E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects suffering with noise and/or age-related tinnitus |
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E.1.1.1 | Medical condition in easily understood language |
Subjects suffering with noise and/or age-related tinnitus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Ear, nose and throat diseases [C09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042398 |
E.1.2 | Term | Subjective tinnitus |
E.1.2 | System Organ Class | 100000004854 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate a clinically- relevant improvement in tinnitus severity after repeat dosing in subjects with subjective tinnitus |
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E.2.2 | Secondary objectives of the trial |
• To further investigate if repeat administration of AUT00063 is safe and well tolerated;
• To assess the effect on the different domains of tinnitus;
• To assess the effect of repeat administration of AUT00063 on neural activity of the brain in subjects with tinnitus. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or Female, English-speaking, subjects ≥18 years of age who are UK residents registered with a UK General Practitioner
2. Experiencing stable tinnitus (consistent from day to day) with a Tinnitus Functional Index (TFI) score of ≥24 and ≤68;
3. Tinnitus has existed for not less than 6 months, and not more than 18 months at study start. Initially, recruitment will focus on subjects with tinnitus experienced up to 12 months prior to screening (sub-acute). However, recruitment rate will be actively monitored at weekly intervals and if it falls below target recruitment then the recruitment window will be extended up to 18 months (chronic).
4. Sensorineural hearing loss (Pure Tone Average (of thresholds at, 500, 1000, 2000 and 4000Hz) ≥20 and ≤60dB Hearing Loss (HL));
5. Normal Life expectancy for age of subject, as documented by the Investigator;
6. Female subjects of childbearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test on the randomisation and baseline assessment visit, and practice two reliable methods of contraception throughout the study. A female is considered of childbearing potential unless she is:
o Postmenopausal for at least 12 months prior to study drug administration;
o Without a uterus and/or both ovaries; or
o Has been surgically sterile for at least 6 months prior to study drug administration.
o Reliable methods of contraception are:
Hormonal methods or intrauterine device in use > 90 days prior to study drug administration;
Barrier methods plus spermicide in use at least 14 days prior to study drug administration; or
Vasectomised partner.
7. Able to understand and comply with the requirements of the study, and sign Informed Consent forms.
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E.4 | Principal exclusion criteria |
1. History of hypersensitivity or idiosyncratic reaction to any component of the test medication;
2. Any acute disabling illness;
3. Diabetes mellitus with an HbA1C >8% (64mmol/mol);
4. Previous cardiac rhythm disorders or ECG rhythm abnormalities whether symptomatic or not and considered clinically significant;
5. Severe hearing impairment such that verbal communication is unreliable;
6. History of important cardiac, endocrine, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major diseases deemed clinically significant at the time of the study by the Investigator and which might be jeopardised by entering the study;
7. Moderate or severe depression or generalised anxiety as indicated by a score of ≥11 out of 21 on the Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith 1983);
8. Alcohol or drug abuse, deemed clinically significant by the Investigator;
9. History of poor cooperation, non-compliance with medical treatment, or unreliability;
10. Participation in any clinical research study evaluating another investigational drug or therapy within 30 days or at least 5 half-lives (whichever is longer), of the investigational drug prior to consenting to study entry;
11. Participation in hearing study, involving an intervention, within 3 months from last study visit;
12. Use of central nervous system active drugs except analgesics and those as specified in section 10.2.2
13. Non-study treatments for the management of tinnitus, severe insomnia, major depressive disorder, severe anxiety, or post-traumatic stress disorder following baseline visit on D1; (NB counselling allowed as long as it has been implemented prior to screening visit)
14. Central nervous system pathologies e.g. Multiple Sclerosis, Parkinson’s disease;
15. Tinnitus as a concomitant symptom of a known otological condition (including but not limited to otitis externa, otitis media, otosclerosis, cholesteatoma, Ménière's disease or other vestibular problems, acoustic neuroma, or temporo-mandibular joint disorder);
16. Pulsatile tinnitus (rhythmical sounds that often beat in time with the heartbeat)
17. Intermittent tinnitus (comes and goes from one day to the next
18. Surgery or medical condition that would be expected to significantly affect absorption of medicines;
19. Presence or history of relevant severe adverse reaction to any drug or a history of sensitivity to potassium channel modulators;
20. Blood pressure and heart rate (in seated position) at the screening examination outside the ranges specified;
21. Corrected QTc interval < 330 msec at baseline in men or < 340 msec at baseline in females or > 450 msec at baseline for males and females.
22. Clinically-relevant out of range values in any haematology, urinalysis or clinical chemistry tests.
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E.5 End points |
E.5.1 | Primary end point(s) |
Effect on Tinnitus severity measured as a clinically significant change from baseline in TFI overall score between AUT00063 (800 mg) and placebo at Day 28 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at day 28 stop of treatment |
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E.5.2 | Secondary end point(s) |
The secondary efficacy variable will be the changes from baseline (D1) at Day 28 between treatment groups in Tinnitus loudness matching.
Other efficacy study variables will include the following:
• Percentage of subjects with a clinically significant change from baseline in TFI score between AUT00063 (800 mg) and placebo at on D28;
• Visual Analogue Scale tinnitus loudness (Q2 from TFI questionnaire) at D1 and D28
• Diary card assessment (including day to day variations);
• CGI score;
• LSEQ score;
• Statistically significant difference in Changes from baseline in one or more of the eight domains that comprise the TFI for AUT00063 vs. placebo.
. Safety Variables will include: Vital signs, physical examination findings, AEs, Laboratory data, ECG.
• Pharmacological electroencephalography (phEEG) (at least one study site at D1 and optional D28);
• Auditory Brainstem Response (performed by at least one site) at D1 and D28.
. Plasma Concentration of AUT00063 ng/ml, which will be measured as AUT00063 plasma levels at Day 28. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |