TACTT2: AM-101 in the Treatment of Acute Tinnitus 2

• Sponsor: Auris Medical, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01803646
• Collaborator: (none)
• Enrollment: 343
• Location: 1
• Arms: 2
• Duration (Months): 28
• Patients Per Site Per Month: 12.3

Study Details

Study Description

Brief Summary

The purpose of this research study is to test the safety and effectiveness of the study drug, AM-101. AM-101 is tested for the treatment of tinnitus that started as the result of an injury to the inner ear or due to middle ear inflammation (otitis media). Subjects with tinnitus can take part in the study, if their tinnitus started within the last 3 months.

Condition or Disease	Intervention/Treatment	Phase
Tinnitus	Drug: AM-101; Drug: Placebo	Phase 3

Detailed Description

This phase III study is assessing the drug's safety and is aiming to demonstrate efficacy of repeated intratymanic AM-101 injections in the treatment of acute peripheral tinnitus (up to 3 months from onset).

Study Design

• Study Type: Interventional
• Actual Enrollment: 343 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of AM-101 in the Treatment of Acute Peripheral Tinnitus 2
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AM-101 injection AM-101	Drug: AM-101; AM-101 gel for intratympanic injection
Placebo Comparator: Placebo injection Placebo	Drug: Placebo; Placebo gel for intratympanic injection

Outcome Measures

Primary Outcome Measures

1. Efficacy: Change in Patient-reported Tinnitus Loudness Questionnaire (TLQ) Improvement From Baseline to Follow up Visit 3 (FUV3) [Screening (D-14) versus final follow-up (D83)]

   Starting at the screening visit (SV), each subject recorded the following numerical rating scales (NRS) throughout the entire study duration: - Tinnitus loudness "at its loudest" within the last 24 hours (Tinnitus Loudness Questionnaire [TLQ] NRSLoudest). Subjects were asked "On a scale from 0 to 10, where 0 represents no tinnitus and 10 represents extremely loud tinnitus, what one number best describes your tinnitus at its loudest in the last 24 hours (including right now)?" TLQ NRSLoudest was collected from SV (D-14) to the evening before FUV3 (D83). The ratings were to be recorded every day before going to sleep on an electronic device. As Baseline the10 ratings of the screening period before the first treatment were averaged. For the FUV3 endpoint, the ratings of the 7 days before FUV3 were averaged.

2. Co-Primary Efficacy: Improvement in Tinnitus Functional Index (TFI) Total Score From Baseline to FUV3 [D0 (=TV1) versus Day 84 (=FUV3)]

   The TFI was recorded on an electronic device (electronic patient reported outcome) at Treatment Visit 1 (TV1), before randomization, and at Follow up Visit 1 (FUV1), FUV2 and FUV3. The TFI is a patient reported outcome questionnaire and contains 25 questions. It includes eight subscales: Intrusive, Sense of Control, Cognitive, Sleep, Auditory, Relaxation, Quality of Life, and Emotional. Each question is to be rated on a NRS between 0 and 10 (or 0 to 100%), with a recall period of "over the past week". The TFI total score is considered as valid if there are evaluable answers for at least 19 of the 25 items (76% of items) (Meikle et al. 2012). The repondent's overall TFI score is within a 0-100 range. For the subscales the range is the same. A lower value represents an improvement for all scales. Please refer to the following publicly available link for more information: http://download.lww.com/wolterskluwer_vitalstream_com/PermaLink/EANDH/A/EANDH_2011_09_27_HENRY_200593_SDC15.pdf

3. Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) [Day 35]

   Occurence of deterioration of hearing (Air and Bone conduction) in the treated ear at FUV2. Deterioration is defined as a deterioration of hearing threshold of at least 15 dB from Baseline at the average of 2 contiguous frequencies.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Persistent subjective peripheral tinnitus (unilateral or bilateral) following traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma, tympanic membrane trauma) or otitis media with onset no longer than 3 months prior to randomization

2. Age ≥ 18 years and ≤ 75 years (≥ 14 years and ≤ 75 years at selected sites);

3. Negative pregnancy test (woman of childbearing potential);

4. Willing and able to use adequate hearing protection, respectively to refrain from engaging in activities or work involving loud noise exposure where sufficient hearing protection is not possible or ensured;

5. Willing and able to protect ear canal and middle ear from water exposure as long as tympanic membrane is not fully closed.

Other protocol-defined inclusion criteria may apply.

Exclusion Criteria:

1. Fluctuating tinnitus;

2. Intermittent tinnitus;

3. Tinnitus resulting from traumatic head or neck injury;

4. Presence of chronic tinnitus;

5. Meniere's Disease, history of endolymphatic hydrops, or history of fluctuating hearing loss;

6. History of repeated idiopathic sudden sensorineural hearing loss or history of acoustic neuroma;

7. Ongoing acute or chronic otitis media or otitis externa;

8. Other treatment of tinnitus for the study duration;

9. Known hypersensitivity, allergy or intolerance to the study medication or any history of severe, abnormal drug reaction;

10. Women who are breast-feeding, pregnant or who are planning to become pregnant during the study;

11. Women of childbearing potential who are unwilling or unable to practice contraception, such as hormonal contraceptives, double barrier, sexual abstinence or intercourse with a partner who has been vasectomised for at least three months;

12. Concurrent participation in another clinical study or participation in another clinical study within 30 days prior to randomization.

