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    Clinical Trial Results:
    AM-101 in the Post-Acute Treatment of Peripheral Tinnitus 2 (AMPACT2) – an open-label extension to the TACTT3 study

    Summary
    EudraCT number
    		 2013-001527-39
    Trial protocol
    		 HU   BE   DE   AT   GB   PL   ES  
    Global end of trial date
    19 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2019
    First version publication date
    20 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AM-101-CL-12-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02040207
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Auris Medical AG
    Sponsor organisation address
    Dornacherstr. 210, Basel, Switzerland, 4053
    Public contact
    Thomas Meyer, Auris Medical AG, +41 61201 1350, hear@aurismedical.com
    Scientific contact
    Thomas Meyer, Auris Medical AG, +41 61201 1350, hear@aurismedical.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
    25 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is the evaluation of the safety and local tolerance of up to 3 quarterly treatment cycles each with 3 repeated doses of AM-101 0.87 mg/mL in subjects previously treated in the scope of the TACTT3 study with either AM-101 0.87 mg/mL or placebo. Subjects were followed for up to a cumulative observational period of 1 year in subjects with acute persistent peripheral tinnitus. Subjects who completed TACTT3, could roll-over into treatment cycle 1 of this study (AMPACT2). After completion of treatment cycle 1 they were free to decide if they want to continue with treatment cycle 2. Same for treatment cycle 3. In total 485 subjects were treated in AMPACT2 of which: - 347 subjects participated only in the first treatment cycle, - 66 subjects participated in the first 2 treatment cycles, - 72 subjects completed all 3 treatment cycles. 1 subject was enrolled but not treated. It is not included in the following numbers.
    Protection of trial subjects
    This Clinical Trial was conducted in accordance with the study protocol, the International Conference on Harmonisation (ICH) harmonized tripartite guideline on Good Clinical Practices (GCP) (E6), as well as the ethical principles outlined in the Declaration of Helsinki dated 1989, or in their most current version.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 May 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 92
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    United Kingdom: 42
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 43
    Country: Number of subjects enrolled
    France: 43
    Country: Number of subjects enrolled
    Germany: 163
    Country: Number of subjects enrolled
    Hungary: 64
    Country: Number of subjects enrolled
    Switzerland: 8
    Worldwide total number of subjects
    485
    EEA total number of subjects
    477
    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)
    461
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 486 subjects were enrolled. 1 Subject was enrolled but not treated (this subject is not listed). 485 subjects were treated. Subjects were enrolled at 69 sites. Subjects could only participate if they had been previously enrolled in TACTT3.

    Pre-assignment
    Screening details
    		 Main Inclusion Criteria: Attendance at final visit FUV3 of TACTT3 study and no study drug related or procedure related adverse event (AE) leading to treatment discontinuation in study TACTT3.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This study was an open-label extension study subsequent to the previous blinded, placebo controlled, randomized TACTT3 study. This study was requested by the FDA as long-term safety follow-up of repeated AM-101 injection cycles over 1 year.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1 Cycle AM-101
    Arm description
    		 Subjects participated in 1 treatment cycle and received one round of 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine hydrochloride gel
    Investigational medicinal product code
    AM-101
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Subjects who participated only in treatment cycle 1, received three intratympanic administrations of AM-101 0.87 mg/mL (0.25 mL). In case of eligible bilateral tinnitus, both ears were treated.

    Arm title
    		 2 Cycles AM-101
    Arm description
    		 Subjects that participated in 2 treatment cycles of the AMPACT2 study, received 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4) in cycle 1 and after final follow-up (D84) of cycle 1, they rolled-over to treatment cycle 2 receiving once more 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D84 - D88).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine hydrochloride gel
    Investigational medicinal product code
    AM-101
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Subjects who participated in 2 treatment cycles, received 1x three intratympanic administrations of AM-101 0.87 mg/mL (0.25 mL) within 5 days and a second time three intratympanic injections of AM-101 0.87 mg/mL within 5 days after FUV3 (D84) of treatment cycle 1. In case of eligible bilateral tinnitus, both ears were treated.

