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    Clinical Trial Results:
    A Balanced Randomised Placebo Controlled Double-blind Phase IIa Study to Investigate the Efficacy and Safety of AUT00063 Versus Placebo in Subjective Tinnitus

    Summary
    EudraCT number
    		 2014-002179-27
    Trial protocol
    		 GB  
    Global end of trial date
    02 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Dec 2016
    First version publication date
    08 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AUT032063
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02315508
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Autifony Therapeutics Ltd
    Sponsor organisation address
    Imperial College Incubator, London, United Kingdom, SW7 2AZ
    Public contact
    Alice Grant, Autifony Therapeutics Limited, +44 (0)203 763 9477, alice.grant@autifony.com
    Scientific contact
    John Hutchison, Autifony Therapeutics Limited, john.hutchison@autifony.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate a clinically- relevant improvement in tinnitus severity after repeat dosing in subjects with subjective tinnitus
    Protection of trial subjects
    Before they were screened for the study, Investigators were responsible for informing all subjects of the study design, possible benefits, risks, and outcomes of the treatment, the test products used, and the insurance policy. Subjects were provided with the Ethics approved Participant Information Sheet and given time to consider their participation. Subjects had to provide written informed consent before they entered the study. Safety assessments were conducted at Screening, pre- and post-dose on Day 1, Day 28 and Day 42 (two weeks after last dose). Subjects were also contacted on Day 14 to collect any adverse events and concomitant medications. Safety assessments included: vital signs (blood pressure, heart rate, respiration rate and body temperature), ECGs, physical examinations, safety haematology and biochemistry blood tests. Subjects were excluded at Screening if any of the safety assessments were out of normal range and deemed clinically significant by the Investigator. Stopping criteria were listed in the protocol and included (non-exhaustive) liver chemistry results, an SAE that is considered to be possibly or probably related to the study treatment, an adverse event or protocol deviation occurs that, in the opinion of the investigator, makes it unsafe for the subject to continue in the study. An Independent Data Monitoring Committee (IDMC) reviewed the unblinded safety data on an approximately quarterly basis. The IDMC also conducted one planned interim analysis once approximately 50% of the study subjects had been enrolled and completed the study up to Day 28. The interim analysis focused on an analysis of the primary efficacy endpoint and an assessment of the safety data. The IDMC could recommend termination or modification of the study based upon a review of the totality of the safety and primary efficacy data.
    Background therapy
    		 N/A
    Evidence for comparator
    		 A placebo comparator was used in this study as there are currently no approved pharmaceutical treatments for tinnitus. The study was randomised in order to prevent bias in the allocation of treatment and to ensure the comparability of baseline characteristics between the treatment groups. In order to prevent bias in the conduct of the clinical assessments, the study was double blind, so that neither the investigator nor the subject knew whether the subject was receiving active treatment or placebo. Minimisation techniques were employed to balance stratification variables across the two arms.
    Actual start date of recruitment
    10 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    78
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited at 18 NHS hospitals across England between 10 November 2014 and 08 Oct 2015.

    Pre-assignment
    Screening details
    		 A total of 212 subjects provided informed consent and attended for a screening examination. Of these, 91 satisfied inclusion and exclusion criteria and were randomised into the study, the first subject being randomised on 15 Jan 2015; last subject on 07 Oct 2015.

    Pre-assignment period milestones
    Number of subjects started
    		 212 [1]
    Number of subjects completed
    		 91

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen Fail: 121
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects enrolled was considered as the number of subjects dosed on study, e.g. 91 subjects. The number of subjects that were consented and screened was 212, of these 121 subjects failed screening.
    Period 1
    Period 1 title
    Baseline Pre-dose Day 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    A telephone based Interactive Voice Response System (IVRS) was used to allocate subjects to active or placebo treatments

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AUT00063 800mg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AUT00063
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    N/A - Pre-dose

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    N/A - Pre-dose

    Number of subjects in period 1
    		AUT00063 800mg Placebo
    Started
    44
    47
    Completed
    44
    47
    Period 2
    Period 2 title
    Dosing - Day 1 to Day 28
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    A telephone based Interactive Voice Recognition System (IVRS) was used to randomise subjects to either active or placebo arms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AUT00063 800mg
    Arm description
    		 Subjects were required to take 4 x 200mg capsules of AUT00063 to achieve the 800mg dose, once daily after food.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AUT00063
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were required to take 4 x 200mg capsules of AUT00063 to achieve the 800mg dose, once daily after food.

    Arm title
    		 Placebo
    Arm description
    		 Subjects were required to take 4 capsules once daily after food. Placebo capsules visually match AUT00063 capsules.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were required to take 4 capsules once daily, after food. Placebo capsules visually match AUT00063 capsules.

