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 |
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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. |
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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 | 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 |
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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 |
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.
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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.
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E.2.3 | Trial contains a sub-study | No |
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. |
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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. |
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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.
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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. |
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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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Assessments:
All Treatment Visits and all Follow-Up Visits. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Germany |
Poland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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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. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |