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    Clinical Trial Results:
    Effectiveness of Transtympanic Steroids in unilateral Ménière's disease: a Randomised Controlled Double-Blind Trial

    Summary
    EudraCT number
    		 2008-004803-78
    Trial protocol
    		 GB  
    Global end of trial date
    04 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2016
    First version publication date
    14 May 2016
    Other versions
    Summary report(s)
    		 End of Trial Summary Report

    Trial information

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    Trial identification
    Sponsor protocol code
    1.1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensington, London, United Kingdom,
    Public contact
    Dr Mitesh Patel, Imperial College London, 0044 208 223 7241, Mitesh.Patel1@imperial.ac.uk
    Scientific contact
    Dr Mitesh Patel Professor Adolfo Bronstein, Imperial College London, 0044 208 223 7241, Mitesh.Patel1@imperial.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    There are 20-24% of patients with Meniere's disease who do not respond to first line treatment with diet modification and oral drugs. One of the well established alternative treatment option is the minimally invasive transtympanic treatment, where drugs are injected locally through the ear drum. The most commonly used drug for injection is Gentamicin. Gentamicin provides effective control of vertigo by toxic action on the labyrinth. But it is potentially harmful to hearing organ also and may produce further hearing deterioration in 25% of patients and profound loss in 7%. Recently, steroids are used as an alternative by many ENT surgeons with reports that it provides relief of vertigo without hearing loss or maybe hearing improvemnet also. However, this has not been proven. The main research question is to compare the two drugs and establish their role in Meniere's patients who are not responding to medical treatment.
    Protection of trial subjects
    An audiogram was obtained before the second injection (2 weeks after the first) which was assessed by a blinded consultant (MH) and reported to the pharmacy. Following a 20dB (decibel) drop in hearing across any two consecutive frequencies, the pharmacy (without informing the trial team) switched gentamicin for saline (Figure 1). As steroids do not disturb hearing, patients randomised to steroid were given a second steroid injection. Non responders: If vertigo attacks returned (=non-responder) an unblinded consultant (BMS) prescribed a further course of intratympanic injections but the patient and everybody else remained blind. The clinician had the choice to prescribe the same drug or swap, basing this decision on the patient’s response to previous injections.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    50
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between November 2009-May 2013

    Pre-assignment
    Screening details
    		 Inclusion criteria were patients 18-70 years of age with definite unilateral MD having experienced at least 2 episodes of rotational vertigo lasting at least 20min in the previous 6 months and shown no response to standard medical treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 60
    Number of subjects completed
    		 60

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The double-blind randomisation sequence was generated by constructing 15 blocks of 4 possible combinations, containing 2 Steroid and 2 Gentamicin treatments, to keep drug allocation roughly equal throughout recruitment. The randomisation sequence was retained and concealed by the Charing Cross Hospital and Leicester Royal Infirmary pharmacy aseptic units

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gentamicin (control)
    Arm description
    		 Gentamicin – administered intratympanically. Gentamicin is commonly used as an antibiotic but used for its vestibular suppressant action, i.e., reducing vestibular function and vertigo attacks. There is central compensation of reduced vestibular function following treatment. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 40mg/ml.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    2 initial doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml. Repeat injections if necessary over 2 years. The patients lay supine on a couch with the head turned away from the treated ear. The ear canal was sprayed with 2 to 3 squirts of Lidocaine spray (Xylocaine spray™ 10mg/spray). After 60 seconds the ear canal was completely aspirated. The injection syringe was attached to a 22Gauge spinal needle which, under microscopic control, was inserted in the inferior aspect of the pars tensa. The injection continued until a fluid level could be seen to fill the tympanic cavity and the volume injected was recorded. The patient was asked not to swallow or speak for 20 minutes. Immediately after treatment, all 60 patients were issued the same (Cawthorne-Cooksey) rehabilitation exercises and instructed to begin performing them after 3 days, twice daily, beginning slowly and grading their intensity progressively over 4 weeks.

    Investigational medicinal product name
    Gentamicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    2 initial doses (spaced 2 weeks apart) of 1ml of 40mg/ml. Repeat injections if necessary over 2 years. The patients lay supine on a couch with the head turned away from the treated ear. The ear canal was sprayed with 2 to 3 squirts of Lidocaine spray (Xylocaine spray™ 10mg/spray). After 60 seconds the ear canal was completely aspirated. The injection syringe was attached to a 22Gauge spinal needle which, under microscopic control, was inserted in the inferior aspect of the pars tensa. The injection continued until a fluid level could be seen to fill the tympanic cavity and the volume injected was recorded. The patient was asked not to swallow or speak for 20 minutes. Immediately after treatment, all 60 patients were issued the same (Cawthorne-Cooksey) rehabilitation exercises and instructed to begin performing them after 3 days, twice daily, beginning slowly and grading their intensity progressively over 4 weeks.

