E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of 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 of the safety and local
tolerance of up to 3 quarterly treatment cycles each with 3 repeated doses of
AM-101 0.87 mg/mL1 in subjects previously treated in the scope of the
TACTT3 study with either AM-101 0.87 mg/mL or placebo. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objective of the study is the assessment of the efficacy of up to
3 treatment cycles each with 3 repeated doses of AM-101 0.87 mg/mL in
subjects previously treated with either AM-101 0.87 mg/mL or placebo. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for this study if all of the following criteria apply:
1. Attendance of the final visit FUV3 of study AM-101-CL-12-02
(TACTT3);
TV1 of AMPACT2 should preferably be conducted within 48 hours of
FUV3 of TACTT3, but no later than 14 days thereafter.
2. 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 age2;
3. Willing and able to attend the study visits during at least one treatment
cycle;
4. Able to read and understand study documents, to complete the relevant
questionnaires and rating scales and follow Investigator instructions;
5. Able to understand and follow study personnel instructions during
audiologic measurements;
6. 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;
7. 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;
8. Signed IRB/IEC approved Informed Consent Form (ICF). |
|
E.4 | Principal exclusion criteria |
A subject will not be eligible for this study if any of the following criteria
apply:
1. Study drug related or procedure related adverse event leading to
treatment discontinuation in study AM-101-CL-12-02 (TACTT3);
2. Suspected or diagnosed Meniere’s Disease, endolymphatic hydrops,
acoustic neuroma or history of fluctuating hearing loss;
3. Ongoing purulent acute or chronic otitis media or otitis externa;
4. Abnormality of the tympanic membrane in the affected ear(s) that would
preclude i.t. injection;
5. 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);
6. Any ongoing drug-based therapy for otitis media or otitis externa;
7. 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 enrolment into the openlabel
study (TV1, D0), or that is ongoing or planned for the study
duration;
8. Use of any other NMDA receptor antagonist (e.g. memantine,
dextromethorphan) that is planned for the study duration;
9. Any planned pharmacological or non-pharmacological treatment of
tinnitus for the study duration;
10. History within the past two years or presence of drug abuse or
alcoholism;
11. 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
TACTT3 study prior to enrolment into the open-label study (TV1, D0)
for these diseases;
12. Use of any antidepressant or anti-anxiety medication in the past 2 weeks
prior to enrolment into the open-label study (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 during the previous TACTT3
study prior to enrolment into the open-label study (TV1, D0), not for the
treatment of tinnitus, and if the treatment will be maintained throughout
the duration of the study;
13. Any clinically relevant respiratory, cardiovascular, neurological disorder
(except vertigo), as determined by the Investigator;
14. Any clinically relevant abnormalities in physical examination on Day 0
(TV1, D0);
15. Women who are breast-feeding, pregnant or who are planning to become
pregnant during the study;
16. Women of childbearing potential who are unwilling or unable to use an
effective method of avoiding pregnancy from enrolment into the openlabel
study (TV1, D0) until the end of the study (FUV3, FUV6 or FUV9).
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);
17. Involvement or planned involvement in legal action related to the present
peripheral tinnitus during the course of the study;
18. Concurrent participation in another clinical study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary safety endpoint:
• Occurrence of deterioration in hearing threshold ≥ 15 dB from before
the start of each treatment cycle (TV1, TV4, TV7) to the
corresponding 35-day-Follow-Up Visit of the respective treatment
cycle (FUV2, FUV5 or FUV8) at the average of two contiguous test
frequencies in the treated ear. It will be evaluated with air and bone
conduction hearing threshold values. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
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. In addition from TV4 to
TV5, TV6, FUV4 and FUV6 for all subjects who perform Treatment
Cycle 2 and from TV7 to TV8, TV9, FUV7 and FUV9 for all subjects
who perform Treatment Cycle 3. It will be evaluated with air and bone
conduction hearing threshold values;
• Occurrence of deterioration in hearing threshold ≥ 15 dB at the
average of two contiguous test frequencies from baseline (TV1) to
FUV5 for all subjects who perform Treatment Cycles 1 and 2 and
from baseline (TV1) to FUV8 for all subjects who perform Treatment
Cycles 1, 2 and 3. It will be evaluated with air and bone conduction
hearing threshold values;
• Difference in occurrence of deterioration of hearing threshold ≥ 15 dB
from baseline (TV1) to TV2, TV3, FUV1, FUV2 and FUV3 at the
average of two contiguous test frequencies between treated and
untreated contralateral ear (subjects with unilaterally treated tinnitus
only). In addition from TV4 to TV5, TV6, FUV4, FUV5 and FUV6
for all subjects who perform Treatment Cycle 2 and from TV7 to
TV8, TV9, FUV7, FUV8 and FUV9 for all subjects who perform
Treatment Cycle 3. It will be evaluated with air and bone conduction
hearing threshold values;
• Difference in occurrence of deterioration in hearing threshold ≥ 15 dB
from baseline (TV1) to FUV5 at the average of two contiguous test
frequencies between treated and untreated contralateral ear (subjects
with unilaterally treated tinnitus only) for all subjects who perform
Treatment Cycles 1 and 2 and from baseline (TV1) to FUV8 for all
subjects who perform Treatment Cycles 1, 2 and 3. It will be
evaluated with air and bone conduction hearing threshold values;
• Occurrence and severity of Adverse Events (AEs) and Serious
Adverse Events (SAEs), differentiated by relatedness, and by
treatment-emergence and procedure-emergence.
Exploratory safety endpoints:
• Change from baseline in haematology and blood chemistry values;
• Change from baseline in vital signs.
Exploratory efficacy endpoints:
The exploratory efficacy analysis will be conducted on the improvement from
time of pre-injection to follow-up visits within each treatment cycle. In
addition, improvements from baseline (TV1) over two and three treatment
cycles will be considered.
• Improvement in TFI total score from baseline;
• Improvement in TFI item number 2 (tinnitus loudness) from baseline;
• Improvement in TFI item number 3 (tinnitus annoyance) from
baseline;
• Improvement in patient global impression of tinnitus severity status
(PGISTinnitus) from baseline;
• Patient global impression of change in tinnitus severity (PGICTinnitus)
from baseline.
Baseline data (TV1, D0) will be taken from FUV3 of study AM-101-CL12-
02 if the two visits were conducted within 48 hours. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
open-label extension study to TACTT3 (Eudra-CT no. 2012-004099-20) |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
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 | 9 |
E.8.9.1 | In the Member State concerned days | |
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 |