate Apeldoorn Dizziness Centre 11

Department of Research and Education, Gelre Hospital, Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, 12

The Netherlands, Hester J. van der Zaag-Loonen Epidemiologist 13

Apeldoorn Dizziness Centre Gelre Hospital, Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, The 14

Netherlands, Tjasse D. Bruintjes ENT-surgeon 15


Netherlands, Peter Paul G. van Benthem ENT-surgeon 17

Correspondence to: Correspondence to: Correspondence to: Correspondence to: Babette F. van Esch, PhD Candidate Apeldoorn Dizziness Centre, 18

Email: [email protected], Phone: +31 (0) 55 844 6343, Fax: +31(0) 55-5818194 19

Keywords:Keywords:Keywords:Keywords: Menière’s disease, interventions, umbrella systematic review 20

Word Word Word Word count:count:count:count: Abstract: 218 words; manuscript: 2133 words 21

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ABSTRACT ABSTRACT ABSTRACT ABSTRACT 34

Introduction: The large number of treatment modalities for patients diagnosed with Menière’s disease 35

(MD) complicates the selection of the best available evidence as evidence in terms of reducing vertigo 36

complaints has never been conclusive. We aim to provide a ranking of the current pharmacological 37

and non-pharmacological treatments for MD. 38

Method and analysis: We will identify all available systematic reviews on the treatment of MD. An 39

online database search will be conducted in association with the UK Cochrane Centre, particularly the 40

Ear, Nose and Throat Group. We will screen the systematic reviews for eligible RCTs to execute a 41

network meta-analysis. The characteristics of each RCT will be summarised, including the general 42

design, the participants, the interventions, the outcome measurements, the duration of therapy and 43

adverse events. The risk of bias will be assessed by means of the Cochrane Collaboration’s risk of bias 44

tool. The included studies will be assessed for methodological and statistical heterogeneity, latter will 45

be quantified by means of the I2 statistic. The primary outcome will be the effectiveness of treatment in 46

terms of control of vertigo attacks related to complications or adverse events. Secondary outcome 47

measures will be the loss or improvement of hearing, severity of tinnitus, perception of aural fullness, 48

duration of symptoms correlated with the improvement of symptoms and quality of life. 49

Discussion: The outcome of this study will help clinicians and patients to select the best available 50

treatment for MD. 51

Trial registration numberTrial registration numberTrial registration numberTrial registration number: : : : PROSPERO CRD42015024243 52

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Strengths and limitation of this study Strengths and limitation of this study Strengths and limitation of this study Strengths and limitation of this study 53

� To date, this is the first umbrella systematic review protocol to summarise the evidence for 54

pharmacological and non-pharmacological treatments for Menière’s disease. 55

� We expect to provide a ranked appraised overview of therapies for Menière’s disease and 56

compare them for their effectiveness. 57

� The main limitation of this study identifying all the effective interventions for Menière’s disease 58

will be overcome by identifying all interventional systematic reviews and extracting RTCs from 59

these studies. 60

61

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INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION 62

Menière’s disease (MD) is an inner ear disorder characterised by incapacitating attacks of vertigo 63

accompanied by nausea and vomiting, fluctuating sensorineural hearing loss as well as tinnitus and/or 64

aural fullness. Even though the disease was first described in 1861 by Prosper Menière1 , there are still 65

many unanswered questions regarding the pathophysiology of the disease. Furthermore, a definite 66

and effective evidence-based treatment has not been established yet. 67

The main aim of the treatment in MD is to reduce the frequency and intensity of the vertigo attacks 68

and at the same time to preserve hearing and vestibular function.2 Psychological suffering and reduced 69

quality of life are linked to MD, as disabling vertigo attacks can occur without warning.3,4

Therefore, an 70

effective prophylactic treatment is necessary to improve the quality of life of MD patients. Current 71

pharmacological treatment options include betahistine, diuretics, oral steroids or intratympanic 72

application of gentamicin or corticosteroids.5 However, evidence in terms of reducing vertigo 73

complaints has never been conclusive6,7,8

, except for intratympanic gentamicin treatment.9 Non-74

pharmacological treatment options include positive pressure therapy (the Meniett device), ablative 75

surgery such as vestibular nerve section, labyrinthectomy and endolymphatic sac surgery.2,5,10

As for 76

the pharmacological treatment modalities, high quality evidence is also lacking for non-77

pharmacological therapies10,11

. Since so many treatments exist without conclusive results, it may be 78

hard for patients and their physicians to select the best available treatment. To date, no umbrella 79

systematic review exists evaluating and ranking the available treatment modalities in MD. The present 80

study aims to establish which treatment is the most effective for controlling vertigo or reducing the 81

frequency and intensity of vertigo attacks and has the smallest proportion of adverse events. 82

83

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METHODSMETHODSMETHODSMETHODS 84

Study designStudy designStudy designStudy design 85

A large number of pharmacological and non-pharmacological trials for the treatment of MD exist as 86

well as several systematic reviews (SRs). We will perform a search to identify SRs examining the 87

effectiveness of therapy for MD. We will screen these interventional SRs for eligible RCTs and data 88

from these RCTs will be extracted to execute a network meta-analysis. The current review has been 89

registered at PROSPERO CRD42015024243. The steps throughout the SR are shown in Figure 1Figure 1Figure 1Figure 1. This 90

protocol is reported in line with PRISMA-P.12

91

92

Search strategy Search strategy Search strategy Search strategy 93

In association with the UK Cochrane Centre, particularly the Ear, Nose and Throat Review Group, we 94

will rerun all previous search strategies of Cochrane’s SRs for pharmacological and non-95

pharmacological interventions for MD. Eligible RCTs will be extracted which examine the effectiveness 96

of pharmacological and non-pharmacological therapies in MD. In addition, we will search the Database 97

of Abstracts of Reviews of Effect (DARE), MEDLINE and EMBASE for SRs which evaluate treatment 98

modalities other than those evaluated by the Cochrane collaboration. In case SRs investigate the same 99

treatment modality, we will extract the RCTs from the most recent published review. As no current 100

worldwide recommended guidelines exist for the treatment of MD, we intend to include all 101

systematically reviewed interventions. We will use Medical Subject Headings (MeSH) and key words in 102

the search strategy for additional SRS. We will use the following keys words with synonymous word: 103

‘Menière’s disease’, ‘systematic review’. Details of the search strategy are shown in Table 1. Table 1. Table 1. Table 1. 104

105

Table 1. Table 1. Table 1. Table 1. Search strategy for systematic reviews for Menière’s disease. 106

107

#1 exp Meniere disease* [therapy]