Other protocol-defined exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medpace	Cincinnati	Ohio	United States	45227

Sponsors and Collaborators

• Auris Medical, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Auris Medical, Inc.
• ClinicalTrials.gov Identifier: NCT01803646
• Other Study ID Numbers: AM-101-CL-12-01
• First Posted: Mar 4, 2013
• Last Update Posted: May 29, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Tinnitus

Study Results

Participant Flow

Recruitment Details	A total of 86 sites were initiated in Canada, the United States, the Czech Republic, Israel, Turkey and Republic of South Korea. In total, 69 sites screened each at least 1 subject and 64 sites randomized subjects for treatment.
Pre-assignment Detail	A total of 478 subjects were screened, 343 subjects were randomized, and 336 subjects were treated. 7 subjects were randomized (3 to AM-101 and 4 to placebo) but not treated; these subjects were excluded from the analysis sets. The majority (92%) of subjects completed the study.

Arm/Group Title	AM-101 0.87 mg/mL Gel	Placebo Gel
Arm/Group Description	Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)	Three intratympanic administration of placebo gel within 5 days (D0-D4).
Period Title: Overall Study
STARTED	204	139
COMPLETED	187	129
NOT COMPLETED	17	10

Baseline Characteristics

Arm/Group Title	AM-101 0.87 mg/mL Gel	Placebo Gel	Total
Arm/Group Description	Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)	Three intratympanic administration of placebo gel within 5 days (D0-D4).	Total of all reporting groups
Overall Participants	204	139	343
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	188 92.2%	125 89.9%	313 91.3%
>=65 years	16 7.8%	14 10.1%	30 8.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.4 (14.6)	44.2 (15.2)	43.7 (14.8)
Sex: Female, Male (Count of Participants)
Female	43 21.1%	37 26.6%	80 23.3%
Male	161 78.9%	102 73.4%	263 76.7%
Region of Enrollment (participants) [Number]
United States	122 59.8%	82 59%	204 59.5%
Czechia	38 18.6%	26 18.7%	64 18.7%
Canada	20 9.8%	14 10.1%	34 9.9%
Israel	2 1%	1 0.7%	3 0.9%
South Korea	15 7.4%	12 8.6%	27 7.9%
Turkey	7 3.4%	4 2.9%	11 3.2%

Outcome Measures

1. Primary Outcome

Title	Efficacy: Change in Patient-reported Tinnitus Loudness Questionnaire (TLQ) Improvement From Baseline to Follow up Visit 3 (FUV3)
Description	Starting at the screening visit (SV), each subject recorded the following numerical rating scales (NRS) throughout the entire study duration: - Tinnitus loudness "at its loudest" within the last 24 hours (Tinnitus Loudness Questionnaire [TLQ] NRSLoudest). Subjects were asked "On a scale from 0 to 10, where 0 represents no tinnitus and 10 represents extremely loud tinnitus, what one number best describes your tinnitus at its loudest in the last 24 hours (including right now)?" TLQ NRSLoudest was collected from SV (D-14) to the evening before FUV3 (D83). The ratings were to be recorded every day before going to sleep on an electronic device. As Baseline the10 ratings of the screening period before the first treatment were averaged. For the FUV3 endpoint, the ratings of the 7 days before FUV3 were averaged.
Time Frame	Screening (D-14) versus final follow-up (D83)

Outcome Measure Data

Analysis Population Description

Valid for Efficacy dataset includes all subjects treated with at least one i.t. injection (AM-101 or placebo), a valid TLQ NRSLoudest or TFI rating at baseline and at least one valid post-baseline rating. Ten subjects had neither TLQ nor TFI baseline and 2 subjects had no valid rating for the TLQ resulting in 324 evaluable subjects.

Arm/Group Title	AM-101 0.87 mg/mL Gel	Placebo Gel
Arm/Group Description	Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)	Three intratympanic administration of placebo gel within 5 days (D0-D4).
Measure Participants	195	129
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.80	0.63

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AM-101 0.87 mg/mL Gel, Placebo Gel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Co-Primary Efficacy: Improvement in Tinnitus Functional Index (TFI) Total Score From Baseline to FUV3
Description	The TFI was recorded on an electronic device (electronic patient reported outcome) at Treatment Visit 1 (TV1), before randomization, and at Follow up Visit 1 (FUV1), FUV2 and FUV3. The TFI is a patient reported outcome questionnaire and contains 25 questions. It includes eight subscales: Intrusive, Sense of Control, Cognitive, Sleep, Auditory, Relaxation, Quality of Life, and Emotional. Each question is to be rated on a NRS between 0 and 10 (or 0 to 100%), with a recall period of "over the past week". The TFI total score is considered as valid if there are evaluable answers for at least 19 of the 25 items (76% of items) (Meikle et al. 2012). The repondent's overall TFI score is within a 0-100 range. For the subscales the range is the same. A lower value represents an improvement for all scales. Please refer to the following publicly available link for more information: http://download.lww.com/wolterskluwer_vitalstream_com/PermaLink/EANDH/A/EANDH_2011_09_27_HENRY_200593_SDC15.pdf
Time Frame	D0 (=TV1) versus Day 84 (=FUV3)

