Tinnitus Clinical Trial - Frequently Asked Questions
Q. What is the QUIET-1 study?
A. The QUIET-1 study is a clinical study to determine whether or not a new test drug, AUT00063, can reduce symptoms of tinnitus in comparison to a placebo (dummy drug) after 4 weeks of treatment.
Q. What is AUT00063?
A. This is a synthetic small molecule which modulates specific voltage gated potassium ion channels present on certain nerve cells important for hearing; the safety and tolerability of "063" has been tested in a group of healthy volunteers but the QUIET-1 study is the first test in people with tinnitus.
Q. Can I have some details of the drug itself, and how was administered during the trial?
A. AUT00063 is an orally active preparation that was taken as 4 capsules once daily with breakfast each day continuously for 28 days. This drug is presented in yellow capsules each of 200mg. Special tests and important questionnaires compared tinnitus on day 28 with day 1 of taking "063".
Q. Why has the trial been stopped?
A. Autifony Therapeutics has just completed the interim analysis on the QUIET-1 tinnitus clinical trial with AUT00063, and has received a recommendation from the Independent Data Monitoring Committee to terminate recruitment, based on the 58 subjects analysed, due to lack of efficacy. The Committee compared the outcome of the AUT00063-treated subjects with those that received placebo, and concluded that on a statistical basis it would not be possible to reach the magnitude of positive outcome needed to show improvement over the control.
Q. Why do you think the trial failed to show any benefit to tinnitus sufferers?
A. We don’t yet know that. At present, we only know that the aggregated, group data did not show any beneficial effect of AUT00063 on Tinnitus compared to placebo. We will analyse all the data in detail over the next weeks and months, to explore if any subgroups may have benefited from treatment and to see what can be learned from the study.
Q. Will you publish your findings?
A. We are committed to ensuring that our research can help inform future studies and committed to publishing our data , particularly as we are likely to learn things that could add to the understanding of tinnitus, as well as about future clinical trial design. These are all things may help further research in the area.
Q. Were there any safety issues? Does this mean that AUT00063 development will be discontinued now?
A. Importantly, there were no safety or tolerability issues identified with AUT00063 in this study. The Age Related Hearing Loss trial, “CLARITY” with AUT00063 that we are conducting in the US will continue as planned. The scientific rationale and the clinical endpoints for the CLARITY trial are completely different to the tinnitus study, and the absence of efficacy of AUT00063 in the QUIET-1 tinnitus trial does not alter our belief that we have the potential to provide benefit in other hearing indications.
Q. What about the people who have taken AUT00063 as part of this trial? Should they have any reason for concern?
A. No, as mentioned before, there were no safety or tolerability issues identified with AUT00063. We have only seen aggregate data to date and do not know if AUT00063 is having an effect at the individual level. We are very grateful to everyone who volunteered to take part in the study.
Q. Will subjects from the Tinnitus study be told if they were on drug or placebo?
A. Yes, eventually, but first we need to continue to analyse the data in a so-called blinded manner i.e. without knowing who took what, so that we are not biased in evaluating effects. When the analysis is fully complete, Autifony will be sharing a code-break with each site to let subjects know what they took as well as any outcomes.
Q. What does this mean for Autifony?
A. This is extremely disappointing news for us as well as for patients, as we had invested a huge amount of resources and effort, together with support from Innovate UK, in the hope that AUT00063 would prove to be a breakthrough in tinnitus treatment. However, unfortunately failure to show efficacy is not an unusual event in drug discovery and development, where as few as one in ten drug candidates that enter clinical trials result in a new medicine on the market. In parallel to the detailed evaluation of the tinnitus data to see where this will lead for tinnitus sufferers, Autifony will continue its other programmes, which include the evaluation of AUT00063 in age-related hearing loss, and the development of a new molecule for the treatment of schizophrenia.
Q. Do you think the short duration of the QUIET-1 trial was to blame for the observed lack of efficacy?
A. We acknowledge that the length of the treatment period in the QUIET-1 study (28 days) was not as long as in some past tinnitus trials, and we are aware that some drugs may take longer than 1 month to produce a significant effect. The 28 day limit was partly set by the limit of the safety data that we have from AUT00063, but in addition, we have routinely seen rapid, acute effects of the drug in preclinical models of hearing loss and tinnitus, so it was a reasonable to think that an effect might be seen in patients within 1 month.
Q. Does Autifony plan to continue research and drug development for tinnitus sufferers?
A. We will first ensure that we have understood all of the data from the QUIET-1 study, and we will consider whether there is reason to believe that Kv3 modulation still has potential to treat tinnitus (or perhaps a subgroup of tinnitus). Autifony is also looking at other targets that could be considered for this disorder since we know there is such a high unmet need.
Q. Can you explain why you were so sure to stop the trial after only half of the subjects have been evaluated?
A. Demonstration of efficacy in a placebo-controlled clinical trial such as QUIET-1 requires that there is a clear and statistically significant difference in treatment response between active drug (AUT00063) and placebo on the “primary outcome measure”. In QUIET-1, the primary outcome measure was the Tinnitus Functional Index, which is a well validated scale for assessing the severity of a person's tinnitus. We intended to recruit up to 152 subjects to be sure to have enough to test our hypothesis that AUT00063 improved tinnitus, but we planned the interim analysis after 50-60 subjects in order to check that the trial was going in the right direction, and to ensure there were no safety issues. There were no safety issues, but the TFI data from 58 subjects completed showed no indication of any effect of AUT00063 compared to placebo, and using statistical models we can be sure that even if we were to continue through to 152 subjects, this result would be highly unlikely to change.
Q. Now the study has closed, will Autifony suggest possible treatment or therapy?
A. Companies such as Autifony are not allowed to offer specific personal advice on healthcare to the general public; this is a matter for discussion with your GP or specialist. The British Tinnitus Association website www.tinnitus.org.uk has information on various forms of management.