Acute Inner Ear Hearing Loss

Primary objective The primary objective of the trial is the confirmation of the efficacy of AM-111 in the recovery of severe to profound idiopathic sudden sensorineural hearing loss. Secondary objectives The secondary objectives of the trial are:  Further evaluation of the dose response relationship for AM-111 in the recovery of ISSNHL;  Assessment of the efficacy of AM-111 in achieving complete remission of ISSNHL-related tinnitus;  Assessment of safety and local tolerance of AM-111.

AM-111

Dstereoisomer of c-Jun N-terminal Kinase

Injection

0, 0.4, 0.8 mg/ mL 約0.25 mL

Efficacy endpoints
Primary efficacy endpoint
Absolute improvement in PTA from baseline to FUV3.
Secondary efficacy endpoints
 Absolute improvement in PTA from baseline to FUV1, FUV2 and
FUV4 ;
 Proportion of subjects receiving corticosteroid reserve therapy;
 Frequency of complete hearing recovery at FUV3 and FUV4;
 Frequency of complete tinnitus remission at FUV4 in subjects with
ISSNHL-related tinnitus at baseline.
Exploratory efficacy endpoints
 Hearing Handicap Inventory for Adults (HHIA) at FUV3 and FUV4;
 Absolute improvement in SDS at 80 dB from baseline to follow-up
visits;
 Patient global impression of change (PGIC) in hearing loss severity
from baseline to FUV2, FUV3 and FUV4;
 Absolute improvement in patient reported tinnitus loudness
TLQLoudest in subjects with ISSNHL-related tinnitus at baseline from
TV to all weekly follow-up assessments;
 Absolute improvement in patient reported tinnitus annoyance
TAQWorst in subjects with ISSNHL-related tinnitus at baseline from
TV to all weekly follow-up assessments.
Safety endpoints
Primary safety endpoint
Occurrence of clinically relevant hearing deterioration (defined as increase in air conduction hearing threshold ≥ 10 dB at the average of any
two contiguous test frequencies) from baseline to FUV3 in the treated
ear. The analysis will be conducted also with bone conduction hearing
threshold values.
Secondary safety endpoints
 Occurrence of clinically relevant hearing deterioration from baseline
to all FUVs (other than FUV3) (air conduction) in the treated ear;
 Difference in occurrence of clinically relevant hearing deterioration
from baseline to all FUVs between treated and untreated contralateral ear;
 Occurrence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs), differentiated by causal relationship to:
o The IMP;
o The intratympanic IMP administration;
o Other trial procedures; or
o Other reasons not related to the trial.

1.Unilateral ISSNHL with onset within 72 hours prior to study treat-ment;
2.Mean hearing threshold of equal to or worse than (≥) 60 dB aver-aged across the 3 most affected contiguous air conduction audio-metric pure tone frequencies (“pure tone average”, PTA);*
3.Mean hearing loss of equal to or worse than (≥) 40 dB averaged across the air conducted PTA frequencies compared with the unaf-fected contralateral ear or reference values from a pre-existing audi-ogram or ISO 7029;2000 norm values in case of asymmetric hearing prior to the ISSNHL incident;*
4.Age ≥ 18 and ≤ 65 years on the day of screening;
5.Negative urine pregnancy test for women of childbearing potential. Women are not considered to be of childbearing potential if they meet one of the following criteria:
oThey have had a hysterectomy or tubal ligation at least one cycle prior to signing the Informed Consent Form (ICF) or
oThey are post-menopausal, with at least one year since their last menstrual period;
6.Willing and able to attend the trial visits;
7.Able to read and understand trial documents and follow Investigator instructions;
8.Able to understand and follow trial personnel instructions during audiologic measurements;
9.Willing and able to use adequate hearing protection and to refrain from engaging in activities or work involving loud noise exposure where sufficient hearing protection is not possible or ensured;
10.Willing and able to protect the ear canal and middle ear from water exposure for as long as the tympanic membrane is not fully closed;
11.Signed Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approved ICF.

* Inclusion criteria 2 and 3 have to be confirmed in subjects assessed within the first 24 hours from ISSNHL onset by a second measure that is conducted at the earliest 24 hours after onset of ISSNHL. This confirmatory assessment will serve as baseline value.

1.Bilateral ISSNHL;
2.Acute hearing loss from noise trauma, barotrauma or head trauma;
3.History of autoimmune hearing loss, radiation-induced hearing loss, endolymphatic hydrops or Menière’s disease in the affected ear;
4.History of chronic inflammatory or suppurative ear disease or cho-lesteatoma in the affected ear;
5.History of acoustic neuroma or other retrocochlear damage in the affected ear;
6.History of otosclerosis in the affected ear;
7.Suspected perilymph fistula or membrane rupture in the affected ear;
8.Congenital hearing loss;
9.History of ISSNHL in the past 2 years;
10.Otitis media or otitis externa that is ongoing or ended within 7 days prior to study treatment;
11.Radiation therapy in the head and neck area within the past 5 years;
12.Abnormality of the tympanic membrane in the affected ear that would preclude i.t. administration;
13.Any pre-treatment within two weeks prior to enrolment, ongoing treatment or planned treatment of ISSNHL-related hearing loss or tinnitus including pharmacological medication or non-pharmacological treatment (other than prednisolone or prednisone reserve therapy following FUV2);
14.Any therapy known as ototoxic (e.g. aminoglycosides, cisplatin, loop diuretics, quinine etc.) in the 3 months prior to trial inclusion;
15.History within the past 2 years or presence of drug abuse or alcoholism;
16.Subjects with diagnosed anxiety disorders, depression, schizophre-nia or other significant psychiatric diseases requiring current drug treatment or subjects who required treatment in the previous 3 months prior to enrolment for any of these diseases;
17.Any clinically relevant respiratory, cardiovascular, neurological disorder (except vertigo or tinnitus) or other abnormality that in the opinion of the Investigator or Sponsor may pose a safety risk to a subject in this study, which may confound efficacy or safety assessment, or may interfere with study participation;
18.Known or suspected ongoing active infection of HIV, hepatitis C or B, or herpes zoster;
19.Women who are breast-feeding, pregnant or who are planning to become pregnant during the study;
20.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 (FUV4). Effective methods of avoiding pregnancy are contraceptive methods with a Pearl index of less than 1 used consistently and correctly (including implantable, injectable, oral and transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or female condoms with spermicide, or cervical cap, or a sterile sexual partner, or being abstinent);
21.Concurrent participation in another clinical study or participation in another clinical study within 30 days prior to randomisation (TV).