Clinical Trials Register

Summary
EudraCT Number:	2012-004099-20
Sponsor's Protocol Code Number:	AM-101-CL-12-02
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-09-18
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2012-004099-20

A.3

Full title of the trial

Efficacy and Safety of AM-101 in the Treatment of Acute Peripheral Tinnitus 3 (TACTT3)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to observe efficacy and safety of AM-101 in patients with tinnitus

A.3.2

Name or abbreviated title of the trial where available

TACTT3

A.4.1

Sponsor's protocol code number

AM-101-CL-12-02

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Auris Medical AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Auris Medical AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Auris Medical AG
B.5.2	Functional name of contact point	Information
B.5.3	Address:
B.5.3.1	Street Address	Dornacherstrasse 210
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4053
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4161201 1350
B.5.5	Fax number	+4161201 1351
B.5.6	E-mail	ear@aurismedical.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	AM-101
D.3.4	Pharmaceutical form	Gel for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intratympanic use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Esketamine Hydrochloride
D.3.9.1	CAS number	33643-47-9
D.3.9.2	Current sponsor code	AM-101
D.3.9.3	Other descriptive name	ESKETAMINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB25811
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.0
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Gel for injection
D.8.4	Route of administration of the placebo	Intratympanic use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

acute peripheral tinnitus following traumatic cochlear injury or otitis media

E.1.1.1

Medical condition in easily understood language

acute tinnitus

E.1.1.2

Therapeutic area

Diseases [C] - Ear, nose and throat diseases [C09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10043882
E.1.2	Term	Tinnitus
E.1.2	System Organ Class	10013993 - Ear and labyrinth disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is the evaluation and confirmation of the efficacy of repeated i.t. AM 101 injections in the treatment of acute peripheral tinnitus.
In Stratum A and Stratum B (Part 2) the following populations will be
formally assessed for confirmation of efficacy:
• The overall population of subjects;
• The subpopulation of subjects with otitis media aetiology;
• The subpopulation of subjects with severe tinnitus

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are a) the further assessment of the safety and local tolerance of repeated i.t. AM 101 injections in the treatment of acute peripheral tinnitus, and b) the evaluation of the efficacy of repeated i.t. AM-101 injections in the treatment of post-acute peripheral tinnitus and in the subpopulation of subjects with severe tinnitus.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A subject will be eligible for inclusion in this study if all of the following criteria apply:
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 three months (Stratum A) or between three and 6 months (Stratum B) prior to randomization (D0), as documented by medical report or by documented medical history.
Persistent tinnitus is given when the question, “When you were thinking of your tinnitus in the past two weeks, could you always hear it or only sometimes?” is answered with “Always”, and the question, “Did your tinnitus in the past two weeks occur all of the time, most of the time, a good bit of the time, some of the time, a little of the time, none of the time?” is answered with “All of the time” or “Most of the time” or “A good bit of the time”. The words, "past two weeks" may be replaced with “since onset” if tinnitus started less than two weeks ago.
2. Age ≥ 18 years and ≤ 75 years;
3. Negative urine pregnancy test for women of childbearing potential; Women are not considered to be of childbearing potential if they meet 1 of the following criteria:
a. They have had a hysterectomy or tubal ligation at minimum 1 cycle prior to signing the ICF or
b. They are post menopausal, defined as ≥1 year since their last menstrual period for women ≥55 years of age or ≥1 year since their last menstrual period and have a follicle stimulating hormone (FSH) level in menopausal range for women <55 years of age;
4. Willing and able to attend the study visits;
5. Able to read and understand study documents, to complete the relevant questionnaires and rating scales and follow Investigator instructions;
6. Able to understand and follow study personnel instructions during audiologic measurements;
7. 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;
8. Willing and able to protect ear canal and middle ear from water exposure as long as tympanic membrane is not fully closed after IMP administration;
9. Signed IRB/IEC approved Informed Consent Form (ICF).

