TNF-α Treatment of Blast-Induced Tinnitus

Study Overview
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Brief Summary
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This study evaluates the therapeutic effects of Etanercept (Enbrel) on the treatment of blast/noise induced tinnitus in adults. Half of the participants will receive 2 x 25mg/ Entanercept injections, and the other half will receive placebo injections.

Detailed Description
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The primary objectives are to test if: 1) Etanercept significantly reduces tinnitus distress as measured by Tinnitus Functional Index (TFI); and 2) Etanercept improves hearing. In addition, the investigators will test if: 1) Etanercept treatment leads to sustained therapeutic effects over time; The secondary objective is to test if: 1) Etanercept reduces tinnitus loudness measured by visual numeric scale (VNS) rating.

Official Title
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Clinical Trial of Etanercept (TNF-α Blocker) for Treatment of Blast-Induced Tinnitus

Conditions
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Tinnitus, Noise Induced

Intervention / Treatment
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* Biological: Etanercept
* Other: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tinnitus of at least a moderate severity as defined by a score of ≥ 25 points or higher on the Tinnitus Functional Index (TFI) questionnaire associated with one or more of the following: Blast or noise exposure Traumatic brain injury (TBI) and/or concussion diagnosed by a health care provider. Able to provide written informed consent. Age: Minimum 18 years of age at the time of enrollment. Other concurrent treatments: A four-week washout from any other tinnitus treatment or management program is required prior to entering this study. Psychological status: Stable enough to complete this study per the opinion of the research team. Hearing function: All degrees of hearing function can be included, recognizing that individuals with profound, bilateral hearing loss will not be able to perform tinnitus evaluations and hearing tests but will be able to rate subjective tinnitus loudness, annoyance and impact on life. This is an important sub-population because of the challenges in treating them with acoustic therapy and the need for a medical intervention. Additional tinnitus characteristics: a) Tinnitus history: Onset associated with blast and/or noise exposure or associated with diagnosed TBI and/or concussion. Subjects will have blast exposure, noise exposure, traumatic brain injury (TBI), and/or concussion impact, defined as exposure/impact less than or longer than six months at time of enrollment. (i) Participants enrolled with tinnitus associated with TBI and/or concussion must have received a diagnosis of TBI and/or concussion by a health care provider. b) Stability: Constant (not pulsatile, intermittent, varying to a high degree in loudness or changing in location of perception). Fluctuating tinnitus reduces the reliability of test-retest measures for loudness. c) Location of tinnitus perception: Unrestricted. Tinnitus may be unilateral, bilateral, or perceived in the head. Exclusion Criteria: History or evidence of significant brain malformation, cerebral vascular events (such as strokes), neurodegenerative disorders affecting the brain (such as Parkinson's disease, ALS, Huntington's disease or Multiple sclerosis), or prior brain surgery. History of Guillain-Barré syndrome. Active neoplasm such as lymphoma or solid tumors. History of neoplasm, excluding successfully treated squamous cell carcinoma or basal carcinoma of the skin or cervical cancer. Diagnosis of congestive heart failure. History of seizures or epileptic activity. Subjects with cardiac pace makers, other electronic implants (including cochlear implants), or intracranial or intraocular metallic particles. Subjects who currently have an active infection, including tuberculosis, HIV, hepatitis B, and/or chicken pox. Scheduled to receive a live vaccine during study participation or received a live vaccine within 2 weeks prior to screening visit/procedures. Diagnosis of active neurologic disease, auto-immune disease, diabetes, or a weak immune system. For the purposes of this protocol, active neurologic disease is defined as multiple sclerosis or any other disease involving demyelination disorder or any finding suggesting a demyelination disease or disorder. Migraines/migraine headaches are not a condition that would exclude a potential patient from participation in the study unless associated with a demyelination disease or disorder. Autoimmune thyroid disease is not considered an exclusionary autoimmune disease for participation in this study. Ongoing treatment with one of the following contraindicated medications: abatacept or any other biologic therapy, cyclophosphamide or sulfasalazine. Subjects who cannot communicate reliably with research team members or who are not likely to cope with the requirements of the trial. Subjects who have participated in a drug clinical trial within the last 30 days before the start of this one. Current substance abuse (defined as a score of 2 or greater on the CAGE Substance Abuse Screening Tool). Pregnancy or planned pregnancy during the study. Women who are lactating or are of child-bearing-age without use of contraception. Participation in greater than two previous clinical drug-trials for tinnitus. MMSE score < 24. Clinically significant out of range laboratory values (contact medical monitor to discuss).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etanercept Injection Group<br>Subjects will receive 2 X 25mg/ 1ml etanercept injection (experimental) weekly for 12 weeks. | Biological: Etanercept<br>* To treat blast or noise induced tinnitus<br>* Other names: Enbrel;|
| Placebo Comparator: Placebo Injection Group<br>Subjects will receive 2 X 1ml saline injection (placebo) weekly for 12 weeks. | Other: Saline<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome for tinnitus severity is the Tinnitus Functional Index (TFI). | Subjects with tinnitus associated with blast and/or noise exposure will receive 12 consecutive weekly treatments of Etanercept. Tinnitus Functional Index (TFI) questionnaire will be administered at baseline, and weeks 1, 4, 8 and 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 4, 8, 12 and 24 weeks after the final administration of Etanercept, this will be the same as study schedule week 16, 20, 24 and 36 respectively. A seven-point decrease on the TFI score will be considered clinically significant. Scores range from 0 to 100; A higher score means more severe and a lower score means less severe in tinnitus. Mean score of 21 (range 18-31) small problem. Mean score of42 (range 32-53) moderate problem. Mean score of 65 (range 54-72) big problem. Mean score of 78 (range 73-100) very big problem. | 36 weeks | 
