Clinical Trial Results:
Efficacy of AM-111 in Patients with Acute Sensorineural Hearing Loss: A Multi-Centre, Double-Blind, Randomised, Placebo-Controlled, Dose-Escalation Phase II Study
Summary
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EudraCT number |
2008-000132-40 |
Trial protocol |
DE CZ |
Global end of trial date |
17 Jul 2012
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Aug 2016
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First version publication date |
06 Aug 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AM-111-CL-08-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Auris Medical AG
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Sponsor organisation address |
Falknerstr. 4, Basel, Switzerland, 4001
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Public contact |
Thomas Meyer, Auris Medical AG, +41 61 201 13 50, ear@aurismedical.com
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Scientific contact |
Thomas Meyer, Auris Medical AG, +41 61 201 13 50, ear@aurismedical.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Jun 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Jul 2012
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Jul 2012
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the study was the evaluation of the therapeutic benefit of a single intratympanic (i.t.) AM-111 injection in comparison to placebo in the treatment of acute sensorineural hearing loss (ASNHL).
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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, respectively in their most current version.
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Background therapy |
Reserve therapy option: Subjects whose pure tone average (PTA) recovered on average less than 10 dB from baseline to Day7 were given the option to receive a 5-day course of prednisolone by way of oral administration (2 x 50 mg daily). | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Feb 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 41
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Country: Number of subjects enrolled |
Poland: 143
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Country: Number of subjects enrolled |
Czech Republic: 26
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Worldwide total number of subjects |
210
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EEA total number of subjects |
210
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
210
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Twenty-five European sites (academic tertiary referral centers and private ENT practices) from 3 EU countries participated in the study. A total of 210 patients were screened. Of these, all 210 patients were randomised. | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Main inclusion criteria were: Age 18 - 60 years; unilateral ISSNHL or uni-or bilateral AAT; hearing loss at least 30 dB; onset not more than 48h before. All 210 screened patients have been randomised. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Whole study period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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AM-111 0.4 mg/mL | ||||||||||||||||||||||||||||||||||||
Arm description |
Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
JNK inhibitor (D-JNKI-1)
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Investigational medicinal product code |
AM-111
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Other name |
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Pharmaceutical forms |
Gel for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
Single intratympanic application of AM-111 0.4 mg/mL (0.25 mL). In case of bilateral AAT, only the worse affected ear was treated.
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Arm title
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AM-111 2.0 mg/mL | ||||||||||||||||||||||||||||||||||||
Arm description |
Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
JNK inhibitor (D-JNKI-1)
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Investigational medicinal product code |
AM-111
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Other name |
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Pharmaceutical forms |
Gel for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
Single intratympanic application of AM-111 2.0 mg/mL (0.25 mL). In case of bilateral AAT, only the worse affected ear was treated.
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Arm title
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Placebo pooled | ||||||||||||||||||||||||||||||||||||
Arm description |
The study consisted of 2 dose cohorts each randomised individually against placebo in a 2:1 ratio. In the results presentation the 2 placebo groups from the 2 cohorts were pooled and are presented as 1 pooled placebo group. Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
0.25 mL of gel without active were injected. In case of bilateral AAT, only the worse affected ear was treated.
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Baseline characteristics reporting groups
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Reporting group title |
AM-111 0.4 mg/mL
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Reporting group description |
Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AM-111 2.0 mg/mL
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Reporting group description |
Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo pooled
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Reporting group description |
The study consisted of 2 dose cohorts each randomised individually against placebo in a 2:1 ratio. In the results presentation the 2 placebo groups from the 2 cohorts were pooled and are presented as 1 pooled placebo group. Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
AM-111 0.4 mg/mL
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Reporting group description |
Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||
Reporting group title |
AM-111 2.0 mg/mL
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Reporting group description |
Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. | ||
Reporting group title |
Placebo pooled
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Reporting group description |
The study consisted of 2 dose cohorts each randomised individually against placebo in a 2:1 ratio. In the results presentation the 2 placebo groups from the 2 cohorts were pooled and are presented as 1 pooled placebo group. Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment. |
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End point title |
Absolute improvement of pure tone average (PTA) | ||||||||||||||||
End point description |
The absolute improvement of PTA given in dB between Day 0 and Day 7 based on the average of the three most affected contiguous frequencies.
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End point type |
Primary
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End point timeframe |
Day 0 to Day 7.
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Statistical analysis title |
Absolute Change in PTA (dB) from baseline to Day 7 | ||||||||||||||||
Statistical analysis description |
Global comparison with analysis set "valid for efficacy" was used.
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Comparison groups |
Placebo pooled v AM-111 2.0 mg/mL
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Number of subjects included in analysis |
135
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.611 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Confidence interval |
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Statistical analysis title |
Absolute Change in PTA (dB) from baseline to Day 7 | ||||||||||||||||
Statistical analysis description |
Global comparison with analysis set "valid for efficacy" was used.
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Comparison groups |
AM-111 0.4 mg/mL v Placebo pooled
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Number of subjects included in analysis |
133
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.203 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Confidence interval |
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End point title |
Co-primary: Relative Change in PTA (%) | ||||||||||||||||
End point description |
Relative changes from baseline in (%)
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End point type |
Primary
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End point timeframe |
Day 0 to Day 7
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Statistical analysis title |
Relative Change Placebo pooled vs AM-111 2.0 mg/mL | ||||||||||||||||
Statistical analysis description |
Valid for efficacy analysis set was used.
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Comparison groups |
AM-111 2.0 mg/mL v Placebo pooled
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Number of subjects included in analysis |
135
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.12 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Statistical analysis title |
Relative Change Placebo pooled vs AM-111 0.4 mg/mL | ||||||||||||||||
Statistical analysis description |
Valid for efficacy analysis set was used.
