| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjective Ringing in the Ears |
|
| 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 | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042398 |
| E.1.2 | Term | Subjective 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 objective of this study is to evaluate the efficacy, safety and tolerability of neramexane in comparison to placebo in patients with subjective tinnitus.
|
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate the efficacy of Neramexane in comparison to placebo based on the total and factorial scores of TBF-12, the individual responder rate, the Tinnitus Rating Scale, the Tinnitus Severity Scale, HADS, APSA and SF-36 measurements during the study. Further objectives are the exploratory evaluation of pharmacokinetic, pharmacogenetic, audiological and psychoacoustical characterisation of the study population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed written informed consent obtained from the patient
2) Patients with a clinical diagnosis of first onset, persistent (i.e. tinnitus should never be absent for > 24 hours in a row), subjective, uni- or bilateral tinnitus present for at least 3 months but not more than 12 months. In case of bilateral tinnitus this criterion applies to both ears.
3) Outpatients (female) between 18 and 75 years of age (inclusively) at screening
4) For females of childbearing potential (last menses less than one year prior to enrolment): negative pregnancy test at Screening and at Baseline (i.e. prior to entry in the double-blind treatment phase); not breast-feeding; either surgically sterile or agreement to use a medically accepted, effective contraception during the entire duration of the study. An effective method of birth control is defined as those, alone or in combination, which result in a low failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, non-hormonal IUDs, sexual abstinence or vasectomised partner or double contraception methods (e.g. condome with spermicide cream).
5) TBF-12 total score ≥ 9 and TSSw ≥ 4
6) HADS depression subscore ≤ 10 and HADS anxiety subscore ≤ 10
7) Physical examination and laboratory evaluations from the screening visit must be normal, or abnormal findings must be judged either “not clinically relevant” or “clinically relevant but of no concern” by the Investigator
8) Patient must be willing and able to comply with the protocol and study procedures |
|
| E.4 | Principal exclusion criteria |
1) Clinical diagnosis of intermittent or pulsatile tinnitus
2) Patients who have tinnitus as a concomitant symptom of an otological/neurological disease (such as otitis media, Menière’s disease, otosclerosis, etc)
3) Hearing impairment related to disturbance of sound conduction (air conduction threshold more than 20 decibel (dB) worse than in bone conduction in at least two tested frequencies) in at least one ear
4) Patients with evidence of clinically relevant and active
-Pulmonary
-Cardiovascular (e.g. sinus bradycardia < 41 bpm, sinus pauses, ventricular fibrillation, non-sustained sinus bradycardia, 2:1 AV block, complete heart block, first degree AV block if > 300 msec, AV block Mobitz II, prolonged QTc if > 500 msec, WPW syndrome, ST elevation, abnormal U wave, cardiac insufficiency NYHA III-IV or a history of myocardial ischaemia/infarction within the last 6 months)
-Renal
-Hepatic
-Gastrointestinal
-Neurological (e.g. epileptic seizures, multiple sclerosis, serious head/cervical trauma with residual deficits)
-Psychiatric (e.g. dementia, schizophrenia, current major depressive episode)
-Infectious (e.g. HIV infection/AIDS, tuberculosis)
-Endocrine
disorder of concern or other severe or uncontrolled systemic diseases which might interfere with the trial (patients with controlled diabetes who are normoglycemic under treatment may be included).
5) A systolic blood pressure (while seated) greater than 180 mmHg or less than 90 mmHg or diastolic blood pressure (while seated) greater than 105 mmHg or less than 45 mmHg
6) Patients with an oncology diagnosis (hematology or solid tumor) who are undergoing treatment, who have completed treatment within the last six months, and/or who still have evidence of active disease. (Patients with localized, benign dermatologic lesions may be included)
7) Former treatment with memantine, neramexane, rimantadine, amantadine
8) Documented history of hypersensitivity or intolerance to NMDA antagonists
9) Known hypersensitivity to the study drug or one of the ingredients of the formulation
10) Current absence from work due to tinnitus or application for a pension/retirement pay or granted pension/retirement because of tinnitus or filed or pending lawsuit for compensation claims because of tinnitus
11) Concomitant drugs and supplements intended for tinnitus treatment as well as non-pharmacological tinnitus treatments, e.g. biofeedback, maskers, noisers, acupuncture, hyperbaric oxygen therapy, low-power laser therapy, autogenic training, behavioural or psychotherapy during the last 28 days,
12) Patients who are taking any non-authorised concomitant medication as defined in Appendix 7 of the study protocol
13) Patients who plan to undergo elective surgery under local or general anaesthesia during the trial
14) Known or suspected alcoholism or drug abuse within the last three years
15) Patients who have participated in an investigational drug study or who have received treatment with an investigational drug within 30 days (or 5 half-lifes, whichever is longer) of screening
16) Pregnant or breastfeeding women
17) Employees or direct relatives of an employee of the CRO, the investigational site or Merz Pharmaceuticals
18) Patients who are lawfully kept in an institution or are imprisoned
19) Previous participation in this clinical study
20) Evidence or suspicion that the patient might not comply with the study directives and/or that he/she is not reliable or trustworthy.
21) Evidence or suspicion that the patient is not willing or unable to understand the information that is given to him/her as part of the informed consent, in particular regarding the risks and discomfort to which he/she would agree to be exposed.
22) Patients with hearing aids who received their devices less than 6 months
before Screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the absolute change in the TBF-12 score from Baseline to Week 17 and Week 29 or to premature discontinuation if the patient ends treatment before Week 17 or Week 29. The confirmatory analysis will be performed using an ANCOVA model with treatment, country and gender as factors and Baseline TBF-12 as covariate to compare placebo and neramexane.
For US FDA approval, the change in the tinnitus severity from Baseline to Week 17 and Week 29 or to premature discontinuation is regarded as co-primary variable. The analysis strategy for the primary and the co-primary variable will be identical.
Tests for treatment differences will be two-sided with a type 1 error level of α=5%. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 29 and Week 17 (hierarchichal test procedure) |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 15 |
| 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 |
| Brazil |
| Mexico |
| United States |
|
| 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
|
| end of trial is defined as last subject last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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