E.4

Principal exclusion criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Fluctuating tinnitus;
Fluctuating tinnitus is given when the question “Over the last 2 weeks, has the pitch of your tinnitus [risen / decreased / fluctuated / remained steady / not clear]?” is answered with “fluctuated” or “not clear”.
2. Intermittent tinnitus;
Intermittent tinnitus is given when the question “When you were thinking of your tinnitus in the past two weeks, could you always hear it or only sometimes?” is answered with “only sometimes”.
3. Tinnitus resulting from traumatic head or neck injury;
4. Onset of tinnitus more than 3 months ago (Stratum A), respectively more than 6 months ago (Stratum B);
5. Suspected or diagnosed Meniere’s Disease, history of endolymphatic hydrops, or history of fluctuating hearing loss;
6. History of repeated idiopathic sudden sensorineural hearing loss (defined as at least two events of ISSNHL in the last 24 months) or history of acoustic neuroma;
7. Ongoing purulent acute or chronic otitis media or otitis externa;
8. Abnormality of the tympanic membrane in the affected ear(s) that would preclude i.t. injection;
9. Subjects with current hearing loss in the affected ear(s) of 75 dB or more in one or more test frequencies (250 Hz, 500 Hz, 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz, 8 kHz);
10. Subjects with fluctuating hearing (≥20 dB difference in any two contiguous test frequencies over the screening period; SV, D-14 to TV1, D0);
11. Any drug-based therapy for otitis media or otitis externa that is ongoing or was performed in the past two weeks prior to randomization (TV1, D0);
12. Any drug-based therapy known as potentially tinnitus-inducing (e.g. aminoglycosides, cisplatin, loop diuretics, high doses of aspirin [> 2 g/day] or quinine) in the past 2 weeks prior to randomization (TV1, D0) or that is ongoing or planned for the study duration;
13. Use of any other NMDA receptor antagonist (e.g. memantine, dextromethorphan) in the past 2 weeks prior to randomization (TV1, D0), or that is ongoing, or that is planned for the study duration;
14. Any ongoing or planned pharmacological or non-pharmacological treatment of tinnitus for the study duration;
15. History within the past two years or presence of drug abuse or alcoholism;
16. Subjects with diagnosed anxiety disorders, depression, bipolar disorder, schizophrenia or other significant psychiatric diseases requiring current drug treatment or subjects who required treatment in the previous 3 months prior to randomization (TV1, D0) for these diseases;
17. Use of any antidepressant or anti-anxiety medication in the past 2 weeks prior to randomization (TV1, D0), or that is ongoing, or that is planned for the study duration unless the medication was taken in a low dose and permanently for at least 3 months prior to randomization (TV1, D0), not for the treatment of tinnitus, and if the treatment will be maintained throughout the duration of the study;
18. Any clinically relevant respiratory, cardiovascular, neurological disorder (except vertigo), as determined by the Investigator;
19. Any clinically relevant abnormalities in laboratory test or physical examination prior to randomization;
20. Known hypersensitivity, allergy or intolerance to the study medication or any history of severe, abnormal drug reaction;
21. Women who are breast-feeding, pregnant or who are planning to become pregnant during the study;
22. Women of childbearing potential who are unwilling or unable to use an effective method of avoiding pregnancy from the screening visit until the end of the study (FUV3). Effective methods of avoiding pregnancy are contraceptive methods with a Pearl index of less than 1 used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or female condoms with spermicide, or cervical cap, or a sterile sexual partner);
23. Involvement or planned involvement in legal action related to the present acute peripheral tinnitus during the course of the study.
24. Concurrent participation in another clinical study or participation in another clinical study within 30 days prior to randomization (TV1, D0).

E.5 End points

E.5.1

Primary end point(s)

Alternate Primary efficacy endpoints:
• Improvement in TFI total score from baseline to FUV3
• Improvement in patient-reported tinnitus loudness TLQ NRSLoudest
from baseline to FUV3.
Key secondary efficacy endpoint:
• Improvement in TFI total score from baseline to FUV3.
Exploratory efficacy endpoints:
• Improvement in patient global impression of tinnitus severity status
(PGISTinnitus) from baseline to FUV1, FUV2 and FUV3;
•Proportion of subjects categorized as responder with respect to TFI
total score. Responders are defined as subjects who have at least a
13point reduction in patient-reported TFI total score from baseline to
FUV3;
• Improvement in TFI item 1 ("What percentage of your time awake
were you consciously AWARE OF your tinnitus?") from baseline to FUV1,
FUV2 and FUV3;
• Improvement in TFI item 2 ("How strong or loud was your
tinnitus?") from baseline to FUV1, FUV2 and FUV3;
• Improvement in tinnitus loudness by loudness matching from baseline
to FUV1, FUV2 and FUV3.
In general, baseline data will be taken from the most recent assessment
performed prior to randomization. For TLQ NRSLoudest and TAQ
NRSWorst baseline will be the average of the last 7 daily ratings in the
10 days preceding randomization.

Primary safety endpoint:
• The primary safety endpoint is the occurrence of deterioration in
hearing threshold ≥ 15 dB from baseline to FUV2 at the average of two
contiguous test frequencies (air conduction) in the treated ear. It will be
conducted with air and bone conduction hearing threshold values.

E.5.1.1

Timepoint(s) of evaluation of this end point

last follow-up visit (FUV3)

E.5.2

Secondary end point(s)

Other secondary efficacy endpoints:
• Proportion of subjects categorized as responder. Responders are defined as subjects who have at least a 2-point reduction in patient-reported tinnitus loudness TLQ NRSLoudest from baseline to FUV3;
• Improvement in TFI total score from baseline to FUV1 and FUV2;
• Improvement in patient-reported tinnitus loudness TLQ NRSLoudest from baseline to FUV1, FUV2 and FUV3;
• Improvement in patient-reported tinnitus annoyance TAQ NRSWorst from baseline to FUV1, FUV2 and FUV3;
• Improvement in TFI Sleep score from baseline to FUV1, FUV2 and FUV3 ;
• Patient global impression of change in tinnitus severity (PGICTinnitus) at FUV1, FUV2 and FUV3.

Secondary safety endpoints:
• Occurrence of deterioration of hearing threshold ≥ 15 dB from baseline to TV2, TV3, FUV1 and FUV3 at the average of two contiguous test frequencies in the treated ear;
• Difference in occurrence of deterioration of hearing threshold ≥ 15 dB from baseline to TV2, TV3, FUV1, FUV2 and FUV3 at the average of two contiguous test frequencies between treated and untreated contralateral ear (subjects with unilateral tinnitus only);
• Occurrence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs), differentiated by treatment-emergence and procedure-emergence.
Exploratory safety endpoints:
• Change from baseline in haematology and blood chemistry values;
• Change from baseline in vital signs.

E.5.2.1

Timepoint(s) of evaluation of this end point

last follow-up visit (FUV3)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

700

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

750

F.4.2.2

In the whole clinical trial

750

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After participation in the trial, patients will be treated with the current standard therapy in their country. After the end of this double-blind study, eligible patients may also have the possibility to participate in the open-label extention study.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-09-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-12-28

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