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    Clinical Trial Results:
    A Pilot Double-blind, Placebo-controlled Crossover Study to Explore the Possible Benefit of AUT00063, an Oral Modulator of Voltage-gated Potassium Channels, in Adult Post-lingual Unilateral Cochlear Implant Recipients: The QuicK+fire-study

    Summary
    EudraCT number
    		 2015-003929-34
    Trial protocol
    		 GB  
    Global end of trial date
    10 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Apr 2018
    First version publication date
    11 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AUT042063
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02832128
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Autifony Therapeutics Limited
    Sponsor organisation address
    Stevenage Bioscience Catalyst, Stevenage, United Kingdom,
    Public contact
    Clinical Project Manager, Autifony Therapeutics Limited , info@autifony.com
    Scientific contact
    Clinical Project Manager, Autifony Therapeutics Limited , +44 203 763 9477, alice.sharman@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
    28 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this pilot study was to explore whether repeat doses of AUT00063 can provide an indication of improvement in performance of tests across a battery of speech and hearing assessments in Cochlear Implant (CI) users. For this purpose, the performance of volunteers who recently received a unilateral CI for post-lingual deafness was assessed by means of speech tests such as the tests comprising the new Minimum Speech Test Battery (MSTB) (Advanced Bionics 2011). The study also explored the effects of repeat doses of AUT00063 on parameters of central auditory processing measured using tests that involve direct stimulation via the CI. In addition, the safety and tolerability of AUT00063 was evaluated in the study subjects. Fifteen subjects were randomised in a 1:1 ratio to receive either AUT00063 (800 mg/day) or matched placebo for 28 days, followed by a 2- to 4-week washout period before commencing the second 28-day dosing period with the other medication.
    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 and Day 28 in both periods and Day 42 (two weeks after last dose). Subjects were also contacted on Day 14 of both periods to collect any adverse events and concomitant medications. Safety assessments included: vital signs (blood pressure, heart rate, and 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 was considered to be possibly or probably related to the study treatment, an adverse event or protocol deviation that occurred that, in the opinion of the investigator, made it unsafe for the subject to continue in the study.
    Background therapy
    		 N/A
    Evidence for comparator
    		 A placebo comparator was used in this study as there are currently no approved pharmaceutical interventions to improve hearing.
    Actual start date of recruitment
    05 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    6
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited in the UK (only) between July 2016 and December 2016. Fifteen subjects were enrolled; 8 subjects in the AUT00063 - Placebo group and 7 subjects in the Placebo - AUT00063. All 8 subjects in the AUT00063 - Placebo group completed both periods. Four subjects in the Placebo - AUT00063 group completed and 3 dropped out.

    Pre-assignment
    Screening details
    		 A total of 21 subjects attended screening visits. Of these, 15 satisfied satisfied inclusion and exclusion criteria and were randomised into the study, the first subject being screened on 05 July 2016; last subject screened on 15 December 2016.

    Pre-assignment period milestones
    Number of subjects started
    		 21 [1]
    Number of subjects completed
    		 15

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen Fail: 6
    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 enrolled is the number of subjects randomised. Six subjects failed screening and are not reported.
    Period 1
    Period 1 title
    Dosing: Day 1 to Day 28 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 AUT00063
    Arm description
    		 AUT00063 800mg
    Arm type
    		 Experimental

    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
    		 -
    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 1
    		AUT00063 Placebo
    Started
    14
    15
    Completed
    12
    15
    Not completed
    2
    0
         Adverse event, non-fatal
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dosing: Day 1 to Day 28
    Reporting group description
    		 -

    Reporting group values
    		 Dosing: Day 1 to Day 28 Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 6 6
        From 65-84 years
    		 9 9
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.3 ( 14.55 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 5 5
    Cochlear Implant Device
    Units: Subjects
        MED-EL
    		 5 5
        Cochlear
    		 9 9
        Advanced Bionics
    		 1 1
    Years since onset of severe/ profound hearing loss
    Units: Years
        arithmetic mean (standard deviation)
    		 22.87 ( 21.797 ) -
    Years since confirmed qualification for a CI
    Units: Years
        arithmetic mean (standard deviation)
    		 1.64 ( 0.633 ) -
    Years since CI implantation
    Units: Years
        arithmetic mean (standard deviation)
    		 1.40 ( 0.828 ) -
    Subject analysis sets

    Subject analysis set title
    AUT00063 - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were allocated to AUT00063 first and then Placebo in the cross over design

    Subject analysis set title
    Placebo - AUT00063
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were assigned to Placebo first and then AUT00063 in the cross over deisgn

    Subject analysis sets values
    		 AUT00063 - Placebo Placebo - AUT00063
    Number of subjects
    8
    7
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    1
    5
        From 65-84 years
    7
    2
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.8 ( 6.80 )
    60.0 ( 18.82 )
    Gender categorical
    Units: Subjects
        Female
    6
    4
        Male
    2
    3
    Cochlear Implant Device
    Units: Subjects
        MED-EL
    3
    2
        Cochlear
    5
    4
        Advanced Bionics
    0
    1
    Years since onset of severe/ profound hearing loss
    Units: Years
        arithmetic mean (standard deviation)
    20.50 ( 21.024 )
    25.57 ( 24.020 )
    Years since confirmed qualification for a CI
    Units: Years
        arithmetic mean (standard deviation)
    1.63 ( 0.744 )
    1.67 ( 0.516 )
    Years since CI implantation
    Units: Years
        arithmetic mean (standard deviation)
    1.38 ( 0.916 )
    1.43 ( 0.787 )

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    AUT00063 - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were allocated to AUT00063 first and then Placebo in the cross over design

