Transtympanic Gentamicin vs. Steroids in Refractory Meniere's Disease

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00802529
• Collaborator: Imperial College Healthcare NHS Trust (Other), Medical Research Council (Other)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 73
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This trial aims to compare transtympanic steroids against the standard treatment (transtympanic gentamicin) in refractory unilateral Meniere's disease.

Condition or Disease	Intervention/Treatment	Phase
Meniere's Disease	Drug: Methylprednisolone; Drug: Gentamicin	Phase 2/Phase 3

Detailed Description

Meniere's disease is characterised by episodic spontaneous vertigo attacks with hearing loss, ringing sounds and fullness in the ear. In one out of five patients, standard first line medical treatment is not effective in controlling vertigo attacks. For these incapacitated patients, gentamicin injections through the ear drum is a well established minimally invasive treatment. Major surgery of the balance organs or nerve, risking complete hearing loss, CSF leak, meningeal infections, are rarely performed nowadays. Gentamicn is very effective in controlling vertigo and acts by chemical ablation of end organs. As hearing and balance organs are entwined around each other, gentamicin treatment does not come without the risk of hearing loss. In fact, meta-analysis shows hearing deterioration in 13% to 35% percent of gentamicin treated patients. On the other hand, steroids are drug of choice for autoimmune inner ear disease and commonly used for sudden hearing loss. They are non toxic drugs without any known side effects during local treatment in ear. We will compare the two in this randomised, double blind trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effectiveness of Transtympanic Steroids in Unilateral Ménière's Disease: a Randomised Controlled Double-Blind Trial
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Steroid (Methylprednisolone) Steroid (Methylprednisolone)	Drug: Methylprednisolone; 2 transtympanic injections at interval of two weeks.
Active Comparator: Gentamicin Gentamicin	Drug: Gentamicin; 2 transtympanic injections at an interval of two weeks. If there is significant hearing loss before second injection, it will be replaced by normal saline in double blinded fashion.

Outcome Measures

Primary Outcome Measures

1. Vertigo Attacks [6month pre-enrollment baseline, 18-24 months after initial treatment]

   The number of vertigo attacks between 18-24months follow-up were taken retrospectively during a face-to-face appointment at 24 months follow-up and compared to 6 month pre-enrollment baseline (as per Committee on Hearing and Equilibrium guidelines).

Secondary Outcome Measures

1. Change in Hearing [Baseline, 1,2,6,12,18 and 24months after initial treatment]

   Hearing was measured as ipsilesional pure-tone threshold at Baseline, 1month, 2months, 6months, 12month, 18months and 24 months follow-up. Hearing level was taken as the average threshold across 0.5, 1, 2 and 3KHz.

2. Change in Speech Discrimination [Baseline, 1,2,6,12 and 24months after initial treatment]

   Speech discrimination was measured at Baseline, 1month, 2months, 6months, 12month and 24 months follow-up. Speech discrimination was assessed by means of ipsilesional suprathreshold word recognition (%). Arthur Boothroyd's isophonemic word lists (AB wordlists, Guymark, Southampton) comprising sets of 10 words were played to the ipsilesional ear at the low-frequency pure-tone threshold of 0·5, 1 and 2 kHz +30dB with masking sound in the contralesional ear if necessary. The formula for masking level was: low-frequency pure-tone threshold in ipsilesional ear - bone conduction mean threshold (0·5, 1 and 2KHz) in contralesional ear - 40dB. Speech loudness and masking were rounded to the nearest 5dB. Step increments and decrements of 10dB for speech loudness and masking were used to attain the maximum speech discrimination score.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with unilateral Ménière's disease (definite or probable, according to Committee on Hearing and Equilibrium guidelines, 1995) with hearing loss and presenting with recurrent vertigo, not responding to medical treatment for at least 6 months will be included. There should be normal, age appropriate hearing in the contralateral ear.

Exclusion Criteria:

• Patients with Ménière's disease in later stages (not having vertigo attacks).

