AM-101 in the Treatment of Post-Acute Tinnitus 1 (AMPACT1)

• ClinicalTrials.gov Identifier: NCT01934010
• Recruitment Status: Completed
• First Posted: September 4, 2013
• Results First Posted: March 9, 2018
• Last Update Posted: May 16, 2018
• Sponsor: Auris Medical, Inc.
• Information provided by (Responsible Party): Auris Medical, Inc.

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Tinnitus
• Intervention: Drug: AM-101
• Enrollment: 260

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.

Arm/Group Title	1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101
Arm/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)	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).	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).
Period Title: Overall Study
Started	114	67	76
Completed	91	56	74
Not Completed	23	11	2
Reason Not Completed
Adverse Event	1	1	0
Withdrawal by Subject	15	6	2
Lost to Follow-up	7	4	0

Baseline Characteristics

Arm/Group Title		1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101	Total
Arm/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)	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).	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).	Total of all reporting groups
Overall Number of Baseline Participants		114	67	76	257
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	114 participants	67 participants	76 participants	257 participants
	<=18 years	0	0	0	0
	Between 18 and 65 years	106	61	64	231
	>=65 years	8	6	12	26
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	114 participants	67 participants	76 participants	257 participants
		43.1 (14.1)	44.7 (13.9)	47.6 (15.5)	44.8 (14.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	114 participants	67 participants	76 participants	257 participants
	Female	25	17	21	63
	Male	89	50	55	194
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	114 participants	67 participants	76 participants	257 participants
United States		71	45	40	156
Czechia		24	7	22	53
Canada		4	11	9	24
Israel		1	1	1	3
South Korea		11	1	4	16
Turkey		3	2	0	5

Outcome Measures

1. Primary Outcome

Title	Frequency of Subjects With a Deterioration of Hearing Threshold at Day 35 (Air Conduction)
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.
Time Frame	Day 1 (TV1) to Day 35 (FUV2) of cycle 1

Outcome Measure Data

Analysis Population Description

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/Group Title	1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101
Arm/Group Description:	Subjects that participated only in 1 treatment cycle. This endpoint counts existing deteriorations at FUV2.	Subjects that participated in 2 treatment cycles. This endpoint lists deteriorations at FUV2.	Subjects that participated in 3 treatment cycles. This endpoint lists deteriorations at FUV2.
Overall Number of Participants Analyzed	103	67	74
Measure Type: Number; Unit of Measure: Number subject affected
	10	2	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 Cycle AM-101, 2 Cycles AM-101
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.128
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1 Cycle AM-101, 3 Cycles AM-101
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.075
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	2 Cycles AM-101, 3 Cycles AM-101
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

2. Primary Outcome

Title	Frequency of Subjects With a Deterioration of Hearing Threshold at Day 119 (Air Conduction)
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.
Time Frame	Day 84 (TV4) to Day 119 (FUV5) of cycle 2

Outcome Measure Data

Analysis Population Description

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/Group Title	2 Cycles AM-101	3 Cycles AM-101
Arm/Group Description:	Subjects that participated in 2 treatment cycles. This endpoint lists deteriorations at FUV5.	Subjects that participated in 3 treatment cycles. This endpoint lists deteriorations at FUV5.
Overall Number of Participants Analyzed	59	75
Measure Type: Number; Unit of Measure: Number subject affected
	1	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	2 Cycles AM-101, 3 Cycles AM-101
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4403
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

3. Primary Outcome

Title	Frequency of Subjects With a Deterioration of Hearing Threshold at Day 203 (Air Conduction)
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.
Time Frame	Day 168 (TV7) up to Day 203 (FUV8) of cycle 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	3 Cycles AM-101
Arm/Group Description:	Subjects that participated in 3 treatment cycles. This endpoint lists deteriorations at FUV8.
Overall Number of Participants Analyzed	74
Measure Type: Number; Unit of Measure: Number subject affected
	2

4. Secondary Outcome

Title	Frequency of Subjects With a Deterioration of Hearing Threshold at Day 84 (Air Conduction)
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.
Time Frame	Day 1 (TV1) to Day 84 (FUV3) of cycle 1

Outcome Measure Data

Analysis Population Description

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/Group Title	1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101
Arm/Group Description:	Subjects that participated only in 1 treatment cycle. This endpoint counts existing deteriorations at FUV3.	Subjects that participated in 2 treatment cycles. This endpoint lists deteriorations at FUV3.	Subjects that participated in 3 treatment cycles. This endpoint lists deteriorations at FUV3.
Overall Number of Participants Analyzed	91	66	75
Measure Type: Number; Unit of Measure: Number subject affected
	10	3	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 Cycle AM-101, 2 Cycles AM-101
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2401
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1 Cycle AM-101, 3 Cycles AM-101
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0022
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	2 Cycles AM-101, 3 Cycles AM-101
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1001
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

5. Secondary Outcome

Title	Frequency of Subjects With a Deterioration of Hearing Threshold at Day 168 (Air Conduction)
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.
Time Frame	Day 84 (TV4) to Day 168 (FUV6) of cycle 2