    Arm title
    		 Methylprednisolone
    Arm description
    		 Methylprednisolone – Administered intratympanically. Methylprednisolone is a synthetic cortico-steroid drug. It has predominant anti-inflammatory properties with some anti-allergic and mineralocorticoid effects. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    2 initial doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml. Repeat injections if necessary over 2 years. The patients lay supine on a couch with the head turned away from the treated ear. The ear canal was sprayed with 2 to 3 squirts of Lidocaine spray (Xylocaine spray™ 10mg/spray). After 60 seconds the ear canal was completely aspirated. The injection syringe was attached to a 22Gauge spinal needle which, under microscopic control, was inserted in the inferior aspect of the pars tensa. The injection continued until a fluid level could be seen to fill the tympanic cavity and the volume injected was recorded. The patient was asked not to swallow or speak for 20 minutes. Immediately after treatment, all 60 patients were issued the same (Cawthorne-Cooksey) rehabilitation exercises and instructed to begin performing them after 3 days, twice daily, beginning slowly and grading their intensity progressively over 4 weeks.

    Number of subjects in period 1 [1]
    		Gentamicin (control) Methylprednisolone
    Started
    30
    30
    Completed
    29
    28
    Not completed
    1
    2
         Transferred to other arm/group
    -
    2
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Two patient crossed over from methylprednisolone to gentamicin due to non-response One patient in the gentamicin arm was lost to follow-up.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gentamicin (control)
    Reporting group description
    		 Gentamicin – administered intratympanically. Gentamicin is commonly used as an antibiotic but used for its vestibular suppressant action, i.e., reducing vestibular function and vertigo attacks. There is central compensation of reduced vestibular function following treatment. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 40mg/ml.

    Reporting group title
    Methylprednisolone
    Reporting group description
    		 Methylprednisolone – Administered intratympanically. Methylprednisolone is a synthetic cortico-steroid drug. It has predominant anti-inflammatory properties with some anti-allergic and mineralocorticoid effects. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml.

    Reporting group values
    		 Gentamicin (control) Methylprednisolone Total
    Number of subjects
    		 30 30 60
    Age categorical
    Inclusion criteria: 18-70 years of age
    Units: Subjects
        Adults (18-64 years)
    		 25 25 50
        From 65-84 years
    		 5 5 10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.3 ( 10.8 ) 51.6 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 10 24
        Male
    		 16 20 36

    End points

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    End points reporting groups
    Reporting group title
    Gentamicin (control)
    Reporting group description
    		 Gentamicin – administered intratympanically. Gentamicin is commonly used as an antibiotic but used for its vestibular suppressant action, i.e., reducing vestibular function and vertigo attacks. There is central compensation of reduced vestibular function following treatment. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 40mg/ml.

    Reporting group title
    Methylprednisolone
    Reporting group description
    		 Methylprednisolone – Administered intratympanically. Methylprednisolone is a synthetic cortico-steroid drug. It has predominant anti-inflammatory properties with some anti-allergic and mineralocorticoid effects. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml.

    Primary: Attacks of vertigo (Primary Outcome)

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    End point title
    		 Attacks of vertigo (Primary Outcome)
    End point description
    End point type
    Primary
    End point timeframe
    18-24 months follow-up as per AAO-HNS recommendations.
    End point values
    		 Gentamicin (control) Methylprednisolone
    Number of subjects analysed
    30
    30
    Units: number
        number (not applicable)
    2.5
    1.6
    Statistical analysis title
    		 Outcome measure stats
    Statistical analysis description
    There was a significant reduction of vertigo attacks in the final six 6 months (time; F[1,58]65.0; P<0.001). Mean number of vertigo attacks fell from 19.9 to 2.5 in the gentamicin arm and from 16.4 to 1.6 in the steroid arm. There was no significant difference between drugs (drug; F[1,58]1.2;P=0·271, time x drug interaction; F[1,58]0.43; P=0.514).
    Comparison groups
    Gentamicin (control) v Methylprednisolone
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.514 [1]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - No difference between drugs for primary outcome measure

    Secondary: Change in Hearing threshold

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    End point title
    		 Change in Hearing threshold
    End point description
    End point type
    Secondary
    End point timeframe
    2 years follow-up as per AAO-HNS recommendations
    End point values
    		 Gentamicin (control) Methylprednisolone
    Number of subjects analysed
    30 [2]
    30 [3]
    Units: dB
        number (not applicable)
    49.1
    46.9
    Notes
    [2] - Intention-to-treat
    [3] - Intention-to-treat
    Statistical analysis title
    		 Hearing Analysis (Secondary Outcome)
    Comparison groups
    Gentamicin (control) v Methylprednisolone
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 = 0.18 [5]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [4] - Hearing levels did not significantly change from baseline over the 24 months follow-up (time; F[6,54]2.13; P=0.065). There was no significant difference between drugs (drug F[1,58]0.03; P=0.964 ;time x drug interaction; F[6,54]1.55; P=0.18).
    [5] - No significant difference between arms

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    2 years follow-up
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    RF2
    Reporting groups
    Reporting group title
    Adverse Events (Gentamicin)
    Reporting group description
    		 -

    Reporting group title
    Adverse Events (Methylprednisolone)
    Reporting group description
    		 -

    Serious adverse events
    		 Adverse Events (Gentamicin) Adverse Events (Methylprednisolone)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Adverse Events (Gentamicin) Adverse Events (Methylprednisolone)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 30 (10.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Schwannoma
    Additional description: Abdomen
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Buccal polyp
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Otitis media
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Eye disorders
    Retinoschisis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2009
    Otoacoustic emission testing removed from audiological testing battery due to non-availability of equipment

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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