#2 systematic review

#3 #1 AND #2

#4 meta-analysis

#6 #1 AND (#3 OR #4)

#7 #3 OR #6

108

109

110

111

112

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Identification of the studiesIdentification of the studiesIdentification of the studiesIdentification of the studies 113

Two independent reviewers (BE and HZ) will screen title and abstract for possible eligible SRs. These 114

will be downloaded for full-text screening and further evaluation. Authors and journal names will be 115

blinded. No restriction on language will be used. If all eligible SRs are identified we will extract all RCTs 116

and remove all duplicate after full-text screening and reference checking. The reviewers will examine 117

and extract all data from the included RCTs into a data set. We will include RCTs that investigated the 118

efficacy of interventions. As the natural course of MD has a waning pattern, time should be regarded 119

as a therapeutic factor when analysing the efficacy of a therapeutic intervention. Therefore, a study 120

design including a placebo arm is essential to account for the illusion of therapeutic efficacy. 121

Pharmacological trials with a placebo group will be included; trials comparing different 122

pharmacological treatments without a placebo will be excluded. We will include trials which 123

investigated non-pharmacological interventions and compared the efficacy of the intervention with a 124

sham intervention group, a placebo pill group or a placebo control group. 125

The main outcome of efficacy will be the control of vertigo as defined by the American Academy of 126

Otorhinolaryngoly and Head and Neck Surgery (AAO-HNS) guidelines of 1995.13

Secondary outcome 127

measures will be hearing, severity of tinnitus, perception of aural fullness, duration of symptoms 128

correlated to the improvement of symptoms, quality of life, complications or adverse events. All 129

articles will be selected after full consent of both authors. If there is any disagreement, this will be 130

settled by discussion with all authors (BE, HZ, TB and/or PB). 131

132

Data extractionData extractionData extractionData extraction 133

After we selected eligible RCTs, the two reviewers (BE and HZ) will independently extract information 134

from the RCTs on predesigned data-extraction forms. To begin with, we will extract the general 135

information from each RCT covering the country, number of centres, number of participants, study 136

design, the number of treatment arms, allocation ratio, and conflict of interest and funding. Then, 137

study characteristics of the MD patients will be extracted including sex, age, age at onset of disease, 138

subclassification of MD types (diagnostic criteria defined by the AAO-HNS of 1995) and duration and 139

frequency of vertigo attacks before start of treatment. Patients suffering from MD at any age will be 140

included. We will grade studies which used the 1995 AAO-HNS criteria for 'definite' and 'certain' MD as 141

'I'. We will grade studies in which less clear but rigorous criteria were used as 'II'. Studies in which no or 142

less clear diagnostic criteria were used will be graded as 'III'. Furthermore, details of the interventions 143

will be extracted for both the experimental and control groups. For the pharmacological interventions 144

we will record the drug category (e.g., anticholamines, diuretics), generic name of the drug, dose per 145

day, way of administration (e.g. oral, intratympanic), additional treatments and period of treatment. In 146

addition, for the non-pharmacological interventions we will extract the type of intervention (e.g. 147

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Meniett device, endolymphatic sac surgery) and any additional treatments (pre-study or during trial 148

participation). Last, we will extract information of the effect on the primary and secondary outcome 149

measures and we will record the incidence of adverse events. Study characteristics will be displayed for 150

the intervention arm and comparator as shown Table 2Table 2Table 2Table 2 and for pharmacological and non-151

pharmacological interventions as shown in Table 3Table 3Table 3Table 3. 152

153

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TTTTable 2. able 2. able 2. able 2. Study characteristics pharmacological interventions.

Study Intervention Sample

size

Sex ratio (♂:♀)

Age

(mean±

SD)

Age at onset

(mean ±SD)

Classification

MD

Frequency

attacks

(per year)

Duration

attacks

(hrs)

Drug

category

Generic

name

Dose/day

(mg)

Way of

administration

Period treatment

(months, mean

±SD )

Adverse

events (%)

Complications

Author

et al. year

Table 3. Table 3. Table 3. Table 3. Study characteristics non-pharmacological interventions .

Study Intervention Sample size Sex ratio (♂:♀)

Age (mean

±SD)

Age at onset

(mean ±SD)

Classification

MD

Frequency attacks

(per year)

Duration

attacks

(hrs)

Additional

treatment

Period treatment

(months, mean ±SD)

Adverse

events (%)

Complications

Author

et al. year

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Outcome assessment Outcome assessment Outcome assessment 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). The effectiveness of the

therapy reflected by the primary outcome is assessed after 6 months of follow-up. 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. We will ensure accurate assessment of the outcome

measures as independent reviewers (BE and HZ) extract the information from the selected RCTs and a

third reviewer (TB and/or PB) will check the completeness and correctness of the extracted data.

Risk of bias assessment Risk of bias assessment Risk of bias assessment 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 (e.g. improper statistical analysis). Two independent reviewers (BE and

HZ) will independently evaluate the quality of 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 six domains will be evaluated and displayed in a table (see Table Table Table Table 4444). If there is any

disagreement on inclusion or exclusion, this will be settled by discussion, if necessary in the presence a

third reviewer (TB and/or PB).

Table 4Table 4Table 4Table 4. . . . Risk of bias assessment based on the Cochrane risk of bias tool.

Study Random

sequence

generation

Allocation

concealment

Blinding of

participants

Blinding of

outcome

assessment

Incomplete

outcome

data

Missing

data

Selective

reporting

Other

bias

... et al.

year

High risk or

low risk or

unclear

idem Idem Idem Idem idem

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Statistical analysis Statistical analysis Statistical analysis Statistical analysis

Data for the statistical analysis will be entered into Review Manager (Version 5.3). For each intervention

a statistical analysis will be performed. As defined by the AAO-HNS 1995 guideline, classified control of

vertigo will be our primary outcome. In addition, studies which report the vertigo attack frequency as a

continuous outcome, we intend to calculate the effect size using the mean difference (MD) or the

standardised mean difference (SMD). The same applies for the loss of hearing, and duration of

symptoms. When appropriate data will be categorised or dichotomised for control of vertigo, the

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. Latter will be

quantified by the I2 statistic. An I

2 value greater than 50% is considered to indicate substantial

heterogeneity (Handbook 2011, The Cochrane Collaboration)15

. If the data are sufficiently

homogenous, we will pool outcome data. It is expected that 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, 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.

Dealing with missing dataDealing with missing dataDealing with missing dataDealing with missing data

We expect missing data in the selected trials for the SR. All authors for correspondence will be

contacted and asked for the original data. If only a per protocol analysis has been carried out, authors

for correspondence will be contacted for intention to treat analysis.

Subgroup analysis Subgroup analysis Subgroup analysis Subgroup analysis

We will perform subgroup analysis to investigate for 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

), duration of disease, and

range of patients’ age. As 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 Sensitivity analysis Sensitivity analysis Sensitivity analysis

We will perform a sensitivity analysis to address whether the eight potential played a significant role in

the robustness of our study findings. High risk of bias studies will be analyses separately to evaluate if

the effectiveness of the intervention is not solely based on these trials and if trial results are robust.

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DISCUSSIONDISCUSSIONDISCUSSIONDISCUSSION

We expect to provide an overview of ranked therapies for MD after comparing the evidence of

effectiveness. As results will be related to the duration of disease, MD patients and their physicians

may choose their treatment of preference after considering the estimated efficacy, known

complications, risks and adverse events related to the stage of the disease.

Acknowledgements Acknowledgements Acknowledgements Acknowledgements

The authors are grateful for the support of the members of the ENT Group of the UK Cochrane Centre, particularly

Jenny Bellorini, for conducting the systematic searches for randomised controlled trials for interventions of

Menière’s disease.

Contributors Contributors Contributors Contributors

BE, HZ, TB and PB contributed to the design and conception of the study protocol. The search strategy was

developed and run by the ENT Group. BE and HZ will screen studies on title and abstract and full text. If

disagreement over inclusion or exclusion arrives, this will be settled by discussion with all authors (BE, HZ, TB

and/or PB). BE and HZ will independently extract data from the articles and a third reviewer (TB and/or PB) will

check the completeness and correctness of the extracted data of the outcome assessment. All authors drafted and

revised this study protocol and approved it for publication.

FundingFundingFundingFunding

This work was supported solely from institutional and/or departmental sources from the Apeldoorn Dizziness

Centre, Gelre Hospital, Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, The Netherlands.

Competing interestsCompeting interestsCompeting interestsCompeting interests

None declared.

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RRRREFERENCES EFERENCES EFERENCES EFERENCES

1. Menière P. Memoire sur les lesions de l’orellei interne dinnant lieu à des symptômes de

congestion cerebrale apolectiforme. Gazette Medical de Paris 1861 ; 16 :597-601.

2. Minor LB, Schessel Da, Carey JP. Ménière’s disease. Curr Opin Neurol 2004;17:9-16.

3. Best C, Eckhardt-Henn A, Tschan R et al. Pshychiatric comorbidity in different organic vertigo

syndromes. J Neurol. 2009;256:58-65.

4. Yardley L,. Kirby S. Evaluation of booklet-based self management of symptoms in Ménière’s

disease: a randomized controlled trial. Psychosom Med. 2006;68:762-769.

5. Sajjadi H, Paparella MM. Ménière’s disease. Lancet. 2008;372 :406-14.

6. James Al, Burton MJ. Betahistine for Ménière’s disease or syndrome. Cochrane Databsase Syst

Rev. 2001 :1CD001873.

7. Thirlwall AS, Kundu S. Diuretics for Ménière’s disease or syndrome. Cochrane Database Syst

Rev. 2006;3:CD003599.

8. Phillips JS, Westerberg B. Intratympanic steroids for Ménière’s disease or syndrome. Cochrane

Database Syst Rev. 2011;7:CD008514.

9. Pullens B, van Benthem PP: Intratympanic gentamicin for Ménière’s disease or syndrome.

Cochrane Database Syst Rev. 2011;3:CD008234.

10. Pullens B, Verschuur HP, van Benthem PP. Surgery for Ménière’s disease. Cochrane Database

Syst Rev. 2013;2:CD005395.

11. Van Sonsbeek S, Pullens B, van Benthem PP. Positive pressure therapy for Ménière’s disease or

syndrome. Cochrane Database Syst Rev.2015;3:CD00008419.

12. Shamseer L., Moher D, Clarke M, et al. Preferred reporting items for systematic review and

meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2014;349:g7647.

13. Committee on Hearing and Equilibrium. Committee on Hearing and Equilibrium guidelines for

the diagnosis and evaluation of therapy in Menière’s disease. American Academy of

Otolaryngology – Head and Neck Foundation. Inc. Otolaryngology – Head and Neck Surgery.

1995;113:181-5.

14. Higgins JP, Thompson SG, Deek JJ et al. Measuring inconsistency in meta-analyses. BMJ

2003;327:557-60.

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PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to

address in a systematic review protocol*

Section and topic Item No Checklist item

ADMINISTRATIVE INFORMATION

Title:

Identification 1a Identify the report as a protocol of a systematic review

Update 1b If the protocol is for an update of a previous systematic review, identify as such

Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number

Authors:

Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of

corresponding author

Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review

Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes;

otherwise, state plan for documenting important protocol amendments

Support:

Sources 5a Indicate sources of financial or other support for the review

Sponsor 5b Provide name for the review funder and/or sponsor

Role of sponsor or funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol

INTRODUCTION

Rationale 6 Describe the rationale for the review in the context of what is already known

Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions,

comparators, and outcomes (PICO)

METHODS

Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years

considered, language, publication status) to be used as criteria for eligibility for the review

Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other

grey literature sources) with planned dates of coverage

Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be

repeated

Study records:

Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review

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Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the

review (that is, screening, eligibility and inclusion in meta-analysis)

Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any

processes for obtaining and confirming data from investigators

Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data

assumptions and simplifications

Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with

rationale

Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the

outcome or study level, or both; state how this information will be used in data synthesis

Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised

15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and

methods of combining data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ)

15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression)

15d If quantitative synthesis is not appropriate, describe the type of summary planned

Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies)

Confidence in cumulative evidence 17 Describe how the strength of the body of evidence will be assessed (such as GRADE)

* It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important

clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the

PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0.

From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and

meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647.

