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 |
|
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 | 19.0 |
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 | No |
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.
|
|
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 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), or 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) |
Alternative 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.
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.
Exploratory efficacy endpoints:
• Improvement in patient global impression of tinnitus severity status (PGISTinnitus) from baseline to FUV1, FUV2 ;
•Proportion of subjects categorized as responder with respect to TFI
total score. Responders are defined as subjects who have at least a 13-
point 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.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
last follow-up visit (FUV3) |
|
E.5.2 | Secondary end point(s) |
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 and FUV2;
• 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 | 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 | 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) | 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 | 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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
|
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 | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |