E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic sudden sensorineural hearing loss. |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 10061373 |
E.1.2 | Term | Sudden hearing loss |
E.1.2 | System Organ Class | 10013993 - Ear and labyrinth disorders |
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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 |
Confirmation of the efficacy of AM-111 in the recovery of severe to profound idiopathic sudden sensorineural hearing loss. |
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E.2.2 | Secondary objectives of the trial |
• Evaluation of the dose-response relationship for AM-111 in the recovery of ISSNHL; • Assessment of the efficacy of AM-111 in the recovery of speech discrimination (word recognition in quiet); • Assessment of the efficacy of AM-111 in achieving complete remission of ISSNHL-related tinnitus; • Assessment of the safety and local tolerance of AM-111. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Unilateral ISSNHL with onset within 72 hours prior to study treatment; 2. Mean hearing threshold of equal to or worse than (≥) 60 dB averaged across those 3 contiguous air conduction audiometric pure tone frequencies that show the highest mean hearing loss compared with the unaffected contralateral ear or, in case of history of asymmetric hearing, corresponding values from a pre-existing audiogram for the affected ear not older than 2 years prior to the ISSNHL incident (defined as “pure tone average”, PTA);* 3. Mean hearing loss of equal to or worse than (≥) 40 dB averaged across the air conduction thresholds at the pure tone average fre-quencies compared with the unaffected contralateral ear or, in case of history of asymmetric hearing, corresponding values from a pre-existing audiogram for the affected ear not older than 2 years prior to the ISSNHL incident;* 4. Age ≥ 18 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: a. They have had a hysterectomy or tubal ligation at least one cycle prior to signing the Informed Consent Form (ICF) or b. They 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 and trial personnel instructions during visits, including audiology measurements; 8. 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 for the duration of their participation in this study; 9. 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; 10. Signed Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approved ICF. * In subjects assessed within the first 24 hours from ISSNHL onset, inclusion criteria 2 and 3 have to be confirmed by a second measure that is conducted, at the earliest, 24 hours after the onset of ISSNHL. This confirmatory assessment will serve as baseline value. |
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E.4 | Principal exclusion criteria |
1. Bilateral ISSNHL; 2. Acute hearing loss from noise trauma, barotrauma or head trauma; 3. Air-bone gap greater than 20 dB at the average of 3 contiguous test frequencies below 4 kHz, when the air-bone gap is measurable; 4. History of autoimmune hearing loss, radiation-induced hearing loss, endolymphatic hydrops or Menière’s disease in either ear; 5. History of chronic inflammatory or suppurative ear disease or cholesteatoma in the affected ear; 6. Current evidence or history of acoustic neuroma or other retrocochlear damage in the affected ear; 7. History of otosclerosis in the affected ear; 8. Suspected perilymph fistula or membrane rupture in the affected ear; 9. Congenital hearing loss; 10. History of ISSNHL in the past 2 years; 11. Otitis media or otitis externa that is ongoing or ended within 7 days prior to study treatment; 12. Radiation therapy in the head and neck area within the past 5 years; 13. Abnormality of the tympanic membrane in the affected ear that would preclude intratympanic administration; 14. Any pre-treatment or ongoing treatment for ISSNHL-related hearing loss or tinnitus (except for oral corticosteroid background therapy that was started within 36 hours prior to randomization); 15. Any other planned pharmacological or non-pharmacological treatment for hearing loss or tinnitus for the duration of the trial; 16. Any therapy known as ototoxic (e.g. aminoglycosides [systemic or ototopical with middle ear exposure], cisplatin, loop diuretics, quinine etc.) in the 3 months prior to treatment visit; 17. History within the past 2 years or presence of drug abuse or alcoholism; 18. Subjects with diagnosed anxiety disorders, psychosis, depression, schizophrenia, attempted suicide or other significant psychiatric conditions that can impact their ability to cooperate and comply with the study protocol; 19. Subjects who have answered “yes” to Suicidal Ideation question 4 or 5 of the C-SSRS; 20. Any clinically relevant autoimmune, respiratory, cardiovascular, neurological disorder (except vertigo or tinnitus) or other abnormality that in the opinion of the Investigator may pose a safety risk to a subject in this study, which may confound efficacy or safety assessment, or may interfere with study participation; 21. Known HIV, hepatitis B or hepatitis C infection, or symptomatic herpes zoster infection; 22. Women who are breast-feeding, pregnant or who are planning to become pregnant during the study; 23. Women of childbearing potential who are unwilling or unable to use an effective method of avoiding pregnancy from screening until the end of the study (FUV4). Effective methods of avoiding pregnancy are contraceptive methods with a Pearl index of less than 1 when 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); 24. Concurrent participation in another clinical study or participation in another clinical study within 30 days prior to randomization (TV). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint: The primary endpoint is the absolute improvement of PTA in dB from baseline to FUV4 based on the average of the three most affected contiguous audiometric test frequencies. Improvement is defined as the baseline PTA value minus FUV4 value (positive numbers indicating improvement).
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 also be conducted with bone conduction hearing threshold values. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint: Day 91 / FUV4. |
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E.5.2 | Secondary end point(s) |
Main secondary efficacy endpoint: • Absolute improvement in WRS(80dB) from baseline to FUV4. An improvement in WRS of at least 15 percentage points is considered clinically relevant. Other secondary efficacy endpoints: • Absolute improvement in PTA from baseline to FUV1, FUV2 and FUV3; • Absolute improvement in WRS(80 dB) from baseline to follow-up visits FUV1, FUV2 and FUV3; and • Frequency of complete tinnitus remission in subjects with ISSNHL-related tinnitus at baseline, determined at FUV4. Complete tinnitus remission is achieved when a subject rates both TLQLoudest and TAQWorst as zero, and answers the question about tinnitus presence with “No”.
Secondary safety endpoints: • Occurrence of clinically relevant hearing deterioration in the treated ear (air conduction) from baseline to all FUVs (other than FUV3); • 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), assessed for causal relationship with respect to: o The IMP, and /or o The intratympanic IMP administration procedure. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Main secondary endpoint: Day 91 / FUV4. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | No |
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 |
Canada |
Czech Republic |
France |
Korea, Republic of |
Poland |
Serbia |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 14 |