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Interventions for Menière’s disease: protocol for an umbrella systematic review and a network meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2015-010269.R1

Article Type: Protocol

Date Submitted by the Author: 26-Apr-2016

Complete List of Authors: van Esch, Babette; Gelre Hospital Apeldoorn, Apeldoorn Dizziness Centre; University Medical Centre Utrecht, Otorhinolaryngology - Head and Neck Surgery van der Zaag-Loonen, Hester; Gelre Hospital Apeldoorn, Apeldoorn Dizziness Centre Bruintjes, Tjasse; Gelre Hospital Apeldoorn, Apeldoorn Dizziness Centre van Benthem, Peter Paul; University Medical Centre Leiden, Departement of Otorhinolaryngology

<b>Primary Subject Heading</b>:

Ear, nose and throat/otolaryngology

Secondary Subject Heading: Patient-centred medicine, Evidence based practice, Medical management, Qualitative research

Keywords:

Risk management < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Rationing < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Adult otolaryngology < OTOLARYNGOLOGY, Quality in health care < HEALTH SERVICES ADMINISTRATION & MANAGEMENT


BMJ Open on S

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Interventions for Menière’s disease: protocol Interventions for Menière’s disease: protocol Interventions for Menière’s disease: protocol Interventions for Menière’s disease: protocol for for for for an an an an 1

umbrella systematic review and umbrella systematic review and umbrella systematic review and umbrella systematic review and a a a a network metanetwork metanetwork metanetwork meta----analysisanalysisanalysisanalysis 2

3

Babette F. van Esch, MD, Hester J. van der Zaag-Loonen, MD, PhD, Tjasse D. Bruintjes, MD, PhD, Peter 4

Paul G. van Benthem, MD, PhD

5

6

Apeldoorn Dizziness Centre, Gelre Hospital, Apeldoorn, The Netherlands 7

8

Addresses authorsAddresses authorsAddresses authorsAddresses authors 9


Netherlands, Babette F. van Esch PhD Candidate Apeldoorn Dizziness Centre 11


Netherlands, Hester J. van der Zaag-Loonen Epidemiologist 13


Netherlands, Tjasse D. Bruintjes ENT-surgeon 15

Leiden University Medical Centre, Albinusdreef 2, 2300 RC, Leiden, The Netherlands, Peter Paul G. van 16

Benthem ENT-surgeon 17

Correspondence to: Correspondence to: Correspondence to: Correspondence to: Babette F. van Esch, PhD Candidate Apeldoorn Dizziness Centre, 18

Email: [email protected] , Phone: +31 (0) 55 844 6343, Fax: +31(0) 55-5818194 19

Keywords:Keywords:Keywords:Keywords: Menière’s disease, interventions, umbrella systematic review 20

Word Word Word Word count:count:count:count: Abstract: 257 words; manuscript: 2133 word 21

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ABSTRACT ABSTRACT ABSTRACT ABSTRACT 22

Introduction: The large number of treatment modalities for patients diagnosed with Menière’s disease 23

(MD) complicates the selection of the best available treatment as the comparative efficacy of these 24

interventions is not clear. We aim to identify the treatment or treatments with the highest efficacy of 25

current pharmacological and non-pharmacological treatments for MD. 26

Method and analysis: We will identify all available systematic reviews on the treatment of MD. An 27

online database search will be conducted in association with the UK Cochrane Centre, particularly the 28

Ear, Nose and Throat Group. We will screen the systematic reviews for eligible randomised controlled 29

trials (RCTs) to execute a network meta-analysis. In addition, online databases will be checked for 30

eligible RCTs on treatments that were published after the latest systematic search was conducted. The 31

characteristics of each RCT will be summarised, including the general design, the participants, the 32

interventions, the outcome measurements, the duration of therapy and adverse events. The risk of bias 33

will be assessed by means of the Cochrane Collaboration’s risk of bias tool. The included studies will be 34

assessed for methodological and statistical heterogeneity, the latter will be quantified by means of the 35

I2 statistic. The primary outcome will be the efficacy of treatment in terms of control of vertigo attacks. 36

Secondary outcome measures will be the loss or improvement of hearing, severity of vertigo attacks 37

and tinnitus, perception of aural fullness, quality of life and the incidence of adverse events and 38

complications. 39

Ethics and dissemination: Formal ethical approval is not required, as primary data will not be 40

collected. The review will be disseminated in peer-reviewed publications and conference presentations. 41

Trial registration numberTrial registration numberTrial registration numberTrial registration number: : : : PROSPERO CRD42015024243 42

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Strengths and limitation of this study Strengths and limitation of this study Strengths and limitation of this study Strengths and limitation of this study 43

� To date, this is the first umbrella systematic review protocol to summarise the evidence for 44

pharmacological and non-pharmacological treatments for Menière’s disease. 45

� The protocol has been created according to the published PRISMA-P guidelines. 46

� We aim to identify the treatment or treatments with the highest efficacy for Menière’s disease 47

based on controlling vertigo or reducing the frequency of vertigo attacks. 48

� The main limitation of this study identifying all the interventions for Menière’s disease will be 49

overcome by seeking for all interventional systematic reviews that have been published and 50

adding RCTs that were published subsequent to the date the latest systematic search was 51

conducted. 52

53

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INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION 54

Menière’s disease (MD) is an inner ear disorder characterised by incapacitating attacks of vertigo 55

accompanied by nausea and vomiting, fluctuating sensorineural hearing loss as well as tinnitus and/or 56

aural fullness. Even though the disease was first described in 1861 by Prosper Menière1 , there are still 57

many unanswered questions regarding the pathophysiology of the disease. Furthermore, a definite 58

and effective evidence-based treatment has not been established yet. 59

The main aim of the treatment in MD is to reduce the frequency and intensity of the vertigo attacks 60

and at the same time to preserve hearing and vestibular function.2 Psychological suffering and reduced 61

quality of life are linked to MD, as disabling vertigo attacks can occur without warning.3,4

Therefore, an 62

effective prophylactic treatment is necessary to improve the quality of life of MD patients. Current 63

pharmacological treatment options include betahistine, diuretics, oral steroids or intratympanic 64

application of gentamicin or corticosteroids.5 However, evidence in terms of reducing vertigo 65

complaints has never been conclusive6,7,8

, except for intratympanic gentamicin treatment.9 Non-66

pharmacological treatment options include positive pressure therapy (the Meniett device), ablative 67

surgery such as vestibular nerve section, labyrinthectomy and endolymphatic sac surgery.2,5,10

As for 68

the pharmacological treatment modalities, high quality evidence is also lacking for non-69

pharmacological therapies10,11

. Since so many treatments exist without conclusive results, it may be 70

hard for patients and their physicians to select the best available treatment. To date, no umbrella 71

systematic review exists that summarises the body of evidence and states implications for clinical 72

practice. 73

74

Objective Objective Objective Objective 75

The present study aims to systematically summarise the interventions for MD, aiming to identify the 76

treatment or treatments with the highest efficacy and to identify areas for future valuable research. 77

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METHODSMETHODSMETHODSMETHODS 78

Study designStudy designStudy designStudy design 79

A large number of pharmacological and non-pharmacological trials for the treatment of MD exist. We 80

will conduct an umbrella systematic review of published RCTs of those interventions that have been 81

systematically reviewed. From here we seek to evaluate the efficacy of therapy for MD. The current 82

review has been registered at PROSPERO CRD42015024243. The steps throughout the conduct of the 83

umbrella systematic review are shown in Figure 1Figure 1Figure 1Figure 1. This protocol is reported in line with PRISMA-P.12