    Arm title
    		 3 Cycles AM-101
    Arm description
    		 Subjects that participated in all 3 treatment cycles of the AMPACT2 study, received 3 x 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days. The subjects could only roll-over if they completed the final follow-up of the previous cycle and were still eligible. In cycle 1 treatment was within D0 - D4. Cycle 2 treatment within D84 - D88. And treatment for cycle 3 within D168-D172. Final follow-up after 3 treatment cycles was FUV9 (D252).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine hydrochloride gel
    Investigational medicinal product code
    AM-101
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Subjects who participated in all three treatment cycles, received 3 times three intratympanic administrations of AM-101 0.87 mg/mL (0.25 mL). Please refer to arm description for details. In case of eligible bilateral tinnitus, both ears were treated.

    Number of subjects in period 1
    		1 Cycle AM-101 2 Cycles AM-101 3 Cycles AM-101
    Started
    347
    66
    72
    Completed
    312
    62
    69
    Not completed
    35
    4
    3
         Exclusion criteria met
    1
    -
    -
         Consent withdrawn by subject
    14
    3
    1
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    2
    -
    -
         Lost to follow-up
    16
    1
    2
         not able to join visits
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1 Cycle AM-101
    Reporting group description
    		 Subjects participated in 1 treatment cycle and received one round of 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4)

    Reporting group title
    2 Cycles AM-101
    Reporting group description
    		 Subjects that participated in 2 treatment cycles of the AMPACT2 study, received 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4) in cycle 1 and after final follow-up (D84) of cycle 1, they rolled-over to treatment cycle 2 receiving once more 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D84 - D88).

    Reporting group title
    3 Cycles AM-101
    Reporting group description
    		 Subjects that participated in all 3 treatment cycles of the AMPACT2 study, received 3 x 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days. The subjects could only roll-over if they completed the final follow-up of the previous cycle and were still eligible. In cycle 1 treatment was within D0 - D4. Cycle 2 treatment within D84 - D88. And treatment for cycle 3 within D168-D172. Final follow-up after 3 treatment cycles was FUV9 (D252).

    Reporting group values
    		 1 Cycle AM-101 2 Cycles AM-101 3 Cycles AM-101 Total
    Number of subjects
    		 347 66 72 485
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 330 65 66 461
        From 65-84 years
    		 17 1 6 24
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.8 ( 12.83 ) 41.8 ( 11.40 ) 43.4 ( 12.32 ) -
    Gender categorical
    Units: Subjects
        Female
    		 89 19 24 132
        Male
    		 258 47 48 353

    End points

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    End points reporting groups
    Reporting group title
    1 Cycle AM-101
    Reporting group description
    		 Subjects participated in 1 treatment cycle and received one round of 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4)

    Reporting group title
    2 Cycles AM-101
    Reporting group description
    		 Subjects that participated in 2 treatment cycles of the AMPACT2 study, received 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4) in cycle 1 and after final follow-up (D84) of cycle 1, they rolled-over to treatment cycle 2 receiving once more 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D84 - D88).

    Reporting group title
    3 Cycles AM-101
    Reporting group description
    		 Subjects that participated in all 3 treatment cycles of the AMPACT2 study, received 3 x 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days. The subjects could only roll-over if they completed the final follow-up of the previous cycle and were still eligible. In cycle 1 treatment was within D0 - D4. Cycle 2 treatment within D84 - D88. And treatment for cycle 3 within D168-D172. Final follow-up after 3 treatment cycles was FUV9 (D252).

    Primary: Primary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction)

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    End point title
    		 Primary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction)
    End point description
    Valid for Safety Analysis Set was used. Air conduction: The atmospheric transmission of sound to the inner ear through the external auditory canal and via structures of the middle ear. The ability of hearing is measured in decibel (dB). The hearing threshold, is the lowest sound pressure where the subject can still perceive a sound. The endpoint deterioration of hearing threshold ≥15 dB in two contiguous test frequencies means that hearing worsens ≥15 dB in two neighboring sound frequencies.
    End point type
    Primary
    End point timeframe
    Day 1 (TV1) to Day 35 (FUV2) of cycle 1
    End point values
    		 1 Cycle AM-101 2 Cycles AM-101 3 Cycles AM-101
    Number of subjects analysed
    323 [1]
    66 [2]
    72 [3]
    Units: Number subjects affected
        number (not applicable)
    27
    3
    7
    Notes
    [1] - Subjects who participated only in 1 treatment cycle and are valid for this endpoint.
    [2] - Subjects who received two treatment cycles and are valid for this endpoint.
    [3] - Subjects who received 3 treatment cycles and are valid for this endpoint.
    Statistical analysis title
    		 Subjects participating in 1 Cycle vs. 2 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that had only 1 treatment cycle or those that decided later to have 2 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV2 for all subjects in those groups.
    Comparison groups
    1 Cycle AM-101 v 2 Cycles AM-101
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4462
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Subjects participating in 1 Cycle vs. 3 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that had only 1 treatment cycle or those that decided later to have 3 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV2 for all subjects in those groups.
    Comparison groups
    1 Cycle AM-101 v 3 Cycles AM-101
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6483
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Subjects participating in 2 Cycles vs. 3 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that decided to participate in 2 treatment cycles or those that decided later to have 3 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV2 for all subjects in those groups.
    Comparison groups
    2 Cycles AM-101 v 3 Cycles AM-101
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3302
    Method
    		 Fisher exact
    Confidence interval

    Primary: Primary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 119 (Air Conduction)

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    End point title
    		 Primary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 119 (Air Conduction) [4]
    End point description
    Valid for Safety Analysis Set was used. Air conduction: The atmospheric transmission of sound to the inner ear through the external auditory canal and via structures of the middle ear. The ability of hearing is measured in decibel (dB). The hearing threshold, is the lowest sound pressure where the subject can still perceive a sound. The endpoint deterioration of hearing threshold ≥15 dB in two contiguous test frequencies means that hearing worsens ≥15 dB in two neighboring sound frequencies.
    End point type
    Primary
    End point timeframe
    Day 84 (TV4) to Day 119 (FUV5) of cycle 2
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Deterioration of hearing threshold at FUV5 (Day 119) is only evaluable for subjects that participated in 2 or 3 treatment cycles. For subjects that participated only in one treatment cycle, the study had already ended after FUV3 (Day 84). Therefore, only one statistical comparison between subjects that participated in 2 vs. 3 treatment cycles, is possible.
    End point values
    		 2 Cycles AM-101 3 Cycles AM-101
    Number of subjects analysed
    58
    71
    Units: Number subjects affected
    5
    4
    Statistical analysis title
    		 Subjects participating in 2 Cycles vs. 3 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that decided to participate in 2 treatment cycle or those that decided later to have 3 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV5 for all subjects in those groups.
    Comparison groups
    2 Cycles AM-101 v 3 Cycles AM-101
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7304
    Method
    		 Fisher exact
    Confidence interval

    Primary: Primary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 203 (Air Conduction)

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    End point title
    		 Primary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 203 (Air Conduction) [5] [6]
    End point description
    Valid for Safety Analysis Set was used. Air conduction: The atmospheric transmission of sound to the inner ear through the external auditory canal and via structures of the middle ear. The ability of hearing is measured in decibel (dB). The hearing threshold, is the lowest sound pressure where the subject can still perceive a sound. The endpoint deterioration of hearing threshold ≥15 dB in two contiguous test frequencies means that hearing worsens ≥15 dB in two neighboring sound frequencies.
    End point type
    Primary
    End point timeframe
    Day 168 (TV7) up to Day 203 (FUV8) of cycle 3
    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: Deterioration of hearing threshold at FUV8 (Day 203) is only evaluable for subjects that participated in 3 treatment cycles. For subjects that participated in 1 or 2 treatment cycles, the study had already ended after FUV3 (Day 84) or FUV6 (Day 168). Therefore no statistical analysis is possible.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Deterioration of hearing threshold at FUV8 (Day 203) is only evaluable for subjects that participated in 3 treatment cycles. For subjects that participated in 1 or 2 treatment cycles, the study had already ended after FUV3 (Day 84) or FUV6 (Day 168). Therefore no statistical analysis is possible.
    End point values
    		 3 Cycles AM-101
    Number of subjects analysed
    70
    Units: Number subjects affected
    3
    No statistical analyses for this end point

    Secondary: Secondary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction)

