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    Clinical Trial Results:
    AM-101 in the Post-Acute Treatment of Peripheral Tinnitus 1 (AMPACT1) – an open-label extension to the TACTT2 study

    Summary
    EudraCT number
    		 2013-005588-24
    Trial protocol
    		 CZ  
    Global end of trial date
    19 Jan 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Jun 2018
    First version publication date
    25 Feb 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Data for safety endpoints with "Frequency of Subjects with a Deterioration of Hearing Threshold" have to be corrected.

    Trial information

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    Trial identification
    Sponsor protocol code
    AM-101-CL-12-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01934010
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Auris Medical Inc.
    Sponsor organisation address
    500 North Michigan Avenue, Suite 600, Chicago, Illinois, United States, 60611
    Public contact
    Thomas Meyer, Auris Medical Inc., +1 312 396 4150, hear@aurismedical.com
    Scientific contact
    Thomas Meyer, Auris Medical Inc., +1 312 396 4150, 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
    23 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the phase 3 open-label extension (OLE) 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 TACTT2 study with either AM-101 0.87 mg/mL or placebo. A total cumulative observational period of 1 year in subjects with acute persistent peripheral tinnitus who were previously enrolled into and completed TACTT2 was reached. Subjects who completed TACTT2, could roll-over into treatment cycle 1 of this study (AMPACT1). 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 257 subjects were treated in AMPACT1 of which: - 114 subjects participated only in the first cycle, - 67 subjects participated in the first 2 treatment cycles, - 76 subjects participated in all 3 treatment cycles.
    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
    02 Jun 2014
    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
    Czech Republic: 53
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United States: 156
    Worldwide total number of subjects
    257
    EEA total number of subjects
    53
    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)
    231
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 260 subjects were enrolled and 257 subjects were treated in overall 59 active sites in Canada (6), the United States (35), the Czech Republic (7), Israel (2), Turkey (3) and Republic of South Korea (6). Subjects could only participate if they had been previously enrolled and completed the participation in the TACTT2 study.

    Pre-assignment
    Screening details
    		 Main Inclusion Criteria: Attendance at final visit FUV3 of TACTT2 study, aged 18 to 75 years, documented persistent subjective peripheral tinnitus following traumatic cochlear injury or otitis media (OM) with onset no longer than 3 months prior to randomization into TACTT2.

    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 TACTT2 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 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).
    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 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).
    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
    114
    67
    76
    Completed
    91
    56
    74
    Not completed
    23
    11
    2
         Consent withdrawn by subject
    15
    6
    2
         Adverse event, non-fatal
    1
    1
    -
         Lost to follow-up
    7
    4
    -

    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 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).

    Reporting group values
    		 1 Cycle AM-101 2 Cycles AM-101 3 Cycles AM-101 Total
    Number of subjects
    		 114 67 76 257
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 106 61 64 231
        From 65-84 years
    		 8 6 12 26
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.1 ± 14.1 44.7 ± 13.9 47.6 ± 15.5 -
    Gender categorical
    Units: Subjects
        Female
    		 25 17 21 63
        Male
    		 89 50 55 194

    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 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).

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

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    End point title
    		 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 ear can perceive still 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
    103 [1]
    67 [2]
    74 [3]
    Units: Number subjects affected
    10
    2
    2
    Notes
    [1] - Subjects who participated only in 1 treatment cycle and are valid for safety analysis.
    [2] - Subjects who received two treatment cycles and are valid for safety analysis.
    [3] - Subjects who received 3 treatment cycles and are valid for safety analysis.
    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
    2 Cycles AM-101 v 1 Cycle AM-101
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128
    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
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.075
    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 FUV2 for all subjects in those groups.
    Comparison groups
    2 Cycles AM-101 v 3 Cycles AM-101
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

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

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    End point title
    		 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 ear can perceive still 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
    59
    75
    Units: Number subjects affected
    1
    0
    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
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4403
    Method
    		 Fisher exact
    Confidence interval

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

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    End point title
    		 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 ear can perceive still 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
    74
    Units: Number subjects affected
    2
    No statistical analyses for this end point

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

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    End point title
    		 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 ear can perceive still 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
    91
    66
    75
    Units: Number subjects affected
    10
    3
    0
    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
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2401
    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
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022
    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
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1001
    Method
    		 Fisher exact
    Confidence interval

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

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    End point title
    		 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 ear can perceive still 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
    55
    76
    Units: Number subjects affected
    0
    1
    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
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

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

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    End point title
    		 Frequency of Subjects With a Deterioration of Hearing Threshold at Day 252 (Air Conduction) [8]
    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 ear can perceive still 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 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
    74
    Units: Number subjects affected
    2
    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. In non-serious adverse events section, under occurrences (all), reported numbers are "subjects affected".
    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
    		 -

    Reporting group title
    2 Cycles AM-101
    Reporting group description
    		 -

    Reporting group title
    3 Cycles AM-101
    Reporting group description
    		 -

    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
    2 / 114 (1.75%)
    1 / 67 (1.49%)
    1 / 76 (1.32%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Liver function test increased
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 67 (0.00%)
    0 / 76 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lip and/or oral cavity cancer
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 67 (0.00%)
    0 / 76 (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
    Reproductive system and breast disorders
    Adnexa uteri cyst
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adnexa uteri mass
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 67 (0.00%)
    1 / 76 (1.32%)
         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: 2%
    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
    25 / 114 (21.93%)
    25 / 67 (37.31%)
    37 / 76 (48.68%)
    Surgical and medical procedures
    Artificial crown procedure
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 67 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 114 (4.39%)
    7 / 67 (10.45%)
    9 / 76 (11.84%)
         occurrences all number
    5
    7
    9
    Dizziness
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 67 (1.49%)
    2 / 76 (2.63%)
         occurrences all number
    0
    1
    2
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    3 / 114 (2.63%)
    9 / 67 (13.43%)
    7 / 76 (9.21%)
         occurrences all number
    3
    9
    7
    Ear pain
         subjects affected / exposed
    10 / 114 (8.77%)
    13 / 67 (19.40%)
    8 / 76 (10.53%)
         occurrences all number
    10
    13
    8
    Hypoacusis
         subjects affected / exposed
    5 / 114 (4.39%)
    4 / 67 (5.97%)
    4 / 76 (5.26%)
         occurrences all number
    5
    4
    4
    Otorrhoea
         subjects affected / exposed
    1 / 114 (0.88%)
    4 / 67 (5.97%)
    3 / 76 (3.95%)
         occurrences all number
    1
    4
    3
    Tinnitus
         subjects affected / exposed
    0 / 114 (0.00%)
    2 / 67 (2.99%)
    5 / 76 (6.58%)
         occurrences all number
    0
    2
    5
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 67 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    0
    0
    3
    Vertigo
         subjects affected / exposed
    0 / 114 (0.00%)
    2 / 67 (2.99%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    1
    Eustachian tube dysfunction
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 67 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    1
    0
    2
    Hyperacusis
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 67 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 67 (1.49%)
    2 / 76 (2.63%)
         occurrences all number
    1
    1
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 114 (0.00%)
    2 / 67 (2.99%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 114 (3.51%)
    2 / 67 (2.99%)
    6 / 76 (7.89%)
         occurrences all number
    4
    2
    6
    Bronchitis
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 67 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 67 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 67 (1.49%)
    2 / 76 (2.63%)
         occurrences all number
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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