84

85

Figure 1Figure 1Figure 1Figure 1 86

87

Eligibility criteria Eligibility criteria Eligibility criteria Eligibility criteria 88

Types of studies Types of studies Types of studies Types of studies 89

The following study designs will be eligible for inclusion: 90

- Systematic review (SR) or meta-analysis (MA) 91

- RCTs or placebo controlled trials 92

We will screen interventional SRs for eligible RCTs and data from these RCTs will be extracted to 93

execute a network meta-analysis. In addition, online databases will be checked for eligible RCTs on 94

treatments that were systematically reviewed yet published subsequent to the date the latest 95

systematic search was conducted. 96

97

Types of participantsTypes of participantsTypes of participantsTypes of participants 98

Due to the great variability in the clinical presentation of MD, the disorder is not always easy to 99

diagnose. The American Academy of Otolaryngology - Head and Neck Surgery (AAO-HNS) has 100

produced diagnostic guidelines in order to facilitate the diagnosis of MD and to improve comparability 101

of outcome measures when performing trials on patients with MD. 13

In 2015, a new set of diagnostic 102

criteria were jointly formulated by the Classification Committee of the Bárány Society, the Japan 103

Society of Equilibrium Research, the European Academy of Otology and Neurotology, the AAO-HNS 104

and the Korean Balance Society in order to develop an international consensus on diagnostic criteria 105

for MD in order to facilitate future collaborative studies14

. However, as these international diagnostic 106

criteria were only published recently and previous research widely used the AAO-HNS 1995 diagnostic 107

guidelines, the latter set of criteria will be used to identify 'definite' Ménière's disease patients in the 108

current review. 109

110

Types of intervention Types of intervention Types of intervention Types of intervention 111

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We will include RCTs analysing the efficacy of any treatment modality in MD. Treatment modalities that 112

have not been assessed systematically will not be included in the umbrella systematic review. As the 113

natural course of MD has a waning pattern, time should be regarded as a therapeutic factor when 114

analysing the efficacy of a therapeutic intervention. Therefore, a study design including a placebo arm 115

is essential to account for the illusion of therapeutic efficacy. Pharmacological trials with a placebo 116

group will be included; trials comparing different pharmacological treatments without a placebo will 117

be excluded. We will include trials that investigated non-pharmacological interventions and compared 118

the efficacy of the intervention with a sham intervention group, a placebo pill group or a placebo 119

control group. 120

121

Types of outcome measuresTypes of outcome measuresTypes of outcome measuresTypes of outcome measures 122

Outcomes as defined by the AAO-HNS guidelines of 199513

will be included in this umbrella systematic 123

review. The following outcomes are listed as primary and secondary outcomes: 124

125

Primary outcomes 126

1. The main outcome of efficacy will be the control of vertigo as defined by the AAO-HNS 127

guidelines of 1995.13

The number of vertigo attacks in the interval after treatment (Y) is divided 128

by the number of vertigo spells six months prior to treatment (X) and multiplied by 100. The 129

resulting number indicates the extent of 'control of vertigo'. The AAO-HNS further divides the 130

control of vertigo into classes, where Class A (CoV =0) represents a complete control of 131

vertigo and class B (CoV up to 40%) represents a substantial control of vertigo. Assessment of 132

control of vertigo by any other outcome measures (e.g. mean frequency of vertigo attacks at 133

baseline and at the final assessment) will also be accepted. 134

135

Secondary outcomes 136

Secondary outcome measures will be: 137

1. Hearing (based on the pure-tone audiometry). 138

2. The severity of vertigo attacks (assessed by means of a standardised method (e.g. the Visual 139

Analogue Scale (VAS) or the MD Patients Oriented Severity Index (MD-POSI)). 140

3. The severity of tinnitus (assessed by means of a standardised method (e.g. VAS, Tinnitus 141

Handicap Inventory)). 142

4. Perception of aural fullness (assessed by means of a standardised method (e.g. VAS) 143

5. Quality of life (generic quality of life (e.g. SF-36) and/or disease specific quality of life (e.g. 144

Functional Level Scale, Dizziness Handicap Index)). 145

6. The incidence of adverse events or complications. 146

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Search strategy Search strategy Search strategy Search strategy 147

In association with the UK Cochrane Centre, particularly the Ear, Nose and Throat Review Group, we 148

will conduct a systematic search for all SRs for pharmacological and non-pharmacological 149

interventions for MD. We will search the Database of Abstracts of Reviews of Effect (DARE), MEDLINE 150

and EMBASE for SRs, and eligible RCTs will be extracted that examine the efficacy of pharmacological 151

and non-pharmacological therapies in MD. In case several SRs investigate exactly the same treatment 152

modality in the same population, we will extract the RCTs from the most recent published review. As 153

no current worldwide-recommended guidelines exist for the treatment of MD, we intend to include all 154

systematically reviewed interventions. We will use Medical Subject Headings (MeSH) and key words in 155

the search strategy for additional SRs and RCTs. We will use the following keys words with 156

synonymous word: ‘Menière’s disease’, ‘systematic review’, ‘randomised controlled trial’, placebo 157

controlled trial’. Details of the search strategy are shown in Table 1a Table 1a Table 1a Table 1a and Table 1b. Table 1b. Table 1b. Table 1b. 158

159

Table 1a. Table 1a. Table 1a. Table 1a. Search strategy for systematic reviews for Menière’s disease. 160

161


#2 systematic review

#3 #1 AND #2

#4 meta-analysis

#6 #1 AND (#3 OR #4)

#7 #3 OR #6

162

Table 1b. Table 1b. Table 1b. Table 1b. Search strategy for randomised controlled trials for Menière’s disease. 163

164


#2 randomised controlled trial

#3 #1 AND #2

#4 placebo controlled trial

#6 #1 AND (#3 OR #4)

#7 #3 OR #6

165

166

Two independent reviewers (BE and HZ) will screen title and abstract for potentially eligible SRs. These 167

will be downloaded for full-text screening and further evaluation. Authors and journal names will be 168

blinded. No restriction on language will be used. After identifying all interventions that were 169

