Clinical Trial of Acamprosate for Tinnitus
Condition: Tinnitus
MeSH terms: Tinnitus
Study type: Interventional
Phase: Phase 1

Summary: 
      The objective of this project is to determine whether acamprosate is more effective at
      providing relief for tinnitus than a placebo.

      Acamprosate has been suggested to be effective in reducing tinnitus annoyance in a
      preliminary study. Study evidence indicates that tinnitus is related to increased excitatory
      spontaneous brain activities. Acamprosate may help restore the excitatory/inhibitory balance
      in the brain and thus reduce 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.
    

Detailed description: 
      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.

      Short-term vs. long-term measures: Tinnitus loudness matching and MML measures provide
      quantitative measures about the immediate status of a subject's tinnitus. Loudness and
      annoyance are more integrative, depending on the subject's perception of the tinnitus, but
      are still reflective of the immediate tinnitus conditions of the subject. THI and TFI
      quantify the direct and indirect impact of the tinnitus on the individual. These tools
      evaluate tinnitus effects that are often cumulative over long periods of time (e.g.
      depression, insomnia, changes in social interactions). Medications that alter brain chemistry
      may have an impact on either or both short and long-term tinnitus measures so both categories
      are being evaluated.

      Treatment: Subjects will randomly be assigned to Group 1 (A/B) or Group 2 (B/A) after
      completion of Phase I and its subsequent washout period (Figure 1, periods 1 and 2). Group 1
      will receive acamprosate (Campral) at a dose of 666 mg. three times daily for 24 weeks
      followed by a 4-week washout period and then by taking matched placebos for next 24 weeks.
      Group 2 will receive placebo for 24 weeks followed by a washout and 24 week acamprosate
      trial. The experiment will be double-blinded. The subjects will know that they could be
      taking either a placebo or acamprosate. To insure subjects are blind to the intervention, the
      Campral will be placed in identical capsules to those used for the cellulose placebos that
      will be produced for the study.

      Data acquisition: VAS sheets will be completed during the initial Phase II baseline visit and
      6 sets of time/dated sheets (one for loudness, one for annoyance, plus two spare sheets) will
      be sent home with subjects. Equivalent sets of the THI, TFI and MOCI will be included with
      the VAS sheets and subjects given instruction (verbally and in writing) on how to complete
      and return all data sheets in self-addressed stamped envelopes. Sheet acquisition will follow
      the course that it did in Phase I, however, they will only be collected monthly instead of
      weekly. The subject will return to the clinic after 24 weeks for testing including VAS, THI,
      TFI and MOCI evaluations. At that time they will receive their supply of capsules (medication
      or placebo) and new sets of VAS, THI and MOCI sheets and mailing envelopes for the second
      period of Phase II (Figure 1, period 5).

      Psychoacoustic measures of tinnitus will be measured during the baseline visit, during the
      24-week return visit, and at the conclusion of the 52-week study.
    

Intervention name(s): Acamprosate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Oral administration, 666 mg, tid, for 4 months; Oral administration of 2 pills, tid, for 4 months
Other intervention name(s): Campral
Intervention MeSH terms: Acamprosate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Tinnitus; acamprosate; clinical trial