A balanced randomised placebo controlled blinded phase IIa multi-centre study to investigate the efficacy and safety of AUT00063 versus placebo in subjective tinnitus: The QUIET-1 trial

Hall, Deborah A.; Ray, Jaydip; Watson, Jeannette; Sharman, Alice; Hutchison, J.B.; Harris, Peter Q.; Daniel, Matija; Millar, Bonnie; Large, Charles H.

doi:10.1016/j.heares.2019.03.018

Cited by 17 publications

(13 citation statements)

References 34 publications

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“…Animal research suggests that the drug is very effective at reducing hyperactivity in the auditory brainstem after noise exposure in rodents (Anderson et al, 2018; Glait et al, 2018) and hence might be expected to be effective against similarly generated tinnitus in humans. However, a randomized controlled trial of AUT00063 in humans with subjective tinnitus, QUIET-1, was halted because of lack of efficacy (Hall et al, 2019b). This discrepancy between animal models of tinnitus and clinical trials in humans has various possible explanations: firstly, the pathophysiology of tinnitus in humans may be different from that of laboratory animals (and there remain significant questions about whether the animals do experience tinnitus, and whether our methods for detecting the symptom are reasonable).…”

Section: Obstacles To a Curementioning

confidence: 99%

Why Is There No Cure for Tinnitus?

et al. 2019

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Tinnitus is unusual for such a common symptom in that there are few treatment options and those that are available are aimed at reducing the impact rather than specifically addressing the tinnitus percept. In particular, there is no drug recommended specifically for the management of tinnitus. Whilst some of the currently available interventions are effective at improving quality of life and reducing tinnitus-associated psychological distress, most show little if any effect on the primary symptom of subjective tinnitus loudness. Studies of the delivery of tinnitus services have demonstrated considerable end-user dissatisfaction and a marked disconnect between the aims of healthcare providers and those of tinnitus patients: patients want their tinnitus loudness reduced and would prefer a pharmacological solution over other modalities. Several studies have shown that tinnitus confers a significant financial burden on healthcare systems and an even greater economic impact on society as a whole. Market research has demonstrated a strong commercial opportunity for an effective pharmacological treatment for tinnitus, but the amount of tinnitus research and financial investment is small compared to other chronic health conditions. There is no single reason for this situation, but rather a series of impediments: tinnitus prevalence is unclear with published figures varying from 5.1 to 42.7%; there is a lack of a clear tinnitus definition and there are multiple subtypes of tinnitus, potentially requiring different treatments; there is a dearth of biomarkers and objective measures for tinnitus; treatment research is associated with a very large placebo effect; the pathophysiology of tinnitus is unclear; animal models are available but research in animals frequently fails to correlate with human studies; there is no clear definition of what constitutes meaningful change or “cure”; the pharmaceutical industry cannot see a clear pathway to distribute their products as many tinnitus clinicians are non-prescribing audiologists. To try and clarify this situation, highlight important areas for research and prevent wasteful duplication of effort, the British Tinnitus Association (BTA) has developed a Map of Tinnitus. This is a repository of evidence-based tinnitus knowledge, designed to be free to access, intuitive, easy to use, adaptable and expandable.

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Section: Obstacles To a Curementioning

confidence: 99%

Why Is There No Cure for Tinnitus?

et al. 2019

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“…Many other treatments decreasing tinnitus percept or targeting central auditory processing pathways are at a preclinical phase (Schilder et al, 2019). The modulator of voltage-gated potassium channels (Kv3.1) (AUT00063) was not effective in alleviating tinnitus symptoms (Hall et al, 2019b).…”

Section: Pharmacology-based Interventionsmentioning

confidence: 99%

Multidisciplinary Tinnitus Research: Challenges and Future Directions From the Perspective of Early Stage Researchers

Simões

Daoud

Shabbir

et al. 2021

Front. Aging Neurosci.

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Tinnitus can be a burdensome condition on both individual and societal levels. Many aspects of this condition remain elusive, including its underlying mechanisms, ultimately hindering the development of a cure. Interdisciplinary approaches are required to overcome long-established research challenges. This review summarizes current knowledge in various tinnitus-relevant research fields including tinnitus generating mechanisms, heterogeneity, epidemiology, assessment, and treatment development, in an effort to highlight the main challenges and provide suggestions for future research to overcome them. Four common themes across different areas were identified as future research direction: (1) Further establishment of multicenter and multidisciplinary collaborations; (2) Systematic reviews and syntheses of existing knowledge; (3) Standardization of research methods including tinnitus assessment, data acquisition, and data analysis protocols; (4) The design of studies with large sample sizes and the creation of large tinnitus-specific databases that would allow in-depth exploration of tinnitus heterogeneity.

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“…It is worth noting that the studies of the molecular mechanisms of tinnitus have also made some progress [178,179]. Most of the medications treating tinnitus are off-label use, and drugs specifically developed for tinnitus have been proven ineffective [118,122,124]. The efficacy of the same drug observed in different studies might be inconsistent, and the incidence of side effects is higher than tinnitus management.…”

Section: Discussion On Tinnitus Medications and Managementmentioning

confidence: 99%

“…Indeed, AUT00063 has been shown to inhibit spontaneous hyperactivity induced by noise exposure in the fusiform cells of the dorsal cochlear nucleus, as well as multiunit activity recorded in the inferior colliculus in mice [122,123]. However, a daily dose of 800 mg AUT00063 for 28 days showed safety and tolerance but resulted in no change in TFI scores [124]. Patients with intermittent typewriter-like tinnitus all responded positively to carbamazepine, and therefore, it is speculated that carbamazepine alleviates tinnitus by hindering the recovery from inactivation of the voltage-gated sodium channel and thus suppressing subsequent ephaptic axonal transmission in the cochlear nerve [125].…”

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confidence: 99%

Auditory Neural Plasticity in Tinnitus Mechanisms and Management

Wang

Tang

et al. 2020

Neural Plasticity

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Tinnitus, which is the perception of sound in the absence of a corresponding external acoustic stimulus, including change of hearing and neural plasticity, has become an increasingly important ailment affecting the daily life of a considerable proportion of the population and causing significant burdens for both the affected individuals and society as a whole. Here, we briefly review the epidemiology and classification of tinnitus, and the currently available treatments are discussed in terms of the available evidence for their mechanisms and efficacy. The conclusion drawn from the available evidence is that there is no specific medication for tinnitus treatment at present, and tinnitus management might provide better solutions. Therapeutic interventions for tinnitus should be based on a comprehensive understanding of the etiology and features of individual cases of tinnitus, and more high quality and large-scale research studies are urgently needed to develop more efficacious medications.

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A balanced randomised placebo controlled blinded phase IIa multi-centre study to investigate the efficacy and safety of AUT00063 versus placebo in subjective tinnitus: The QUIET-1 trial

Cited by 17 publications

References 34 publications

Why Is There No Cure for Tinnitus?

Why Is There No Cure for Tinnitus?

Multidisciplinary Tinnitus Research: Challenges and Future Directions From the Perspective of Early Stage Researchers

Auditory Neural Plasticity in Tinnitus Mechanisms and Management

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