• Age: patients older than 70 years at the start of the trial.

• Severe disability (e.g. neurological, orthopaedic, cardiovascular) or serious concurrent illness that might interfere with treatment or follow up.

• Active additional neuro-otological disorders that may mimic Ménière's disease (e.g. vestibular migraine, vertebro-basilar TIAs, acoustic neuroma) and thus will make the objective follow up difficult.

• Concurrent ear pathology that may interfere with transtympanic treatment (e.g. active middle ear disease).

• Family history of unexplained deafness (possibility of genetic susceptibility to gentamicin toxicity).

• History of known adverse/allergic reaction to steroids or gentamicin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Imperial college Healthcare NHS Trust	London		United Kingdom

Sponsors and Collaborators

• Imperial College London
• Imperial College Healthcare NHS Trust
• Medical Research Council

Investigators

• Principal Investigator: Adolfo M Bronstein, PhD, FRCP, Imperial College London

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT00802529
• Other Study ID Numbers: CRO1135
• First Posted: Dec 5, 2008
• Last Update Posted: Jun 27, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Imperial College London: Meniere's disease; transtympanic steroids; Randomised controlled trial
• Additional relevant MeSH terms: Meniere Disease; Gentamicins; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	Steroid (Methylprednisolone)	Gentamicin
Arm/Group Description	Methylprednisolone: 2 transtympanic injections at interval of two weeks. Each injection was 62.5mg/ml.	Gentamicin: 2 transtympanic injections at an interval of two weeks. If there is significant hearing loss before second injection, it will be replaced by normal saline in double blinded fashion.Each injection was 40mg/ml.
Period Title: Overall Study
STARTED	30	30
COMPLETED	30	29
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Steroid (Methylprednisolone)	Gentamicin	Total
Arm/Group Description	Methylprednisolone: 2 transtympanic injections at interval of two weeks.	Gentamicin: 2 transtympanic injections at an interval of two weeks. If there is significant hearing loss before second injection, it will be replaced by normal saline in double blinded fashion.	Total of all reporting groups
Overall Participants	30	30	60
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 83.3%	25 83.3%	50 83.3%
>=65 years	5 16.7%	5 16.7%	10 16.7%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.6 (10.2)	53.3 (10.8)	52.5 (10.5)
Sex: Female, Male (Count of Participants)
Female	10 33.3%	15 50%	25 41.7%
Male	20 66.7%	15 50%	35 58.3%
Region of Enrollment (participants) [Number]
United Kingdom	30 100%	30 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Vertigo Attacks
Description	The number of vertigo attacks between 18-24months follow-up were taken retrospectively during a face-to-face appointment at 24 months follow-up and compared to 6 month pre-enrollment baseline (as per Committee on Hearing and Equilibrium guidelines).
Time Frame	6month pre-enrollment baseline, 18-24 months after initial treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	Steroid (Methylprednisolone)	Gentamicin
Arm/Group Description	Methylprednisolone: 2 transtympanic injections at interval of two weeks.	Gentamicin: 2 transtympanic injections at an interval of two weeks. If there is significant hearing loss before second injection, it will be replaced by normal saline in double blinded fashion.
Measure Participants	30	29
Baseline	16.4 (12.45)	19.93 (16.7)
18-24months	1.6 (3.4)	2.5 (5.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Steroid (Methylprednisolone), Gentamicin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments	P-value for Drug x Time interaction.
	Method	ANOVA
	Comments	Time: 2 degrees of freedom (Baseline vs 18-24 months) Drug: 2 degrees of freedom (Gentamicin vs steroid)

