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Hear Res. 2019 Jun;377:153-166. doi: 10.1016/j.heares.2019.03.018. Epub 2019 Mar 27.

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.

Author information

1
NIHR Nottingham Biomedical Research Centre, Ropewalk House, 113 The Ropewalk, Nottingham, NG1 5DU, UK; Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK; Nottingham University Hospitals NHS Trust, Queens Medical Centre, Derby Road, Nottingham, NG7 2UH, UK; University of Nottingham Malaysia, Jalan Broga, 43500, Semeniyh, Selangor Darul Ehsan, Malaysia. Electronic address: deborah.hall@nottingham.ac.uk.
2
Department of Ear, Nose and Throat Surgery, Royal Hallamshire Hospital and Sheffield Children's Hospital, Sheffield Children's NHS Foundation Trust, Sheffield, UK. Electronic address: jaydip.ray@sth.nhs.uk.
3
Autifony Therapeutics Ltd, Stevenage Biosciences Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK. Electronic address: jw@peptinnovate.com.
4
Autifony Therapeutics Ltd, Stevenage Biosciences Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK. Electronic address: alice.sharman@autifony.com.
5
Autifony Therapeutics Ltd, Stevenage Biosciences Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK. Electronic address: john.hutchison@autifony.com.
6
Autifony Therapeutics Ltd, Stevenage Biosciences Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK. Electronic address: peter.harris@autifony.com.
7
Nottingham University Hospitals NHS Trust, Queens Medical Centre, Derby Road, Nottingham, NG7 2UH, UK. Electronic address: msamd1@exmail.nottingham.ac.uk.
8
NIHR Nottingham Biomedical Research Centre, Ropewalk House, 113 The Ropewalk, Nottingham, NG1 5DU, UK. Electronic address: bonnie.millar@nottingham.ac.uk.
9
Autifony Therapeutics Ltd, Stevenage Biosciences Catalyst, Gunnels Wood Road, Stevenage, SG1 2FX, UK. Electronic address: charles.large@autifony.com.

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

PMID:
30939361
DOI:
10.1016/j.heares.2019.03.018
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