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systematically reviewed, we will screen title and abstract for potentially eligible RCTs that were 170

published since the publications of these SRs. Similar to the selection of SRs, these RCTs will be 171

screened on full-text and evaluated. We will remove all duplicate RCTs after full-text screening and 172

reference checking. The reviewers will examine and extract all data from the included RCTs into a data 173

set. 174

175

Data extractionData extractionData extractionData extraction 176

After we selected eligible RCTs, the two reviewers (BE and HZ) will independently extract information 177

from the RCTs on predesigned data-extraction forms. To begin with, we will extract the general 178

information from each RCT covering the country, number of centres, number of participants, study 179

design, the number of treatment arms, allocation ratio, and conflict of interest and funding. Then, 180

study characteristics of the MD patients will be extracted including sex, age, age at onset of disease, 181

subclassification of MD types (diagnostic criteria defined by the AAO-HNS of 1995) and duration and 182

frequency of vertigo attacks before start of treatment. Furthermore, details of the interventions will be 183

extracted for both the experimental and control groups. For the pharmacological interventions we will 184

record the drug category (e.g. anticholamines, diuretics), generic name of the drug, dose per day, way 185

of administration (e.g. oral, intratympanic), additional treatments and period of treatment. In addition, 186

for the non-pharmacological interventions we will extract the type of intervention (e.g. Meniett device, 187

endolymphatic sac surgery) and any additional treatments (pre-study or during trial participation). Last, 188

we will extract information of the effect on the primary and secondary outcome measures and we will 189

record the incidence of adverse events and complications. Study characteristics will be displayed for 190

the intervention arm as shown Table 2 Table 2 Table 2 Table 2 for pharmacological, for non-pharmacological interventions as 191

shown in Table 3Table 3Table 3Table 3. Table 4 Table 4 Table 4 Table 4 and Table 5 Table 5 Table 5 Table 5 show the items that will be extracted from the control groups, 192

respectively the placebo and the sham group. 193

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Table 2. Table 2. Table 2. Table 2. Study characteristics pharmacological interventions. 194

195

StudyStudyStudyStudy Intervention Intervention Intervention Intervention Sample Sample Sample Sample

size size size size

Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)

Age Age Age Age

(mean(mean(mean(mean±±±±

SD)SD)SD)SD)

Age at onsetAge at onsetAge at onsetAge at onset

(mean ±SD)(mean ±SD)(mean ±SD)(mean ±SD)

Classification Classification Classification Classification

MDMDMDMD

Frequency Frequency Frequency Frequency

attacks attacks attacks attacks

(per year) (per year) (per year) (per year)

Duration Duration Duration Duration

attacksattacksattacksattacks

(hrs) (hrs) (hrs) (hrs)

Drug Drug Drug Drug

categorycategorycategorycategory

Generic Generic Generic Generic

namenamenamename

Dose/day Dose/day Dose/day Dose/day

(mg) (mg) (mg) (mg)

Way of Way of Way of Way of

administrationadministrationadministrationadministration

Period treatment Period treatment Period treatment Period treatment

(months, mean (months, mean (months, mean (months, mean

±SD ) ±SD ) ±SD ) ±SD )

Adverse Adverse Adverse Adverse

events (%) events (%) events (%) events (%)

Complications Complications Complications Complications

Author

et al. year

196

Table 3. Table 3. Table 3. Table 3. Study characteristics non-pharmacological interventions . 197

198

StudyStudyStudyStudy Intervention Intervention Intervention Intervention Sample size Sample size Sample size Sample size Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)

Age (mean Age (mean Age (mean Age (mean

±SD)±SD)±SD)±SD)




MDMDMDMD

Frequency attacks Frequency attacks Frequency attacks Frequency attacks





AdditionalAdditionalAdditionalAdditional

treatmenttreatmenttreatmenttreatment

Period treatPeriod treatPeriod treatPeriod treatment ment ment ment

(months, mean ±SD) (months, mean ±SD) (months, mean ±SD) (months, mean ±SD)




Author

et al. year

199

200

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201

Table 4. Table 4. Table 4. Table 4. Study characteristics of placebo group in pharmacological intervention studies. 202

203

StudyStudyStudyStudy Intervention Intervention Intervention Intervention Sample Sample Sample Sample

size size size size

Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)

Age Age Age Age

(mean(mean(mean(mean±±±±

SD)SD)SD)SD)




MDMDMDMD

Frequency Frequency Frequency Frequency

attacks attacks attacks attacks





Drug Drug Drug Drug

categorycategorycategorycategory

Dose/day Dose/day Dose/day Dose/day

(mg) (mg) (mg) (mg)

Way of Way of Way of Way of

administrationadministrationadministrationadministration


(months, mean (months, mean (months, mean (months, mean

±SD ) ±SD ) ±SD ) ±SD )




Author

et al. year

204

Table 5. Table 5. Table 5. Table 5. Study characteristics of sham group in non-pharmacological intervention studies. 205

206

StudyStudyStudyStudy Sham Sham Sham Sham

intervention intervention intervention intervention

Sample size Sample size Sample size Sample size Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)Sex ratio (♂:♀)

Age (mean Age (mean Age (mean Age (mean

±SD)±SD)±SD)±SD)




MDMDMDMD

Frequency attacks Frequency attacks Frequency attacks Frequency attacks





AdditionalAdditionalAdditionalAdditional

treatmenttreatmenttreatmenttreatment


(months, mean ±SD) (months, mean ±SD) (months, mean ±SD) (months, mean ±SD)




Author

et al. year

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Outcome assessment Outcome assessment Outcome assessment Outcome assessment 207

We aim to investigate the efficacy of treatment for MD in controlling vertigo attacks (primary 208

outcome). As defined in the AAO-HNS guideline of 199513

, the control of vertigo will be calculated and 209

classified (Class A, 100% control of vertigo, Class B, 40% control of vertigo). Ideally, the primary 210

outcome is again evaluated after 18 and 24 months following randomisation. However, it is unlikely 211

that a placebo-controlled trial will last this long. Therefore, we will include papers that have assessed 212

the efficacy of the therapy reflected by the primary outcome at 3 to 6 months of follow-up. We will 213

ensure accurate assessment of the outcome measures as independent reviewers (BE and HZ) extract 214

the information from the selected RCTs and a third reviewer (TB and/or PB) will check the 215

completeness and correctness of the extracted data. 216

217

Risk of bias assessment Risk of bias assessment Risk of bias assessment Risk of bias assessment 218

We will assess the methodological quality of the RCTs by use of the Cochrane Collaboration’s risk of 219

bias tool14

within Review Manager v. 5.3 software (Review Manager (Revman) v.5.3 Copenhagen: The 220

Nordic Cochrane Centre, The Cochrane Collaboration, 2012). The tool is based on the following eight 221

potential sources of bias: random sequence generation; allocation concealment; blinding of the 222

participants; blinding of the outcome assessors; incomplete outcome data; missing data and selective 223

outcome reporting, other bias (e.g. improper statistical analysis). Two independent reviewers (BE and 224