    Number of subjects in period 2
    		AUT00063 800mg Placebo
    Started
    44
    47
    Completed
    34
    39
    Not completed
    10
    8
         Consent withdrawn by subject
    1
    -
         Physician decision
    1
    -
         Study closed to recruitment
    -
    1
         Study terminated by Sponsor
    6
    5
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    1
    1
    Period 3
    Period 3 title
    Follow Up - Day 29 to Day 42
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AUT00063 800mg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AUT00063
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    N/A

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    N/A

    Number of subjects in period 3
    		AUT00063 800mg Placebo
    Started
    34
    39
    Completed
    33
    38
    Not completed
    1
    1
         Incomplete visit
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AUT00063 800mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 AUT00063 800mg Placebo Total
    Number of subjects
    		 44 47 91
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 38 40 78
        From 65-84 years
    		 6 7 13
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 10 10 20
        Male
    		 34 37 71

    End points

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    End points reporting groups
    Reporting group title
    AUT00063 800mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    AUT00063 800mg
    Reporting group description
    		 Subjects were required to take 4 x 200mg capsules of AUT00063 to achieve the 800mg dose, once daily after food.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were required to take 4 capsules once daily after food. Placebo capsules visually match AUT00063 capsules.
    Reporting group title
    AUT00063 800mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Compare the change from baseline (D1 to D28) of the TFI overall score between AUT00063 (800 mg) and placebo

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    End point title
    		 Compare the change from baseline (D1 to D28) of the TFI overall score between AUT00063 (800 mg) and placebo
    End point description
    TFI = Tinnitus Functional Index
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose Day 1) to Day 28
    End point values
    		 AUT00063 800mg Placebo
    Number of subjects analysed
    36
    40
    Units: TFI Score change from baseline
        arithmetic mean (standard deviation)
    -1.57 ( 15.215 )
    -5.8 ( 13.861 )
    Statistical analysis title
    		 Change from baseline in TFI overall score at Day28
    Statistical analysis description
    The changes from baseline in TFI score were analysed by means of an ANCOVA model controlling for the randomised factor age, gender, hearing loss and tinnitus severity and with baseline values of TFI, tinnitus duration and Noise Exposure Questionnaire overall score as covariates.
    Comparison groups
    AUT00063 800mg v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.9842
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - The primary efficacy variable will be the effect on Tinnitus severity measured as a clinically significant change (which is considered to be reached at a 13-point mean difference – (Meikle et al., 2012) from baseline in TFI overall score between AUT00063 (800 mg) and placebo at Day 28.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 post dose to Follow Up visit(Day 42)
    Adverse event reporting additional description
    Adverse events were collected at all study visits, from diary card entries (Day 2 -27) and one phone call on Day 14. All adverse events (AEs) were recorded in the CRF. AEs were followed-up until the event is resolved or no queries are outstanding when the subject completes the study (End of Study visit).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    AUT00063 800mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 AUT00063 800mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 47 (2.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia unknown origin
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
    Additional description: Anxiety attack
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AUT00063 800mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 44 (72.73%)
    23 / 47 (48.94%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 44 (29.55%)
    9 / 47 (19.15%)
         occurrences all number
    25
    14
    Dizziness
         subjects affected / exposed
    7 / 44 (15.91%)
    0 / 47 (0.00%)
         occurrences all number
    16
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 47 (2.13%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 47 (2.13%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 47 (2.13%)
         occurrences all number
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2014
    Changes requested by the MHRA - Exclusion criteria was amended to include QTc > 450 msec at baseline. - Emergency un-blinding procedure amended to permit rapid un-blinding. - Inclusion criteria amended to ensure that females of child-bearing potential use two methods of contraception during the trial and at least 30 days after the last dose. - Other non-substantial administrative changes
    13 Nov 2014
    - Testing conditions (250Hz have been deleted) and limits of the sensorineural hearing loss (Inclusion criteria 4.) have been amended to include: =20dB and =60dB. - Exclusion criterion 18. has been changed to only those surgeries or medical conditions that are expected to significantly affect absorption of medicines. - Prohibited concomitant treatments have been amended to remove exclusion of strenuous exercise from screening until day 42. - Other non-substantial changes for clarification
    09 Feb 2015
    - Randomization the minimisation factor “hearing loss” has been amended to include two more pure tone average thresholds at 6 and 8 kHz. - The hearing loss definitions have been amended to mild = ≤40 dB and moderate = ≥41 dB. - Subject Inclusion Criteria the 4th item has been changed to “Sensorineural hearing loss defined by any single audiometric threshold estimate >20 dB for frequencies at 0.5, 1, 2, 4, 6 and 8 kHz, and a Pure Tone Average (of thresholds at, 500, 1000, 2000 and 4000Hz) ≤60dB Hearing Loss (HL)). - The following paragraph has been added to Screening description: Where one or more correctable exclusion criteria are found at screening, after appropriate management the subject can be re-screened. - Interim Analysis and Sample Size Review, the interim analysis has been adapted to be performed when approximately 50% subjects have been enrolled and completed the study up to day 28 which is when the primary efficacy and substantial amount of safety data is available. - Other non-substantial changes
    02 Jul 2015
    - Description of Pre-Screening activities ‘….at the site.” was changed to “within and/or between sites’ to clarify that the data will be interchanged between the sites. - Other non-substantial changes

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Oct 2015
    Following the planned unblinded interim analysis, which was conducted once around 50% of subjects had completed Day 28, on the 30 Sept 2015, the recommendation of the IDMC was to discontinue the QUIET-1 study based on efficacy data. This recommendation was a consequence of the p-value of the primary analysis exceeding the futility boundary stated in the protocol. No safety issues were identified. On the basis of this recommendation and following an internal review of the data by Autifony, Autifony decided to terminate enrolment into the QUIET-1 study, effective from 08 Oct 2015.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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