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    End point title
    		 Secondary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction)
    End point description
    Valid for Safety Analysis Set was used. Air conduction: The atmospheric transmission of sound to the inner ear through the external auditory canal and via structures of the middle ear. The ability of hearing is measured in decibel (dB). The hearing threshold, is the lowest sound pressure where the subject can still perceive a sound. The endpoint deterioration of hearing threshold ≥15 dB in two contiguous test frequencies means that hearing worsens ≥15 dB in two neighboring sound frequencies.
    End point type
    Secondary
    End point timeframe
    Day 1 (TV1) to Day 84 (FUV3) of cycle 1
    End point values
    		 1 Cycle AM-101 2 Cycles AM-101 3 Cycles AM-101
    Number of subjects analysed
    313
    66
    72
    Units: Number subjects affected
    29
    6
    6
    Statistical analysis title
    		 Subjects participating in 1 Cycle vs. 2 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that had only 1 treatment cycle or those that decided later to have 2 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV3 for all subjects in those groups.
    Comparison groups
    1 Cycle AM-101 v 2 Cycles AM-101
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Subjects participating in 1 Cycle vs. 3 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that had only 1 treatment cycle or those that decided later to have 3 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV3 for all subjects in those groups.
    Comparison groups
    1 Cycle AM-101 v 3 Cycles AM-101
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Subjects participating in 2 Cycles vs. 3 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that decided to participate in 2 treatment cycle or those that decided later to have 3 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV3 for all subjects in those groups.
    Comparison groups
    2 Cycles AM-101 v 3 Cycles AM-101
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 168 (Air Conduction)

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    End point title
    		 Secondary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 168 (Air Conduction) [7]
    End point description
    Valid for Safety Analysis Set was used. Air conduction: The atmospheric transmission of sound to the inner ear through the external auditory canal and via structures of the middle ear. The ability of hearing is measured in decibel (dB). The hearing threshold, is the lowest sound pressure where the subject can still perceive a sound. The endpoint deterioration of hearing threshold ≥15 dB in two contiguous test frequencies means that hearing worsens ≥15 dB in two neighboring sound frequencies.
    End point type
    Secondary
    End point timeframe
    Day 84 (TV4) to Day 168 (FUV6) of cycle 2
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Deterioration of hearing threshold at FUV5 (Day 168) is only evaluable for subjects that participated in 2 or 3 treatment cycles. For subjects that participated only in one treatment cycle, the study had already ended after FUV3 (Day 84). Therefore, only one statistical comparison between subjects that participated in 2 vs. 3 treatment cycles, is possible.
    End point values
    		 2 Cycles AM-101 3 Cycles AM-101
    Number of subjects analysed
    62
    72
    Units: Number subjects affected
    4
    6
    Statistical analysis title
    		 Subjects participating in 2 Cycles vs. 3 Cycles
    Statistical analysis description
    Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that decided to participate in 2 treatment cycle or those that decided later to have 3 treatment cycles. The analysis is based on the deterioration of hearing detected at FUV6 for all subjects in those groups.
    Comparison groups
    2 Cycles AM-101 v 3 Cycles AM-101
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7517
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 252 (Air Conduction)

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    End point title
    		 Secondary: Frequency of Subjects With a Deterioration of Hearing Threshold at Day 252 (Air Conduction) [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 168 (TV7) to Day 252 (FUV9) of cycle 3
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Deterioration of hearing threshold at FUV9 (Day 252) is only evaluable for subjects that participated in 3 treatment cycles. For subjects that participated in 1 or 2 treatment cycles, the study had already ended after FUV3 (Day 84 or FUV6 (Day 168). Therefore, no statistical analysis is possible.
    End point values
    		 3 Cycles AM-101
    Number of subjects analysed
    69
    Units: Number subjects affected
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to end of study at all visits.
    Adverse event reporting additional description
    Assessed by Investigator at all visits.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    1 Cycle AM-101
    Reporting group description
    		 Subjects participated in 1 treatment cycle and received one round of 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4)

    Reporting group title
    2 Cycles AM-101
    Reporting group description
    		 Subjects that participated in 2 treatment cycles of the AMPACT1 study, received 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D0 - D4) in cycle 1 and after final follow-up (D84) of cycle 1, they rolled-over to treatment cycle 2 receiving once more 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days (D84 - D88).

    Reporting group title
    3 Cycles AM-101
    Reporting group description
    		 Subjects that participated in all 3 treatment cycles of the AMPACT1 study, received 3 x 3 repeated doses of AM-101 gel (0.87 mg/mL) within 5 days. The subjects could only roll-over if they completed the final follow-up of the previous cycle and were still eligible. In cycle 1 treatment was within D0 - D4. Cycle 2 treatment within D84 - D88. And treatment for cycle 3 within D168-D172. Final follow-up after 3 treatment cycles was FUV9 (D252).

    Serious adverse events
    		 1 Cycle AM-101 2 Cycles AM-101 3 Cycles AM-101
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 347 (0.86%)
    0 / 66 (0.00%)
    4 / 72 (5.56%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cerebellopontine angle tumour
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 66 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 66 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 347 (0.00%)
    0 / 66 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lower motor neurone lesion
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 66 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 347 (0.00%)
    0 / 66 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
    Additional description: Occurence is causally related to procedure (intratympanic injection), Subject had it on both ears with bilateral tinnitus.
         subjects affected / exposed
    0 / 347 (0.00%)
    0 / 66 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 347 (0.00%)
    0 / 66 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 1 Cycle AM-101 2 Cycles AM-101 3 Cycles AM-101
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    157 / 347 (45.24%)
    36 / 66 (54.55%)
    57 / 72 (79.17%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 66 (3.03%)
    3 / 72 (4.17%)
         occurrences all number
    1
    2
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 347 (6.05%)
    4 / 66 (6.06%)
    10 / 72 (13.89%)
         occurrences all number
    21
    4
    10
    Ear and labyrinth disorders
    Ear discomfort
    Additional description: In non-serious adverse event section, under occurences (all), reported numbers are "subjects affected".
         subjects affected / exposed
    26 / 347 (7.49%)
    4 / 66 (6.06%)
    5 / 72 (6.94%)
         occurrences all number
    26
    4
    5
    Ear pain
         subjects affected / exposed
    39 / 347 (11.24%)
    12 / 66 (18.18%)
    12 / 72 (16.67%)
         occurrences all number
    39
    12
    12
    Eustachian tube obstruction
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 66 (3.03%)
    0 / 72 (0.00%)
         occurrences all number
    1
    2
    0
    Hypoacusis
         subjects affected / exposed
    24 / 347 (6.92%)
    8 / 66 (12.12%)
    10 / 72 (13.89%)
         occurrences all number
    24
    8
    10
    Tinnitus
         subjects affected / exposed
    16 / 347 (4.61%)
    3 / 66 (4.55%)
    3 / 72 (4.17%)
         occurrences all number
    16
    3
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 66 (3.03%)
    1 / 72 (1.39%)
         occurrences all number
    1
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 66 (1.52%)
    5 / 72 (6.94%)
         occurrences all number
    2
    1
    5
    Nasal obstruction
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 66 (3.03%)
    1 / 72 (1.39%)
         occurrences all number
    0
    2
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 66 (1.52%)
    4 / 72 (5.56%)
         occurrences all number
    2
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 347 (4.32%)
    8 / 66 (12.12%)
    14 / 72 (19.44%)
         occurrences all number
    15
    8
    14
    Otitis externa
         subjects affected / exposed
    4 / 347 (1.15%)
    3 / 66 (4.55%)
    0 / 72 (0.00%)
         occurrences all number
    4
    3
    0
    Otitis media
         subjects affected / exposed
    5 / 347 (1.44%)
    1 / 66 (1.52%)
    3 / 72 (4.17%)
         occurrences all number
    5
    1
    3
    Otitis media acute
         subjects affected / exposed
    3 / 347 (0.86%)
    1 / 66 (1.52%)
    3 / 72 (4.17%)
         occurrences all number
    3
    1
    3
    Pharyngitis
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 66 (3.03%)
    7 / 72 (9.72%)
         occurrences all number
    1
    2
    7
    Rhinitis
         subjects affected / exposed
    3 / 347 (0.86%)
    4 / 66 (6.06%)
    2 / 72 (2.78%)
         occurrences all number
    3
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2015
    Main change: Cycle 2 and Cycle 3 were not offered any more. Rationale: Participation in the AMPACT2 trial has been offered to AM-101-CL-12-02 (TACTT3) participants as an option without any claims to efficacy beyond the 3 months acute stage, since the compound had never been tested before in patients with tinnitus older than 3 months. Preliminary data from the Stratum B interim analysis in the TACTT3 trial suggests that AM-101 may indeed still be active if initiated beyond the acute stage. However, therapeutic benefits seem to decrease the later treatment is initiated. In particular, the interim analysis of the changes in tinnitus loudness and TFI in Stratum B (tinnitus onset between 3 and 12 months prior) showed for the early post-acute stage higher levels of activity than at the later stage of the time window. In light of the data, which suggest only small therapeutic benefits, if any, from the initiation of treatment with AM-101 beyond 6 and especially beyond 9 months from onset, the Sponsor considers it appropriate to eliminate the optional Cycles 2 and 3 from the AMPACT2 trial. Even with the proposed modification, all TACTT3 participants will have the opportunity to receive for certain one full course / treatment cycle with the active study drug during AMPACT2.

    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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