Clinical Trial of Acamprosate for Tinnitus

The current study includes three phases. The first phase is an open-label screening study used to identify tinnitus subjects responding to acamprosate. These responding subjects will enter the second phase, which is a double blind, placebo-controlled study aimed at confirming the subjects' responses to acamprosate. In the third phase, clinical parameters of both responders and non-responders will be compared using a multi-linear regression model to determine characteristics that define the sub-group of tinnitus patients that are likely to benefit from acamprosate treatment. Participation in the study requires that individuals come to Portland, Oregon at least 6 times over 16 months for evaluation and data collection.

Measurements: Subjects will be brought in for baseline evaluation for Phase II four weeks after finishing their course of acamprosate during Phase I. Subjects will receive a full audiometric evaluation. Subjects with active otologic disease at that time will be excused. Tinnitus pitch and loudness matching per Johnson and Goodwin, (1981) will be performed noting octave confusion. Loudness matching will be performed using a 1 kHz tone presented to the ear contralateral to the tinnitus of interest to minimize complications tinnitus was often too high a level to test (beyond the limits of the equipment). This problem occurs less often when using a 1 kHz comparison tone because most subjects have reasonable auditory thresholds at that frequency. Minimum masking levels (MML) will be determined by measuring the level at which a 2 kHz to 12 kHz band of noise completely masks the tinnitus in the ipsilateral ear. Residual inhibition or post-masking change testing will be conducted at the end of the tinnitus testing. The 2 kHz to 12 kHz band of noise will be elevated to 10 dB above the MML (if tolerable) and remain on continuously in the ear ipsilateral to the tinnitus for 60 seconds. At that point, the masking will be turned off and the subject will be asked to identify any changes in their perceived tinnitus. If partial or complete residual inhibition occurs, their duration will be timed with a stopwatch and recorded. Subjects will also be instructed to complete VAS scores for tinnitus loudness and annoyance, the Tinnitus Handicap Inventory (THI; Newman et al, 1996) which is a 25-item questionnaire that is currently the most widely used estimator of the impact of tinnitus on an individual daily life, and the Maudsley Obsessional-Compulsive Inventory (MOCI; Rachman and Hodgson, 1980) questionnaire, which will not be used as a primary outcome measurement, but will be used in the multiple linear regression analysis of Phase III. Upon completing Phase II of the study, the subjects who do not experience improvements in their tinnitus from acamprosate will be given information about other tinnitus management options and given the opportunity to be evaluated and managed at the OHSU Tinnitus Clinic.

The primary outcome measures for Phase II will include:

Rated tinnitus loudness: VAS scores for tinnitus loudness Rated tinnitus loudness: VAS scores for tinnitus annoyance Tinnitus Severity: Tinnitus Handicap Index Matched tinnitus loudness: Loudness match re: 1kHz tone in the contralateral ear to tinnitus (unless subject has bilateral or unilateral profound hearing loss) Minimum Masking Level: MML with broad band noise in ipsilateral ear to tinnitus (unless subject has bilateral or unilateral profound hearing loss) The Prototype 2 of the Tinnitus Functional Index is a 30-question evaluation tool currently under development with funding from the Tinnitus Research Consortium through a multi-center study hosted by the OHRC. The TFI will serve as a secondary outcome measure of tinnitus severity in Phases II and III. Thus far in development, the TFI has demonstrated good reliability, validity and high sensitivity to measuring treatment-related changes in tinnitus severity (responsiveness). The TFI has not been published, but the investigators believe that it would be beneficial to this study and provide an opportunity to use the TFI in a new clinical setting.

The primary outcomes measures and the MOCI and TFI will be recorded five times during the study: At the baseline visit (Figure 1, beginning of period 3), at the end of the first 24 weeks (between periods 3 and 4), at the end of the wash out period (between periods 4 and 5), at the end of the second 24-week period (end of period 5) and 4 weeks after the completion of the Phase I trial. All audiometric and tinnitus measures and the questionnaire scores will be entered into the PATS data base.