Outcome Measure Data

Analysis Population Description

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/Group Title	2 Cycles AM-101	3 Cycles AM-101
Arm/Group Description:	Subjects that participated in 2 treatment cycles. This endpoint lists deteriorations at FUV6.	Subjects that participated in 3 treatment cycles. This endpoint lists deteriorations at FUV6.
Overall Number of Participants Analyzed	55	76
Measure Type: Number; Unit of Measure: Number subject affected
	0	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	2 Cycles AM-101, 3 Cycles AM-101
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

6. Secondary Outcome

Title	Frequency of Subjects With a Deterioration of Hearing Threshold at Day 252 (Air Conduction)
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.
Time Frame	Day 168 (TV7) to Day 252 (FUV9) of cycle 3

Outcome Measure Data

Analysis Population Description

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/Group Title	3 Cycles AM-101
Arm/Group Description:	Subjects that participated in 3 treatment cycles. This endpoint lists deteriorations at FUV9.
Overall Number of Participants Analyzed	74
Measure Type: Number; Unit of Measure: Number subject affected
	2

Adverse Events

Time Frame	From baseline to end of study at all visits, up to Day 252.
Adverse Event Reporting Description	Assessed by Investigator at all visits. In non-serious adverse events section, under occurrences (all), reported numbers are "subjects affected".
Arm/Group Title	1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101
Arm/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)	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).	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).
All-Cause Mortality
	1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/114 (1.75%)	1/67 (1.49%)	1/76 (1.32%)
Investigations
Liver function test increased † 1	1/114 (0.88%)	0/67 (0.00%)	0/76 (0.00%)
Musculoskeletal and connective tissue disorders
Osteonecrosis † 1	0/114 (0.00%)	0/67 (0.00%)	1/76 (1.32%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lip and/or oral cavity cancer † 1	1/114 (0.88%)	0/67 (0.00%)	0/76 (0.00%)
Reproductive system and breast disorders
Adnexa uteri cyst † 1	0/114 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Adnexa uteri mass † 1	0/114 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (19.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	1 Cycle AM-101	2 Cycles AM-101	3 Cycles AM-101
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	25/114 (21.93%)	25/67 (37.31%)	37/76 (48.68%)
Ear and labyrinth disorders
Ear discomfort † 1	3/114 (2.63%)	9/67 (13.43%)	7/76 (9.21%)
Ear pain † 1	10/114 (8.77%)	13/67 (19.40%)	8/76 (10.53%)
Hypoacusis † 1	5/114 (4.39%)	4/67 (5.97%)	4/76 (5.26%)
Otorrhoea † 1	1/114 (0.88%)	4/67 (5.97%)	3/76 (3.95%)
Tinnitus † 1	0/114 (0.00%)	2/67 (2.99%)	5/76 (6.58%)
Tympanic membrane perforation † 1	0/114 (0.00%)	0/67 (0.00%)	3/76 (3.95%)
Vertigo † 1	0/114 (0.00%)	2/67 (2.99%)	1/76 (1.32%)
Eustachian tube dysfunction † 1	1/114 (0.88%)	0/67 (0.00%)	2/76 (2.63%)
Hyperacusis † 1	0/114 (0.00%)	0/67 (0.00%)	2/76 (2.63%)
Infections and infestations
Influenza † 1	0/114 (0.00%)	2/67 (2.99%)	0/76 (0.00%)
Nasopharyngitis † 1	4/114 (3.51%)	2/67 (2.99%)	6/76 (7.89%)
Bronchitis † 1	0/114 (0.00%)	0/67 (0.00%)	2/76 (2.63%)
Sinusitis † 1	0/114 (0.00%)	0/67 (0.00%)	2/76 (2.63%)
Upper respiratory tract infection † 1	0/114 (0.00%)	1/67 (1.49%)	2/76 (2.63%)
Nervous system disorders
Headache † 1	5/114 (4.39%)	7/67 (10.45%)	9/76 (11.84%)
Dizziness † 1	0/114 (0.00%)	1/67 (1.49%)	2/76 (2.63%)
Psychiatric disorders
Anxiety † 1	1/114 (0.88%)	1/67 (1.49%)	2/76 (2.63%)
Surgical and medical procedures
Artificial crown procedure † 1	0/114 (0.00%)	0/67 (0.00%)	2/76 (2.63%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (19.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Investigator agrees to submit a copy of any intended communication, presentation or publication (abstract, poster, article, etc.) (all together "Communication") at least 2 month in advance of the submission of proposed Communication. The Sponsor shall have 60 days, after receipt of said copies, to object to such proposed Communication. In case of such objection, the Investigator shall refrain from making such Communication for 6 months from date of receipt of such objection.

Results Point of Contact

• Name/Title: Thomas Meyer, CEO
• Organization: Auris Medical Inc.
• Phone: +1 312 396 4150
• EMail: hear@aurismedical.com

• Responsible Party: Auris Medical, Inc.
• ClinicalTrials.gov Identifier: NCT01934010
• Other Study ID Numbers: AM-101-CL-12-03
• First Submitted: August 15, 2013
• First Posted: September 4, 2013
• Results First Submitted: February 8, 2018
• Results First Posted: March 9, 2018
• Last Update Posted: May 16, 2018