Tinnitus
Conditions
Brief summary
The purpose of this research study is to test the safety and local tolerance of repeated treatment cycles of AM-101.
Detailed description
This open-label extension study is assessing the safety and local tolerance of repeated treatment cycles of AM-101 in subjects previously treated in the scope of the TACTT2 study (NCT01803646).
Interventions
DRUGAM-101
AM-101 gel for intratympanic injection
Sponsors
Auris Medical, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 76 Years
Healthy volunteers
No
Inclusion criteria
* Completion of TACTT2 study; * Negative pregnancy test (woman of childbearing potential); * Willing and able to attend the study visits during at least one treatment cycle. Other protocol-defined inclusion criteria may apply.
Exclusion criteria
* Adverse event leading to treatment discontinuation in TACTT2; * Meniere's Disease, endolymphatic hydrops, acoustic neuroma, severe or fluctuating hearing loss, otitis media, otitis externa, abnormality of tympanic membrane; * Ongoing drug-based therapy for otitis media or otitis externa; * Drug-based therapy known as potentially tinnitus-inducing; * Other treatment of tinnitus; * Drug abuse or alcoholism; * Subjects with psychiatric diseases requiring drug treatment; * Use of antidepressant or anti-anxiety medication; * Any clinically relevant disorder or abnormality in physical examination; * Women who are breast-feeding, pregnant or who are planning to become pregnant during the study; * Women of childbearing potential who are unwilling or unable to practice contraception. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction) | Day 1 (TV1) to Day 35 (FUV2) of cycle 1 | 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. |
| Frequency of Subjects With a Deterioration of Hearing Threshold at Day 119 (Air Conduction) | Day 84 (TV4) to Day 119 (FUV5) of cycle 2 | 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. |
| Frequency of Subjects With a Deterioration of Hearing Threshold at Day 203 (Air Conduction) | Day 168 (TV7) up to Day 203 (FUV8) of cycle 3 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction) | Day 1 (TV1) to Day 84 (FUV3) of cycle 1 | 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. |
| Frequency of Subjects With a Deterioration of Hearing Threshold at Day 168 (Air Conduction) | Day 84 (TV4) to Day 168 (FUV6) of cycle 2 | 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. |
| Frequency of Subjects With a Deterioration of Hearing Threshold at Day 252 (Air Conduction) | Day 168 (TV7) to Day 252 (FUV9) of cycle 3 | 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. |
Countries
United States
Participant flow
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 details
Main Inclusion Criteria: * completion of TACTT2 study * negative pregnancy test (women of childbearing potential) * willing and able to attend the study visits during at least one treatment cycle.
Participants by arm
| Arm | Count |
|---|---|
| 1 Cycle AM-101 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) | 114 |
| 2 Cycles AM-101 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). | 67 |
| 3 Cycles AM-101 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). | 76 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 7 | 4 | 0 |
| Overall Study | Withdrawal by Subject | 15 | 6 | 2 |
Baseline characteristics
| Characteristic | 1 Cycle AM-101 | 2 Cycles AM-101 | 3 Cycles AM-101 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 6 Participants | 12 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 106 Participants | 61 Participants | 64 Participants | 231 Participants |
| Age, Continuous | 43.1 years STANDARD_DEVIATION 14.1 | 44.7 years STANDARD_DEVIATION 13.9 | 47.6 years STANDARD_DEVIATION 15.5 | 44.8 years STANDARD_DEVIATION 14.5 |
| Region of Enrollment Canada | 4 participants | 11 participants | 9 participants | 24 participants |
| Region of Enrollment Czechia | 24 participants | 7 participants | 22 participants | 53 participants |
| Region of Enrollment Israel | 1 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment South Korea | 11 participants | 1 participants | 4 participants | 16 participants |
| Region of Enrollment Turkey | 3 participants | 2 participants | 0 participants | 5 participants |
| Region of Enrollment United States | 71 participants | 45 participants | 40 participants | 156 participants |
| Sex: Female, Male Female | 25 Participants | 17 Participants | 21 Participants | 63 Participants |
| Sex: Female, Male Male | 89 Participants | 50 Participants | 55 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 114 | 25 / 67 | 37 / 76 |
| serious Total, serious adverse events | 2 / 114 | 1 / 67 | 1 / 76 |
Outcome results
Primary
Frequency of Subjects With a Deterioration of Hearing Threshold at Day 119 (Air Conduction)
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.
Time frame: Day 84 (TV4) to Day 119 (FUV5) of cycle 2
Population: The safety analysis set includes all subjects that had at least one intratympanic injection. Subjects are only considered at a time point if the hearing threshold is available.~Subjects from Cycle 1 did not participate in Cycle 2 and 3 and are therefore zero.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Cycle AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 119 (Air Conduction) | 1 Number subject affected |
| 2 Cycles AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 119 (Air Conduction) | 0 Number subject affected |
p-value: 0.4403Fisher Exact
Primary
Frequency of Subjects With a Deterioration of Hearing Threshold at Day 203 (Air Conduction)
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.
Time frame: Day 168 (TV7) up to Day 203 (FUV8) of cycle 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Cycle AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 203 (Air Conduction) | 2 Number subject affected |
Primary
Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction)
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.
Time frame: Day 1 (TV1) to Day 35 (FUV2) of cycle 1
Population: The safety analysis set includes all subjects that had at least one intratympanic injection. Subjects are only considered at a time point if the hearing threshold is available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Cycle AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction) | 10 Number subject affected |
| 2 Cycles AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction) | 2 Number subject affected |
| 3 Cycles AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction) | 2 Number subject affected |
Comparison: Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that received 1 treatment cycle with AM-101 or others who received 2 treatment cycles.p-value: 0.128Fisher Exact
Comparison: Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that received 1 treatment cycle with AM-101 or others who received 3 treatment cycles.p-value: 0.075Fisher Exact
Comparison: Fisher's exact test to assess if there is a difference in deterioration of hearing threshold between subjects that received 2 treatment cycles with AM-101 or others who received 3 treatment cycles.p-value: 1Fisher Exact
Secondary
Frequency of Subjects With a Deterioration of Hearing Threshold at Day 168 (Air Conduction)
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.
Time frame: Day 84 (TV4) to Day 168 (FUV6) of cycle 2
Population: The safety analysis set includes all subjects that had at least one intratympanic injection. Subjects are only considered at a time point if the hearing threshold is available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Cycle AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 168 (Air Conduction) | 0 Number subject affected |
| 2 Cycles AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 168 (Air Conduction) | 1 Number subject affected |
p-value: 1Fisher Exact
Secondary
Frequency of Subjects With a Deterioration of Hearing Threshold at Day 252 (Air Conduction)
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.
Time frame: Day 168 (TV7) to Day 252 (FUV9) of cycle 3
Population: The safety analysis set includes all subjects that had at least one intratympanic injection. Subjects are only considered at a time point if the hearing threshold is available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Cycle AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 252 (Air Conduction) | 2 Number subject affected |
Secondary
Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction)
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.
Time frame: Day 1 (TV1) to Day 84 (FUV3) of cycle 1
Population: The safety analysis set includes all subjects that had at least one intratympanic injection. Subjects are only considered at a time point if the hearing threshold is available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 Cycle AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction) | 10 Number subject affected |
| 2 Cycles AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction) | 3 Number subject affected |
| 3 Cycles AM-101 | Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction) | 0 Number subject affected |
p-value: 0.2401Fisher Exact
p-value: 0.0022Fisher Exact
p-value: 0.1001Fisher Exact