2. Secondary Outcome

Title	Change in Hearing
Description	Hearing was measured as ipsilesional pure-tone threshold at Baseline, 1month, 2months, 6months, 12month, 18months and 24 months follow-up. Hearing level was taken as the average threshold across 0.5, 1, 2 and 3KHz.
Time Frame	Baseline, 1,2,6,12,18 and 24months after initial treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Steroid (Methylprednisolone)	Gentamicin
Arm/Group Description	Methylprednisolone: 2 transtympanic injections at interval of two weeks.	Gentamicin: 2 transtympanic injections at an interval of two weeks. If there is significant hearing loss before second injection, it will be replaced by normal saline in double blinded fashion.
Measure Participants	30	29
Baseline	53.25 (21.17)	51.5 (11.29)
1month	49.29 (22.23)	52.18 (15.77)
2months	49.83 (22.31)	48.99 (16.9)
6months	46.67 (23.29)	45.48 (17.7)
12months	47.02 (23.96)	47.34 (19.2)
18months	48.44 (22.1)	44.82 (18.8)
24months	46.9 (24.0)	49.1 (18.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Steroid (Methylprednisolone), Gentamicin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.964
	Comments	P-value for Drug x Time interaction.
	Method	ANOVA
	Comments	Time: 6 degrees of freedom (Baseline, 1, 2, 6, 12, 18 and 24 months) Drug: 2 degrees of freedom (Gentamicin vs steroid)

3. Secondary Outcome

Title	Change in Speech Discrimination
Description	Speech discrimination was measured at Baseline, 1month, 2months, 6months, 12month and 24 months follow-up. Speech discrimination was assessed by means of ipsilesional suprathreshold word recognition (%). Arthur Boothroyd's isophonemic word lists (AB wordlists, Guymark, Southampton) comprising sets of 10 words were played to the ipsilesional ear at the low-frequency pure-tone threshold of 0·5, 1 and 2 kHz +30dB with masking sound in the contralesional ear if necessary. The formula for masking level was: low-frequency pure-tone threshold in ipsilesional ear - bone conduction mean threshold (0·5, 1 and 2KHz) in contralesional ear - 40dB. Speech loudness and masking were rounded to the nearest 5dB. Step increments and decrements of 10dB for speech loudness and masking were used to attain the maximum speech discrimination score.
Time Frame	Baseline, 1,2,6,12 and 24months after initial treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Steroid (Methylprednisolone)	Gentamicin
Arm/Group Description	Methylprednisolone: 2 transtympanic injections at interval of two weeks.	Gentamicin: 2 transtympanic injections at an interval of two weeks. If there is significant hearing loss before second injection, it will be replaced by normal saline in double blinded fashion.
Measure Participants	30	29
Baseline	64.97 (29.28)	72.10 (21.67)
1month	71.78 (26.48)	69.43 (22.94)
2months	76.10 (24.43)	74.31 (23.4)
6months	75.63 (26.39)	76.35 (25.92)
12months	73.43 (27.16)	71.58 (24.69)
24months	76.32 (29.36)	64.99 (30.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Steroid (Methylprednisolone), Gentamicin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.128
	Comments	P-value for Drug x Time interaction.
	Method	ANOVA
	Comments	Time: 5 degrees of freedom (Baseline, 1, 2, 6, 12 and 24 months) Drug: 2 degrees of freedom (Gentamicin vs steroid)

Adverse Events

Arm/Group Title	Steroid (Methylprednisolone)		Gentamicin
Arm/Group Description	Methylprednisolone: 2 transtympanic injections at interval of two weeks.		Gentamicin: 2 transtympanic injections at an interval of two weeks. If there is significant hearing loss before second injection, it will be replaced by normal saline in double blinded fashion.
All Cause Mortality
	Steroid (Methylprednisolone)		Gentamicin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/32 (0%)
Serious Adverse Events
	Steroid (Methylprednisolone)		Gentamicin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Steroid (Methylprednisolone)		Gentamicin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/30 (10%)		3/32 (9.4%)
Ear and labyrinth disorders
Otitis media	1/30 (3.3%)	1	2/32 (6.3%)	2
Eye disorders
Retinoschisis	1/30 (3.3%)	1	0/32 (0%)	0
Gastrointestinal disorders
Cist	1/30 (3.3%)	1	0/32 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Scwannoma	0/30 (0%)	0	1/32 (3.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.