@article{1b3cb179801046a99f65c3fb353488a6,
title = "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",
abstract = "AUT00063 is an experimental new medicine that has been demonstrated to suppress spontaneous hyperactivity by modulating the action of voltage-gated potassium-channels in central auditory cortical neurons of a rodent model. This neurobiological property makes it a good candidate for treating the central component of subjective tinnitus but this has not yet been tested in humans. The main purpose of the QUIET-1 (QUest In Eliminating Tinnitus) trial was to examine the effect of AUT00063 on the severity of tinnitus symptoms in people with subjective tinnitus. The trial was a randomised, placebo-controlled, observer, physician and participant blinded multi-centre superiority trial with two parallel groups and a primary endpoint of functional impact on tinnitus 28 days after the first drug dosing day. The trial design overcame the scale and logistical challenges of delivering a scientifically robust, statistically powered multi-centre study for subjective tinnitus within the National Health Service in England. The trial was terminated early for futility. Overall, 212 participants consented across 18 sites with 91 participants randomised to groups using age, gender, tinnitus symptom severity and hearing status as minimisation factors. While the pharmacokinetic markers confirm the uptake of AUT00063 in the body, within the expected therapeutic range, with respect to clinical benefit findings indicated that AUT00063 was not effective in alleviating tinnitus symptoms (1.56 point change in Tinnitus Functional Index). In terms of clinical harms, results indicated that a daily dose of 800 mg capsules of AUT00063 taken for 28 days was safe and well tolerated. These findings provide significant advances in the drug development field for hearing sciences, but raise questions about the predictive validity of certain rodent models of noise-induced hearing loss and tinnitus, as least for the mechanism evaluated in the present study. Trial Registration: (EudraCT) 2014-002179-27; NCT02315508.",
keywords = "AUT00063, Clinical trial, Hyperactivity, Noise exposure, Potassium channels, Tinnitus",
author = "Hall, {Deborah A.} and Jaydip Ray and Jeannette Watson and Alice Sharman and John Hutchison and Peter Harris and Matija Daniel and Bonnie Millar and Large, {Charles H.}",
note = "Funding Information: The QUIET-1 team acknowledges the support of the National Institute of Health Research Clinical Research Network (NIHR CRN) in participant recruitment. The protocol was co-developed by authors, with expert opinion provided by the Contract Research Organisation (http://www.cromsource.com/). We thank clinical and research staff at the following recruiting sites: Nottingham University Hospitals NHS Trust, Sheffield Teaching Hospitals NHS Foundation Trust, University Hospitals Birmingham NHS Foundation Trust, University College London Hospital NHS Trust, Shrewsbury and Telford Hospital NHS Trust, The Newcastle upon Tyne Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Wigan and Leigh NHS Foundation Trust, Salford Royal NHS Foundation Trust, University Hospital of North Staffordshire NHS Trust, The Pennine Acute Hospitals NHS Trust, Frimley Health NHS Foundation Trust, Portsmouth Hospitals NHS Trust, The Norfolk and Norwich Hospitals NHS Foundation Trust, East and North Hertfordshire NHS Trust, and Plymouth Hospitals NHS Trust. Thanks also to Jordi Lara for data analysis. This work was supported by an INNOVATE UK late-stage Biocatalyst award to Autifony Therapeutics Ltd and University of Nottingham [grant reference 35370-247243]. DAH is an NIHR Senior Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Funding Information: The QUIET-1 team acknowledges the support of the National Institute of Health Research Clinical Research Network (NIHR CRN) in participant recruitment. The protocol was co-developed by authors, with expert opinion provided by the Contract Research Organisation ( http://www.cromsource.com/ ). We thank clinical and research staff at the following recruiting sites: Nottingham University Hospitals NHS Trust , Sheffield Teaching Hospitals NHS Foundation Trust , University Hospitals Birmingham NHS Foundation Trust , University College London Hospital NHS Trust, Shrewsbury and Telford Hospital NHS Trust , The Newcastle upon Tyne Freeman Hospital , The Newcastle upon Tyne Hospitals NHS Foundation Trust , Wigan and Leigh NHS Foundation Trust , Salford Royal NHS Foundation Trust , University Hospital of North Staffordshire NHS Trust , The Pennine Acute Hospitals NHS Trust , Frimley Health NHS Foundation Trust , Portsmouth Hospitals NHS Trust , The Norfolk and Norwich Hospitals NHS Foundation Trust , East and North Hertfordshire NHS Trust , and Plymouth Hospitals NHS Trust . Thanks also to Jordi Lara for data analysis. This work was supported by an INNOVATE UK late-stage Biocatalyst award to Autifony Therapeutics Ltd and University of Nottingham [grant reference 35370-247243 ]. DAH is an NIHR Senior Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jun,
doi = "10.1016/j.heares.2019.03.018",
language = "English",
volume = "377",
pages = "153--166",
journal = "Hearing Research",
issn = "0378-5955",
publisher = "Elsevier",
}