Clinical Trials Register

Summary
EudraCT Number:	2011-005384-24
Sponsor's Protocol Code Number:	AM-101-CL-10-02
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-12-12
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

Germany - BfArM

A.2

EudraCT number

2011-005384-24

A.3

Full title of the trial

TACTT1

Comparison of Single versus Repeat Doses of AM-101 in the Treatment of Acute Inner Ear Tinnitus

Vergleich von Einzel- und Mehrfach-Dosierung von AM-101
bei der Behandlung von akutem Innenohr-Tinnitus (TACTT1)

A.3.1

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

Administration of a single dose or of three doses of AM-101
to patients with Tinnitus (Ringing in the Ears) and comparision of both doses.

Verabreichung von einer Gabe und einer mehrmaligen Gabe von AM-101
an Patienten mit Tinnitus (Ohrgeräusche) und Vergleich der beiden Verabreichungen.

A.3.2

Name or abbreviated title of the trial where available

TACTT1

A.4.1

Sponsor's protocol code number

AM-101-CL-10-02

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01270282

A.5.4

Other Identifiers

Name:

EudraCT

Number:

2011-005384-24

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	Thomas Meyer
B.5.3	Address:
B.5.3.1	Street Address	Aeschenvorstadt 37
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4051
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	004161201 1350
B.5.5	Fax number	004161201 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.3.1	Product name	Esketamine hydrochloride gel
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
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 hydrochlorid
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	810
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 inner ear tinnitus following acute acustic trauma, acute otitis media, middle ear surgery, or inner ear barotrauma

E.1.1.1

Medical condition in easily understood language

Tinnitus caused by noise trauma (e.g. a loud noise), inflammation of the middle ear, or trauma to the ear caused by a difference in pressure of your surroundings or ear surgery.

Tinnitus (Ohrgeräusche), welcher aufgrund eines Lärmtrauma (laute Geräusche),Mittelohrentzündung, einer Operation am Ohr oder einer Luftdruckänderung beim Ohr entstanden ist.

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	14.1
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective:
The primary objective of the study is the evaluation of the appropriate dosing regimen for i.t. AM-101 injections in the treatment of acute inner ear tinnitus.

E.2.2

Secondary objectives of the trial

Secondary objectives:
The secondary objectives of the study are
(a) the further assessment of the safety and local tolerance of i.t.-administered AM-101, and
(b) the further evaluation of AM-101’s biodistribution.

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 tinnitus (unilateral or bilateral) following acute acoustic trauma, acute otitis media, middle ear surgery or inner ear barotraumas with onset up to three months ago (i.e. acute tinnitus), as documented by medical report.
2. Age ≥ 18 years and ≤ 65 years.
3. Negative pregnancy test for women of childbearing potential.
4. Willing and able to attend the study visits.
5.Able to read and understand study documents, and investigator instructions.
6. Signed IEC (Independent Ethics Committee)-approved Informed Consent Form.

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.
2. Intermittent Tinnitus.
3. Menière's Disease.
4. Ongoing acute or chronic Otitis media or Otitis externa.
5. Any drug-based therapy for Otitis media that is ongoing or was performed in the past 2 weeks.
6. Any therapy known as potentially Tinnitus-inducing (e.g. aminoglycosides, cisplatin, loop diuretics, high doses of aspirin [> 5 adult doses/day] or quinine) in the past 2 weeks or that is ongoing or planned for the study duration.
7. Any drug-based therapy for inner ear hearing loss that is ongoing or was performed in the past 2 weeks, e.g. prednisolone, dexamethasone, pentoxyfilline, betahistine, diazepam, car-bamazepine, sodium valproate and antidepressants.
8. Use of any other NMDA receptor antagonist (e.g. memantine, dextromethorphan) in the past 2 weeks, or that is ongoing, or that is planned for the study duration.
9. Any ongoing or planned treatment of Tinnitus for the study duration.
10. History within the past two years or presence of drug abuse or alcoholism.
11. Any clinically relevant respiratory, cardiovascular, neurological (except vertigo), or psychiatric disorder, as determined by the Investigator.
12. Known hypersensitivity, allergy or intolerance to the study medication or any history of severe, abnormal drug reaction.
13. Women who are breast-feeding, pregnant or who are planning to become pregnant during the trial.
14. 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.
15. Concurrent participation in another clinical trial or participation in another clinical trial within 30 days prior to study entry.

E.5 End points

E.5.1

Primary end point(s)

Primary assessment of efficacy
The primary efficacy outcome is the change in Tinnitus loudness by magnitude estimation from Baseline (Treatment Visit 1 = TV1) to 90 days following the last injection (Follow-Up Visit 3 = FUV3).

Assessments of safety
1. Change in hearing threshold ≥ 15 dB from Baseline (TV1) to TV2 (Stage 2 only), TV3 (Stage 2 only), FUV1, FUV2 and FUV3 at the average of two contiguous test frequencies in the treated ear. Primary safety endpoint is the comparison at FUV2.
2. Percent and distribution of severity of AE and SAE.

Pharmacokinetic assessments
Cmax, Tmax and AUC after single dose injection for Esketamine and S-Norketamine.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary efficacy assessment:
Treatment Visit 1 (Day0) and Follow-Up Visit 3 (Post-Injection Day90)

Safety assessment:
All Treatment Visits and Follow-Up Visits. AEs and SAEs during the run of the trial.

E.5.2

Secondary end point(s)

Secondary assessment of efficacy
1. The change in the MML (Minimum Masking Level) from Baseline (TV1) to TV2 and to TV3 (Stage 2 only), and to FUV1, FUV2 and FUV3.
2. The change in Tinnitus loudness by loudness matching from TV1 (Baseline) to FUV1, FUV2 and FUV3.
3. PGIC (Patient Global Impression of Change) scale for tinnitus severity at FUV1, FUV2 and FUV3.
4. The change in Tinnitus annoyance by magnitude estimation from TV1 (Baseline) to TV2 (Stage 2 only), TV3 (Stage 2 only), FUV1, FUV2 and FUV3.
5. The change in Tinnitus loudness by magnitude estimation from TV1 (Baseline) to TV2 (Stage 2 only), TV3 (Stage 2 only), FUV1 and FUV2.
6. The change in Tinnitus sleep impact by magnitude estimation from TV1 (Baseline) to TV2 (Stage 2 only), TV3 (Stage 2 only), FUV1, FUV2 and FUV3.
7. The change in THQ scores from TV1 (Baseline) to FUV3.
8. The change in THI-12 scores from TV1 (Baseline) to FUV3.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary Efficacy Assessments:
All Treatment Visits and all Follow-Up Visits.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Germany

Poland

United States

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

Last Visit of Last Subject

Or

Randomization and patient enrolment will be halted if - based on a review of safety and tolerability data by the Safety Officer, and after consultation between the Safety Officer and the Coordinating Investigators - further treatments are deemed not acceptable for the safety of the patients.

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

E.8.9.2

In all countries concerned by the trial days

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:

F.1.3

Elderly (>=65 years)

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

F.4.2.2

In the whole clinical trial

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)

As deemed appropriate by the physician.

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

2012-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-05-21

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IMP with orphan designation in the indication
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