    Subject analysis set title
    Placebo - AUT00063
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were assigned to Placebo first and then AUT00063 in the cross over deisgn

    Primary: Consonant-Nucleus-Consonant (CNC) in quiet

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    End point title
    		 Consonant-Nucleus-Consonant (CNC) in quiet [1]
    End point description
    Consonant-Nucleus-Consonant (CNC) speech test in quiet; Full Analysis Set; Change from Baseline Grand Total in Percent(of total 150 Phonemes).
    End point type
    Primary
    End point timeframe
    28 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified due to format.
    End point values
    		 AUT00063 Placebo
    Number of subjects analysed
    12
    15
    Units: Mean % Correct
        arithmetic mean (standard deviation)
    1.0 ( 8.33 )
    2.8 ( 8.84 )
    No statistical analyses for this end point

    Primary: AzBio sentences test presented in quiet

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    End point title
    		 AzBio sentences test presented in quiet [2]
    End point description
    AzBio sentences test presented in quiet; Full Analysis Set; Change from Baseline.
    End point type
    Primary
    End point timeframe
    28 Days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified due to format.
    End point values
    		 AUT00063 Placebo
    Number of subjects analysed
    12
    15
    Units: Mean % Correct
        arithmetic mean (standard deviation)
    1.3 ( 6.18 )
    5.1 ( 11.19 )
    No statistical analyses for this end point

    Primary: AzBio sentences test presented in noise

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    End point title
    		 AzBio sentences test presented in noise [3]
    End point description
    AzBio sentences test presented in noise; Full Analysis Set; Change from Baseline.
    End point type
    Primary
    End point timeframe
    28 Days
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified due to format.
    End point values
    		 AUT00063 Placebo
    Number of subjects analysed
    12
    15
    Units: Mean % Correct
        arithmetic mean (standard deviation)
    0.0 ( 10.31 )
    -2.7 ( 9.57 )
    No statistical analyses for this end point

    Primary: BKB-SIN test

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    End point title
    		 BKB-SIN test [4]
    End point description
    Bamford-Kowal-Bench Speech-in-Noise [BKB-SIN] sentence test; Full Analysis Set; Change from Baseline. SNR = signal-to-noise ratio SNR - 50 = 50% correct on BKB-SIN Test
    End point type
    Primary
    End point timeframe
    28 Days
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified due to format.
    End point values
    		 AUT00063 Placebo
    Number of subjects analysed
    12
    15
    Units: Mean Decibels (SNR-50)
        arithmetic mean (standard deviation)
    -1.7 ( 3.46 )
    -1.2 ( 2.71 )
    No statistical analyses for this end point

    Primary: Rate discrimination at low rates

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    End point title
    		 Rate discrimination at low rates [5]
    End point description
    Rate discrimination at low rates (centered on 120 PPS): ANOVA of mean over runs. Full Analysis Set.
    End point type
    Primary
    End point timeframe
    28 Days
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified due to format.
    End point values
    		 AUT00063 Placebo
    Number of subjects analysed
    12
    15
    Units: Pulses Per Second (PPS)
        geometric mean (confidence interval 95%)
    1.211 (1.167 to 1.258)
    1.199 (1.166 to 1.233)
    No statistical analyses for this end point

    Primary: Midpoint comparison for upper limit of rate discrimination

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    End point title
    		 Midpoint comparison for upper limit of rate discrimination [6]
    End point description
    Midpoint comparison for upper limit of rate discrimination (10 trials): ANOVA of upper limit (pps). Full Analysis Set.
    End point type
    Primary
    End point timeframe
    28 Days
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified due to format.
    End point values
    		 AUT00063 Placebo
    Number of subjects analysed
    12
    15
    Units: Pulses Per Second (PPS)
        geometric mean (confidence interval 95%)
    457.178 (349.216 to 598.517)
    490.906 (401.604 to 600.065)
    No statistical analyses for this end point

    Primary: Gap detection

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    End point title
    		 Gap detection [7]
    End point description
    Gap detection (1055 PPS): ANOVA of mean over runs. Full Analysis Set.
    End point type
    Primary
    End point timeframe
    28 Days
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified due to format.
    End point values
    		 AUT00063 Placebo
    Number of subjects analysed
    12
    15
    Units: milliseconds
        geometric mean (confidence interval 95%)
    2.933 (2.562 to 3.359)
    2.964 (2.680 to 3.279)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 dosing to Follow Up visit (Day 42, two weeks post last dose).
    Adverse event reporting additional description
    Treatment Emergent Adverse Events reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    AUT00063 800mg
    Reporting group description
    		 Treatment-emergent AEs

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment-emergent AEs reported

    Serious adverse events
    		 AUT00063 800mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 15 (13.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 AUT00063 800mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 13 (46.15%)
    9 / 15 (60.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 15 (13.33%)
         occurrences all number
    4
    2
    Balance
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Escherichia infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2016
    Reduction of the sample size from 20 subjects to 12 subjects; the sample size was calculated to detect a 25% decrease in gap detection which is judged to provide evidence of a meaningful treatment effect, based on unpublished direct stimulation data from the MRC Brain and Cognition Unit that became available after the study start.
    22 Sep 2016
    A change to the inclusion criteria relating to the speech test score and time post implant to aid recruitment. Criteria "Less than optimal speech perception at the time of enrolment (defined as a score of 25% to 85% for Bamford-Kowal-Bench (BKB) sentences presented in quiet without contralateral hearing aid)", changed to a score of 25% to 95% BKB sentence test. Criteria "Received a unilateral cochlear implant within the last 9 to 36 months for post-lingual deafness", changed to within the last 9 to 48 months.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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