HZ) will independently evaluate the quality of the RCTs. Each aspect will be graded with ‘yes’, ‘no’, or 225

‘unclear’, which will reflect a high risk of bias, low risk of bias and unclear risk of bias, respectively. For 226

each study, all eight domains will be evaluated and displayed in a table (see Table 6Table 6Table 6Table 6). If there is any 227

disagreement on inclusion or exclusion, this will be settled by discussion, if necessary in the presence 228

of a third reviewer (TB and/or PB). In addition, we will grade the diagnostic validity of studies on the 229

basis of the robustness of the methods used to diagnose the disorder (homogeneity of the types of 230

participants). This grading will form the basis to assess the risk of bias and perform sensitivity analyses. 231

We will grade papers that used the AAO-HNS 1995 criteria for ‘definite’ and 'certain' MD as 'I'. We will 232

grade studies in which less clear but rigorous criteria were used as 'II'. Studies in which no or less clear 233

diagnostic criteria were used will be graded as 'III'. 234

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Table 6. Table 6. Table 6. Table 6. Risk of bias assessment based on the Cochrane risk of bias tool. 235

StudyStudyStudyStudy Random Random Random Random

sequence sequence sequence sequence

generation generation generation generation

Allocation Allocation Allocation Allocation

concealment concealment concealment concealment

Blinding of Blinding of Blinding of Blinding of

participants participants participants participants

Blinding of Blinding of Blinding of Blinding of

outcome outcome outcome outcome

assessmentassessmentassessmentassessment

Incomplete Incomplete Incomplete Incomplete

outcome outcome outcome outcome

datadatadatadata

Missing Missing Missing Missing

data data data data

Selective Selective Selective Selective

reportingreportingreportingreporting

Other Other Other Other

bias bias bias bias

... et

al.

year

High risk

or low risk

or unclear

idem Idem Idem Idem idem

236

237

Data analysis Data analysis Data analysis Data analysis 238

Data will be entered into Review Manager (Version 5.3). For each treatment modality we aim to 239

perform a statistical analysis for the primary outcome comparing the interventional arm to the control 240

group (placebo or sham). In addition, studies that report the vertigo attack frequency as a continuous 241

outcome, we intend to calculate the effect size using the mean difference (MD) or the standardised 242

mean difference (SMD). The same applies for the loss of hearing. When appropriate data will be 243

categorised or dichotomised for control of vertigo, the severity of vertigo attacks, the severity of 244

tinnitus, perception of aural fullness, quality of life, complications and adverse events. 245

The included studies will be explored on methodological and statistical heterogeneity. The latter will 246

be quantified by the I2 statistic. An I

2 value greater than 50% is considered to indicate substantial 247

heterogeneity (Handbook 2011, The Cochrane Collaboration)15

. If the data are sufficiently 248

homogenous, we will pool outcome data. It is expected that the data will carry a certain amount of 249

heterogeneity and a random-effects model will be used. Forest plots will be shown for each 250

intervention. If the data turn out to be too heterogeneous for pooling based on methodological 251

heterogeneity and statistical heterogeneity, we will perform a descriptive review and summarise the 252

available evidence for this intervention. The strength of the evidence will be evaluated by use of the 253

GRADE method as generated by the Cochrane Collaboration. Table 7 Table 7 Table 7 Table 7 shows the summery of findings 254

per intervention based on the GRADE method. 255

256

257

258

259

260

261

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Table 7. Table 7. Table 7. Table 7. Summary of findings per intervention. 262

263

Intervention versus control (placebo or sham) for Menière’s disease or syndrome Intervention versus control (placebo or sham) for Menière’s disease or syndrome Intervention versus control (placebo or sham) for Menière’s disease or syndrome Intervention versus control (placebo or sham) for Menière’s disease or syndrome

Type of Type of Type of Type of participants:participants:participants:participants:

Settings:Settings:Settings:Settings:

Intervention: Intervention: Intervention: Intervention:

OutcomesOutcomesOutcomesOutcomes Illustrative comparative risks (95% CI)Illustrative comparative risks (95% CI)Illustrative comparative risks (95% CI)Illustrative comparative risks (95% CI)**** Relative effectRelative effectRelative effectRelative effect

4444 (95% (95% (95% (95%

CI) CI) CI) CI)

No of participants No of participants No of participants No of participants

(studies) (studies) (studies) (studies)

Quality of the Quality of the Quality of the Quality of the

evidence (GRADE)evidence (GRADE)evidence (GRADE)evidence (GRADE)

CommentsCommentsCommentsComments

Assumed riskAssumed riskAssumed riskAssumed risk2222 Corresponding riskCorresponding riskCorresponding riskCorresponding risk

3333

ControlControlControlControl Intervention Intervention Intervention Intervention

Control of vertigo,

Follow-up: mean ...

months

We will use the GRADE approach to rate the overall quality of evidence. The quality of evidence reflects the extent to which we are confident that an estimate of effect is correct and we

will apply this to the interpretation of results. There are four possible ratings: high, moderate, low and very low. A rating of high quality of evidence implies that we are confident in our

estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low quality implies that any estimate of effect obtained is

very uncertain. The GRADE approach rates evidence from RCTs that do not have serious limitations as high quality. However, several factors can lead to the downgrading of the evidence

to moderate, low or very low. The degree of downgrading is determined by the seriousness of the these factor: study limitations (risk of bias); inconsistency; indirectness of evidence;

imprecision and publication bias.

This table will be constructed according to the recommendations described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We will

include the following outcomes in the 'Summary of findings' table: control of vertigo attacks, hearing, severity of vertigo attacks and tinnitus, perception of aural fullness, quality of life

and adverse events.