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Comparison groups |
AM-111 0.4 mg/mL v Placebo pooled
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Number of subjects included in analysis |
133
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.5 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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End point title |
Co-primary: Fequency complete recovery | ||||||||||||||||||||
End point description |
Subjects with complete recovery were counted.
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End point type |
Primary
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End point timeframe |
Day 0 to Day 7
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Statistical analysis title |
Complete recovery rate | ||||||||||||||||||||
Statistical analysis description |
Valid for Efficacy analysis set was used.
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Comparison groups |
AM-111 2.0 mg/mL v Placebo pooled
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Number of subjects included in analysis |
135
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.3 | ||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Complete recovery rate | ||||||||||||||||||||
Statistical analysis description |
Valid for Efficacy analysis set was used.
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Comparison groups |
Placebo pooled v AM-111 0.4 mg/mL
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Number of subjects included in analysis |
133
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.55 | ||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||
Confidence interval |
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End point title |
Safety: Frequency of patients with clinically significant hearing loss in the treated ear | ||||||||||||
End point description |
The primary safety endpoint was defined as the number of subjects with clinically significant hearing loss, defined as deterioration of hearing thresholds of ≥10 dB at the average of any 3 contiguous test frequencies, in the treated ear from baseline to Day 7.
Analysis performed on Valid for Safety group.
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End point type |
Primary
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End point timeframe |
Day 0 to Day 7
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Notes [1] - number of patients with significant clinically hearing loss is shown, same for all reporting groups |
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Statistical analysis title |
Comparison - frequency of significant hearing Loss | ||||||||||||
Statistical analysis description |
Comparison of subjects with clinically significant hearing loss in the treated ear.
Only within-cohort data were used.
Valid for Safety data set is used.
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Comparison groups |
Placebo pooled v AM-111 2.0 mg/mL
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Number of subjects included in analysis |
135
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 1 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Confidence interval |
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Statistical analysis title |
Comparison - frequency of significant hearing Loss | ||||||||||||
Statistical analysis description |
Comparison of subjects with clinically significant hearing loss in the treated ear.
Only within-cohort data were used.
Valid for Safety data set is used.
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Comparison groups |
Placebo pooled v AM-111 0.4 mg/mL
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Number of subjects included in analysis |
129
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.69 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Confidence interval |
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End point title |
Improvement in Speech Discrimination Score (SDS) (all) | ||||||||||||||||
End point description |
Average improvement in SDS between baseline and Day 7. Words were presented at 80 dB stimulus level.
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End point type |
Other pre-specified
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End point timeframe |
Day 0 to Day 7
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Statistical analysis title |
Absolute Change in SDS at 80 dB | ||||||||||||||||
Comparison groups |
Placebo pooled v AM-111 2.0 mg/mL
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Number of subjects included in analysis |
133
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.15 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Statistical analysis title |
Absolute Change in SDS at 80 dB | ||||||||||||||||
Comparison groups |
Placebo pooled v AM-111 0.4 mg/mL
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Number of subjects included in analysis |
131
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.028 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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End point title |
Subgroup analysis: Absolute improvement of pure tone average (PTA) - severe to profound hearing loss | ||||||||||||||||
End point description |
Due to unexpected high spontaneous recovery in mild to moderate hearing loss cases, an additional analysis on the subgroup with severe to profound hearing loss was performed.
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End point type |
Post-hoc
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End point timeframe |
Day 0 - Day 7
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Statistical analysis title |
Absolute Change in PTA in profound to severe HL | ||||||||||||||||
Statistical analysis description |
Subgroup analysis in patients with profound to severe hearing loss on Valid for Efficacy analysis set.
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Comparison groups |
Placebo pooled v AM-111 0.4 mg/mL
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Number of subjects included in analysis |
59
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.017 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Statistical analysis title |
Absolute Change in PTA in profound to severe HL | ||||||||||||||||
Statistical analysis description |
Subgroup analysis in patients with profound to severe hearing loss on Valid for Efficacy analysis set.
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Comparison groups |
AM-111 2.0 mg/mL v Placebo pooled
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Number of subjects included in analysis |
63
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.32 | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
From baseline to end of study at all visits.
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Adverse event reporting additional description |
The occurrence of a treatment emergent adverse event in the same subject more than once was counted only once for non-serious adverse events.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
AM-111 0.4 mg/mL
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AM-111 2.0 mg/mL
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo pooled
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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11 May 2009 |
Modification of inclusion criteria:
- Average hearing loss of at least 30 dB in the 3 most affected contiguous frequencies instead of ≥ 30 dB at each of the 3 frequencies.
- Option to determine the hearing loss against the age and gender adjusted ISO tables and no longer only against the contralateral ear or against a pre-existing audiogram.
- Inclusion of bilateral hearing loss resulting from noise trauma.
Modification of exclusion criteria:
- Requirement of pre-existing audiogram to document history of asymmetric hearing before ASNHL dropped. |
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03 Nov 2010 |
- Change of concentration for second cohort from 6.0 to 0.4 mg/mL; correspondingly waiver of safety and tolerability review prior to start of second cohort (no patient was dosed with 6.0 mg/mL).
- Requirement for ABR measurements prior to study inclusion added to help diagnose retrocochlear lesions.
- Clarification of conditions for prednisolone reserve therapy.
- Comprehensive revision of the statistics section, including: Definition of statistical analysis sets; Imputation of missing values; Endpoint model; Test hypotheses; Adjustment for multiple testing of efficacy endpoints. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |