Methodological aspects of clinical trials in tinnitus: A proposal for an international standard

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Abstract

Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus.

Section snippets

Tinnitus is a world-wide problem of high prevalence and socio-economic relevance

Tinnitus, the phantom sensation of sound in the absence of overt acoustic stimulation, is a significant problem that negatively impacts the quality of life of patients throughout the world. Tinnitus is classified according to whether the perceived noise has an identifiable source (for example, myoclonic contractions of the tensor tympani muscle or blood vessels, objective tinnitus or somatosounds) versus the lack of a specific sound source (subjective tinnitus). Subjective tinnitus is by far

Evidence-based treatment options for tinnitus are limited

Available treatments for the management of tinnitus are diverse. Highest evidence for clinical efficacy is available for cognitive-behavioral therapies [20], [21]. Further established treatments include counseling [22] and various forms of sound therapies [23]; methods that attempt to increase input to the auditory system, such as hearing aids [24], [25] and cochlear implants [26] (for use in patients whose tinnitus is caused by deprivation of signals to the auditory nervous system);

The methodologic quality of clinical trials is variable

Many of the clinical trials in tinnitus have critical methodological limitations including: inappropriate outcome measures and statistical methods, insufficient sample sizes, poorly defined interventions, problems with study blinding and randomization and insufficient reporting of study details [33], [34], [35]. The heterogeneous quality of tinnitus treatment studies is echoed by all Cochrane Reviews regarding tinnitus treatment studies [20], [23], [36], [37], [38], [39] and has led to efforts

Specific methodological challenges for clinical trials in tinnitus

Since tinnitus is a purely subjective condition, its assessment is not trivial. Tinnitus loudness can be assessed by matching procedures or by visual analogue- or numeric rating scales. For the assessment of tinnitus related handicap several questionnaires have been developed and validated. Since no drug has yet been approved for the treatment of tinnitus [41], there is also no standard defined by regulatory authorities with respect to treatment outcome measures. However, variable outcome

There is an urgent need for better evidence of tinnitus treatments

The lack of good evidence hampers both decision making in the therapeutic management of tinnitus patients and the development of clinical guidelines [47], [48], [49]. In light of the urgent need to find effective treatments for the different forms of tinnitus, initiatives have been started to establish an expert consensus of how to clinically characterize tinnitus patients and how to measure outcomes in treatment trials [50]. Based on this consensus, an international database project has been

Clinical trials for investigating the treatment of tinnitus

Randomized clinical trial methodology has been established over many years, especially in the context of the process of drug development, and has resulted in a widely accepted standard. Clinical trials are differentiated according to different phases in the development of therapeutic interventions.

Preclinical trials are performed in vitro (e.g. in cell cultures) or in vivo in animal experiments to obtain preliminary efficacy and toxicity information. Several animal models of tinnitus [53], [54]

Key aspects of trial designs for the study of tinnitus treatments

Key aspects of trial designs in tinnitus patients will be considered as follows:

  • 1.

    Trial type (randomized controlled trials vs. open trials; sample sizes, power calculations)

  • 2.

    Control condition and blinding

  • 3.

    Trial duration

  • 4.

    Study population

  • 5.

    Outcome measures

  • 6.

    Statistical significance vs. clinical relevance

  • 7.

    Trial reporting

  • 8.

    Ethical aspects of clinical trials

A suggestion for a methodological standard of clinical trials in tinnitus

Clinical research in tinnitus is still a relatively young field. Performing clinical trials for evaluating treatment interventions in tinnitus is methodologically challenging for various reasons, which have been discussed above and are essentially related to the subjective nature of tinnitus, the heterogeneity of tinnitus, and the lack of established standards. At the same time, there is a clear need to improve the methodology of clinical trials in order to obtain reliable information about the

Competing interest statement

The authors have no competing interests to report.

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