The study was started in two hospitals, the University Medical Center in Utrecht (UMC Utrecht) and Gelre Hospital Apeldoorn. Before entering the study all patients gave written informed consent for participation in the study. Patients were eligible for the study if they had been diagnosed as having unilateral Ménière’s disease according to the 1995 AAO-HNS criteria: two or more spontaneous episodes of vertigo each lasting 20 min or longer, sensorineural hearing loss documented audiometrically in the diseased ear and the presence of tinnitus, and/or aural fullness in this ear. Causes other than Ménière’s disease were excluded by a diagnostic protocol, including vestibular tests, MRI of the cerebellopontine angle, clinical history, and physical examination. Other inclusion criteria were: Ménière’s disease resistant to conservative medical treatment executed longer than 6 months, (that is, Dizziness Handicap Score of at least 30 points) and ability to provide written informed consent. Patients had to have compromised hearing on the affected side without fluctuations. Exclusion criteria were ipsilateral middle ear pathology, contralateral ear pathology or contralateral hearing loss, allergy for aminoglycosides, or earlier treatment with intratympanic gentamicin. After ITG treatment patients were advised to visit the physiotherapist for, for example, Cawthorn-Cooksey exercises or other patient-specific exercises. Approval of the study was granted by the medical ethics testing committee (METC) of both the University Medical Center Utrecht and Gelre Hospitals Apeldoorn (on 30 December 2008, Protocol ID: 07/343, EudraCT number 2006-005913-37).
For assignment of the participants a computer-generated list of random numbers was used. Patients were randomized to one of three treatment groups. The three groups all received four weekly intratympanic injections. Group 1 received placebo injections (sterile NaCl 0.9% solution), group 2 received two injections with gentamicin 40 mg/mL and two injections with placebo in random order, and group 3 received four injections with gentamicin 40 mg/mL. After treatment the intended follow-up period was 2 years. Three-monthly questionnaires were taken by telephone. If there was any problem the patients were free to contact one of the researchers and all the time they were free to withdraw from the study. At the end of the follow-up a last audiogram, ENG, and the DHI questionnaire were taken.
Primary outcome parameter was the total score on the Dizziness Handicap Inventory (DHI). The DHI is a standardized and validated questionnaire assessing impairments due to dizziness [16–18]. It comprises 25 items, leading to a score range from 0 to 100, with higher scores indicating more perceived impairments. The secondary outcome parameter was hearing loss. Intended follow-up was 2 years. Stopping criteria were the occurrence of SUSARs (Suspected Unexpected Serious Adverse Reactions), one of which was an average hearing deterioration of 30 dB or more over the frequencies of 500, 1,000, 2,000, and 4,000 Hz of the treated ear, or an average deterioration of 15 dB or more over the frequencies of 500, 1,000, 2,000, and 4,000 Hz at the contralateral ear. Harms were reported following the CONSORT extension for harms. During follow-up at the outpatient clinic, the audiograms of the patients were visually compared with the former audiograms.
Power analysis (alfa at 5% and power at 80%) showed that 16 patients per group were needed to show a clinically relevant difference of 12 points on the DHI scores between the three groups . The first interim analysis was planned to be performed when 18 patients were included.
DHI scores and hearing outcomes were compared between the three groups with non-parametric statistics, due to the small numbers (Kruskal Wallis test for continuous variables).