| The primary outcome for tinnitus severity is the Tinnitus Primary Function (TPF). | Subjects with tinnitus associated with blast and/or noise exposure will receive 12 consecutive weekly treatments of Etanercept. Tinnitus Functional Index (TFI) questionnaire will be administered at baseline, and weeks 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 12 and 24 weeks after the final administration of Etanercept, this will be the same as study schedule week 24 and 36 respectively. Scores range from 0 to 100; A higher score means more severe and a lower score means less severe in tinnitus. Mean score of 21 (range 18-31) small problem. Mean score of42 (range 32-53) moderate problem. Mean score of 65 (range 54-72) big problem. Mean score of 78 (range 73-100) very big problem. A 13% decrease on the TPF will be considered clinically significant. | 36 weeks | 
| The primary outcome for hearing sensitivity is the change in pure-tone audiometric threshold | Pure tone audiometric air conduction testing is performed by presenting a pure tone to the ear through an earphone and measuring the lowest intensity in decibels (dB) at which this tone is perceived 50% of the time. This measurement is called threshold. The testing procedure is repeated at specific frequencies from 150 to 8000 hertz (Hz, or cycles per second) for each ear, and the thresholds are recorded on a graph called an audiogram. It ranges from 0 to 110 dB Hearing Level. The lower dB level, the better hearing sensitivity is. Subjects with tinnitus will receive 12 consecutive weekly treatments of Etanercept. Tpure-tone audiometric threshold will be tested at baseline, and weeks nd weeks 1, 4, 8 and 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 12 20, 24 and 36 weeks after the final administration ofEtanercept. | 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary outcome for tinnitus loudness is visual analog scale (VNS) | Subjects with tinnitus associated with blast and/or noise exposure will receive 12 consecutive weekly treatments of Etanercept. Visual Numerical Scale (VNS) for self-rated tinnitus loudness. On the scale of 0-10, a subject is required to rate the loudness of his/her tinnitus. 0 means no tinnitus and 10 as very loud tinnitus. A score of at least 5 out of 10 for tinnitus loudness is required for participation in the study VNS questionnaire will be administered at baseline, and weeks 1, 4, 8 and 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 4, 8, 12 and 24 weeks after the final administration of Etanercept, this will be the same as study schedule week 16, 20, 24 and 36 respectively. | 36 weeks | 
| The secondary outcome for hearing sensitivity is the change in word recognition score. | The word recognition score (WRS) test requires a list of single syllable words unknown to the patient to be presented at the speech recognition threshold. The number of correct words is scored out of the number of presented words to give the WRS. The range of the score is 0-100%, with 0% is the worst and 100% is the best. WRS will be administered at baseline, and weeks 12. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 24 weeks after the final administration of Etanercept. | 36 weeks | 
| The secondary outcome for hospital anxiety and depression scale (HADS). | Hospital Anxiety and Depression Scale (HADS) is used to determine the levels of anxiety and depression that a person is experiencing. The HADS is a fourteen item scale that generates ordinal data. Seven of the items relate to anxiety and seven relate to depression. HADS will be administered at baseline, and weeks12. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 24 and 36 weeks after the final administration of Etanercept. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. A cut-off point for anxiety or depression is f 8/21. | 36 weeks | 
| Secondary outcome for tinnitus loudness is Tinnitus loudness matching | This test involves going into a sound booth and having foam earphones inserted into ear canals by the audiologist. The audiologist will then play a 1 kHz pure-tone presented to the ear contralateral to the side of the tinnitus perception. In cases of bilateral tinnitus that does not lateralize to one side or is perceived in the head the contralateral ear will be selected based on whichever ear has the better pure-tone hearing threshold at 1 kHz. The goal is to find the intensity level of a 1 kHz pure-tone that best matches the loudness of his/her tinnitus. This test will be conducted at Baseline and during the treatment phase at weeks 1, 4, 8, and 12 and also during the post-treatment follow-up phase at 16, 20, 24 and 36 weeks. Tinnitus is usually matched in loudness by a sound with a low Sensation Level, typically in the range 0-30+ dB SL, with 0 dB SL repressing soft and 30+ dB SL as loud tinnitus. | 36 weeks | 
| Secondary outcome for tinnitus loudness is Minimum masking level (MML) | After obtaining the 1 kHz tinnitus loudness match, the audiologist will obtain hearing thresholds for a band of noise for each ear separately. Next, the noise will be presented at the same sensation level binaurally until the participant states the tinnitus is completely or partially masked. The goal is for a subject to tell the audiologist the softest intensity level of noise that will cover (or mask) the sound of the subject's tinnitus. This test will be conducted at Baseline and during the treatment phase at weeks 1, 4, 8, and 12 and also during the post-treatment follow-up phase at 16, 20, 24 and 36 weeks. During administration of MML, increase the level of the masking noise gradually in 1 dB steps until the tinnitus is no longer detectable in that ear. MML is expressed in dB Sensation Level (SL), relative to the Masking Noise Threshold. In most cases the MML ranges from 2 to 30+ dB SL, with a smaller number indicating soft loudness. | 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tinnitus, etanercept, tinnitus function index, tinnitus primary function, audiological evaluation