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AM-101 in the Treatment of Acute Tinnitus 2 (TACTT2)

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ClinicalTrials.gov Identifier: NCT01803646
Recruitment Status : Completed
First Posted : March 4, 2013
Results First Posted : May 29, 2018
Last Update Posted : May 29, 2018
Sponsor:
Information provided by (Responsible Party):
Auris Medical, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Tinnitus
Interventions Drug: AM-101
Drug: Placebo
Enrollment 343
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 Details

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
Hide 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
Reason Not Completed
Protocol Violation             1             0
Adverse Event             1             1
Withdrawal by Subject             9             6
Randomization error             1             2
Lost to Follow-up             5             1
Arm/Group Title AM-101 0.87 mg/mL Gel Placebo Gel Total
Hide 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 Number of Baseline Participants 204 139 343
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 204 participants 139 participants 343 participants
<=18 years
0
   0.0%
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, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 204 participants 139 participants 343 participants
43.4  (14.6) 44.2  (15.2) 43.7  (14.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 204 participants 139 participants 343 participants
Female
43
  21.1%
37
  26.6%
80
  23.3%
Male
161
  78.9%
102
  73.4%
263
  76.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 204 participants 139 participants 343 participants
United States 122 82 204
Czechia 38 26 64
Canada 20 14 34
Israel 2 1 3
South Korea 15 12 27
Turkey 7 4 11
1.Primary Outcome
Title Efficacy: Change in Patient-reported Tinnitus Loudness Questionnaire (TLQ) Improvement From Baseline to Follow up Visit 3 (FUV3)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 195 129
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.80
(0.51 to 1.08)
0.63
(0.38 to 0.87)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AM-101 0.87 mg/mL Gel, Placebo Gel
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.32
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.51 to 0.17
Estimation Comments [Not Specified]
2.Primary Outcome
Title Co-Primary Efficacy: Improvement in Tinnitus Functional Index (TFI) Total Score From Baseline to FUV3
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 180 121
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
10.4
(6.5 to 14.3)
9.6
(5.9 to 13.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AM-101 0.87 mg/mL Gel, Placebo Gel
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.63
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.79
Confidence Interval (2-Sided) 95%
-4 to 2.4
Estimation Comments [Not Specified]
3.Primary Outcome
Title Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 193 130
Measure Type: Count of Participants
Unit of Measure: Participants
Air conduction Subjects with hearing deterioration
12
   6.2%
9
   6.9%
Subjects without hearing deterioration
181
  93.8%
121
  93.1%
Bone conduction Subjects with hearing deterioration
3
   1.6%
4
   3.1%
Subjects without hearing deterioration
190
  98.4%
126
  96.9%
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.821
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 1.0
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%)
Total   0/201 (0.00%)   0/135 (0.00%) 
Hide Serious Adverse Events
AM-101 0.87 mg/mL Gel Placebo Gel
Affected / at Risk (%) Affected / at Risk (%)
Total   5/201 (2.49%)   1/135 (0.74%) 
Cardiac disorders     
Atrial fibrillation  1  0/201 (0.00%)  1/135 (0.74%) 
Infections and infestations     
Urinary tract infection  1  1/201 (0.50%)  0/135 (0.00%) 
Injury, poisoning and procedural complications     
Lower limb fracture  1  1/201 (0.50%)  0/135 (0.00%) 
Tendon rupture  1  1/201 (0.50%)  0/135 (0.00%) 
Nervous system disorders     
Generalised tonic-clonic seizure  1  1/201 (0.50%)  0/135 (0.00%) 
Psychiatric disorders     
Mental disorder  1  1/201 (0.50%)  0/135 (0.00%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
AM-101 0.87 mg/mL Gel Placebo Gel
Affected / at Risk (%) Affected / at Risk (%)
Total   63/201 (31.34%)   38/135 (28.15%) 
Ear and labyrinth disorders     
Ear discomfort  1  14/201 (6.97%)  8/135 (5.93%) 
Ear pain  1  16/201 (7.96%)  10/135 (7.41%) 
Hypoacusis  1  8/201 (3.98%)  4/135 (2.96%) 
Tinnitus  1  8/201 (3.98%)  5/135 (3.70%) 
Tympanic membrane perforation  1  5/201 (2.49%)  4/135 (2.96%) 
Vertigo  1  2/201 (1.00%)  4/135 (2.96%) 
Gastrointestinal disorders     
Nausea  1  4/201 (1.99%)  2/135 (1.48%) 
General disorders     
Injection site pain  1  5/201 (2.49%)  1/135 (0.74%) 
Infections and infestations     
Nasopharyngitis  1  6/201 (2.99%)  4/135 (2.96%) 
Sinusitis  1  4/201 (1.99%)  0/135 (0.00%) 
Upper respiratory tract infection  1  5/201 (2.49%)  2/135 (1.48%) 
Nervous system disorders     
Dizziness  1  10/201 (4.98%)  1/135 (0.74%) 
Headache  1  11/201 (5.47%)  6/135 (4.44%) 
Psychiatric disorders     
Anxiety  1  7/201 (3.48%)  1/135 (0.74%) 
Insomnia  1  4/201 (1.99%)  0/135 (0.00%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
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
Layout table for Results Point of Contact information
Name/Title: Thomas Meyer, CEO
Organization: Auris Medical Inc.
Phone: +1 312 396 4150
EMail: hear@aurismedical.com
Layout table for additonal information
Responsible Party: Auris Medical, Inc.
ClinicalTrials.gov Identifier: NCT01803646    
Other Study ID Numbers: AM-101-CL-12-01
First Submitted: March 1, 2013
First Posted: March 4, 2013
Results First Submitted: January 18, 2018
Results First Posted: May 29, 2018
Last Update Posted: May 29, 2018