*The basis for the assumed risk (e.g. the median proportion of patients with control of vertigo related to the follow-up period). The corresponding risk (and its 95% confidence interval is

based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

264

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Dealing with missing dataDealing with missing dataDealing with missing dataDealing with missing data 265

We expect missing data in the selected trials for the SR. All corresponding authors will be contacted 266

and asked for the original data. If only a per protocol analysis has been carried out, corresponding 267

authors will be contacted for the original data on the intention to treat analysis. 268

269

Subgroup analysis Subgroup analysis Subgroup analysis Subgroup analysis 270

We will perform subgroup analysis to investigate heterogeneity and inconsistency in the selected trials. 271

Subgroup analysis will be performed with regard to subtype of MD (‘certain’, ‘definite’, ‘probable’, or 272

possible’ MD in accordance with the AAO-HNS 1995 criteria13

), stage of disease (as defined by the 273

AAO-HNS 1995 criteria13

), and duration of treatment. As the primary outcome is a patient reported 274

outcome, blinding can be of influence. Therefore, we will consider the method of blinding the most 275

important subgroup analysis. 276

277

Sensitivity analysis Sensitivity analysis Sensitivity analysis Sensitivity analysis 278

We will perform a sensitivity analysis to address whether the eight potential sources of bias played a 279

relevant role in the robustness of our study findings. Studies with a high risk of bias will be analysed 280

separately to evaluate if the efficacy of the intervention is not solely based on these trials and if trial 281

results are robust. 282

283

Publication biasPublication biasPublication biasPublication bias 284

Publications bias will be explored by performing funnel plots if sufficient data are available (10 or more 285

studies). 286

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ETHICS AND ETHICS AND ETHICS AND ETHICS AND DISSEMINATION DISSEMINATION DISSEMINATION DISSEMINATION 287

Formal ethical approval is not required, as primary data will not be collected. The findings will be 288

disseminated in peer-reviewed journals and conference presentations. 289

290

CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION 291

We expect this umbrella systematic review to provide a systematic summary of evidence and we aim to 292

identify the treatment(s) with the highest efficacy for MD and to identify areas for future valuable 293

research. 294

295

Acknowledgements Acknowledgements Acknowledgements Acknowledgements 296

The authors are grateful for the support of the members of the ENT Group of the UK Cochrane Centre, particularly 297

Jenny Bellorini and Samantha Faulkner, for conducting the systematic searches for randomised controlled trials for 298

interventions of Menière’s disease. 299

300

Contributors Contributors Contributors Contributors 301

BE, HZ, TB and PB contributed to the design and conception of the study protocol. The search strategy was 302

developed and run by the ENT Group. BE and HZ will screen studies on title and abstract and full text. If 303

disagreement over inclusion or exclusion arrives, this will be settled by discussion with all authors (BE, HZ, TB 304

and/or PB). BE and HZ will independently extract data from the articles and a third reviewer (TB and/or PB) will 305

check the completeness and correctness of the extracted data of the outcome assessment. All authors drafted and 306

revised this study protocol and approved it for publication. 307

308

FundingFundingFundingFunding 309

This work was supported solely from institutional and/or departmental sources from the Apeldoorn Dizziness 310

Centre, Gelre Hospital, Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, The Netherlands. 311

312

Competing interestsCompeting interestsCompeting interestsCompeting interests 313

None declared. 314

315

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REFERENCES REFERENCES REFERENCES REFERENCES 316

1. Menière P. Memoire sur les lesions de l’orellei interne dinnant lieu à des symptômes de 317

congestion cerebrale apolectiforme. Gazette Medical de Paris 1861 ; 16 :597-601. 318

2. Minor LB, Schessel Da, Carey JP. Ménière’s disease. Curr Opin Neurol 2004;17:9-16. 319

3. Best C, Eckhardt-Henn A, Tschan R et al. Pshychiatric comorbidity in different organic vertigo 320

syndromes. J Neurol. 2009;256:58-65. 321

4. Yardley L,. Kirby S. Evaluation of booklet-based self management of symptoms in Ménière’s 322

disease: a randomized controlled trial. Psychosom Med. 2006;68:762-769. 323

5. Sajjadi H, Paparella MM. Ménière’s disease. Lancet. 2008;372 :406-14. 324

6. James Al, Burton MJ. Betahistine for Ménière’s disease or syndrome. Cochrane Databsase Syst 325

Rev. 2001 :1CD001873. 326

7. Thirlwall AS, Kundu S. Diuretics for Ménière’s disease or syndrome. Cochrane Database Syst 327

Rev. 2006;3:CD003599. 328

8. Phillips JS, Westerberg B. Intratympanic steroids for Ménière’s disease or syndrome. Cochrane 329

Database Syst Rev. 2011;7:CD008514. 330

9. Pullens B, van Benthem PP: Intratympanic gentamicin for Ménière’s disease or syndrome. 331

Cochrane Database Syst Rev. 2011;3:CD008234. 332

10. Pullens B, Verschuur HP, van Benthem PP. Surgery for Ménière’s disease. Cochrane Database 333

Syst Rev. 2013;2:CD005395. 334

11. Van Sonsbeek S, Pullens B, van Benthem PP. Positive pressure therapy for Ménière’s disease or 335

syndrome. Cochrane Database Syst Rev. 2015;3:CD00008419. 336

12. Shamseer L., Moher D, Clarke M, et al. Preferred reporting items for systematic review and 337

meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2014;349:g7647. 338

13. Committee on Hearing and Equilibrium. Committee on Hearing and Equilibrium guidelines for 339

the diagnosis and evaluation of therapy in Menière’s disease. American Academy of 340

Otolaryngology – Head and Neck Foundation. Inc. Otolaryngology – Head and Neck Surgery. 341

1995;113:181-5. 342

14. Lopez-Escamez JA, Carey J, Chung WH et al. Diagnostic criteria for Menière's disease. Journal 343

of Vestibular Research 2015;25:1-7. 344

15. Higgins JP, Thompson SG, Deek JJ et al. Measuring inconsistency in meta-analyses. BMJ 345

2003;327:557-60.346

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Flowchart of the umbrella systematic review

119x253mm (300 x 300 DPI)

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PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to

address in a systematic review protocol*

Section and topic Item No Checklist item

ADMINISTRATIVE INFORMATION

Title:

Identification 1a Identify the report as a protocol of a systematic review

Update 1b If the protocol is for an update of a previous systematic review, identify as such

Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number

Authors:

Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of

corresponding author

Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review

Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes;

otherwise, state plan for documenting important protocol amendments

Support:

Sources 5a Indicate sources of financial or other support for the review

Sponsor 5b Provide name for the review funder and/or sponsor

Role of sponsor or funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol

INTRODUCTION

Rationale 6 Describe the rationale for the review in the context of what is already known

Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions,

comparators, and outcomes (PICO)

METHODS

Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years

considered, language, publication status) to be used as criteria for eligibility for the review

Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other

grey literature sources) with planned dates of coverage

Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be

repeated

Study records:

Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review

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Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the

review (that is, screening, eligibility and inclusion in meta-analysis)

Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any

processes for obtaining and confirming data from investigators

Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data

assumptions and simplifications

Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with

rationale

Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the

outcome or study level, or both; state how this information will be used in data synthesis

Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised

15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and

methods of combining data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ)

15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression)

15d If quantitative synthesis is not appropriate, describe the type of summary planned

Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies)

Confidence in cumulative evidence 17 Describe how the strength of the body of evidence will be assessed (such as GRADE)

* It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important

clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the

PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0.

From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and

meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647.

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