Outcome Measure Data

Analysis Population Description

Valid for Efficacy dataset includes all subjects treated with at least one i.t. injection (AM-101 or placebo), a valid TLQ NRSLoudest or TFI rating at baseline and at least one valid post-baseline rating. Ten subjects had neither TLQ nor TFI baseline plus additional 25 subjects had no baseline for the TFI resulting in 301 evaluable subjects.

Arm/Group Title	AM-101 0.87 mg/mL Gel	Placebo Gel
Arm/Group Description	Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)	Three intratympanic administration of placebo gel within 5 days (D0-D4).
Measure Participants	180	121
Least Squares Mean (95% Confidence Interval) [units on a scale]	10.4	9.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AM-101 0.87 mg/mL Gel, Placebo Gel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.79
	Confidence Interval	(2-Sided) 95%; -4 to 2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2)
Description	Occurence of deterioration of hearing (Air and Bone conduction) in the treated ear at FUV2. Deterioration is defined as a deterioration of hearing threshold of at least 15 dB from Baseline at the average of 2 contiguous frequencies.
Time Frame	Day 35

Outcome Measure Data

Analysis Population Description

Valid for Safety dataset was used. Of the 336 valid for safety subjects, 323 could be evaluated for this endpoint.

Arm/Group Title	AM-101 0.87 mg/mL Gel	Placebo Gel
Arm/Group Description	Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)	Three intratympanic administration of placebo gel within 5 days (D0-D4).
Measure Participants	193	130
Subjects with hearing deterioration	12 5.9%	9 6.5%
Subjects without hearing deterioration	181 88.7%	121 87.1%
Subjects with hearing deterioration	3 1.5%	4 2.9%
Subjects without hearing deterioration	190 93.1%	126 90.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AM-101 0.87 mg/mL Gel, Placebo Gel
	Comments	Analysis for air conduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.821
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AM-101 0.87 mg/mL Gel, Placebo Gel
	Comments	Analysis for bone conduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Assessed by Investigator at all Visits from Screening Visit (SV, D-14) to end of treatment visit FUV3 (D84). Including at treatment visit 1 (TV1), TV2, TV3, FUV1 and FUV2. It was also assessed at Conditional Visits if they were required.
Adverse Event Reporting Description	Safety population includes 336 instead of 343 subjects. As 7 subjects were randomized but not treated (see pre-assignment details).
Arm/Group Title	AM-101 0.87 mg/mL Gel		Placebo Gel
Arm/Group Description	Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)		Three intratympanic administration of placebo gel within 5 days (D0-D4).
All Cause Mortality
	AM-101 0.87 mg/mL Gel		Placebo Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/201 (0%)		0/135 (0%)
Serious Adverse Events
	AM-101 0.87 mg/mL Gel		Placebo Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/201 (2.5%)		1/135 (0.7%)
Cardiac disorders
Atrial fibrillation	0/201 (0%)		1/135 (0.7%)
Infections and infestations
Urinary tract infection	1/201 (0.5%)		0/135 (0%)
Injury, poisoning and procedural complications
Lower limb fracture	1/201 (0.5%)		0/135 (0%)
Tendon rupture	1/201 (0.5%)		0/135 (0%)
Nervous system disorders
Generalised tonic-clonic seizure	1/201 (0.5%)		0/135 (0%)
Psychiatric disorders
Mental disorder	1/201 (0.5%)		0/135 (0%)
Other (Not Including Serious) Adverse Events
	AM-101 0.87 mg/mL Gel		Placebo Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/201 (31.3%)		38/135 (28.1%)
Ear and labyrinth disorders
Ear discomfort	14/201 (7%)		8/135 (5.9%)
Ear pain	16/201 (8%)		10/135 (7.4%)
Hypoacusis	8/201 (4%)		4/135 (3%)
Tinnitus	8/201 (4%)		5/135 (3.7%)
Tympanic membrane perforation	5/201 (2.5%)		4/135 (3%)
Vertigo	2/201 (1%)		4/135 (3%)
Gastrointestinal disorders
Nausea	4/201 (2%)		2/135 (1.5%)
General disorders
Injection site pain	5/201 (2.5%)		1/135 (0.7%)
Infections and infestations
Nasopharyngitis	6/201 (3%)		4/135 (3%)
Sinusitis	4/201 (2%)		0/135 (0%)
Upper respiratory tract infection	5/201 (2.5%)		2/135 (1.5%)
Nervous system disorders
Dizziness	10/201 (5%)		1/135 (0.7%)
Headache	11/201 (5.5%)		6/135 (4.4%)
Psychiatric disorders
Anxiety	7/201 (3.5%)		1/135 (0.7%)
Insomnia	4/201 (2%)		0/135 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.