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TNF-α Treatment of Blast-Induced Tinnitus

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04066348
Recruitment Status : Not yet recruiting
First Posted : August 26, 2019
Last Update Posted : August 26, 2019
Sponsor:
Collaborators:
Brooke Army Medical Center
Portland VA Medical Center
John D. Dingell VA Medical Center
University of Arizona
University of Iowa
University of Miami
University of Illinois at Urbana-Champaign
Information provided by (Responsible Party):
Dr. Jinsheng Zhang, Wayne State University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Blast-Induced Tinnitus, Noise Induced Tinnitus Biological: Etanercept Phase 2

Detailed Description:

The primary objectives are to test if: 1) Etanercept significantly reduces tinnitus distress as measured by Tinnitus Functional Index (TFI) and Tinnitus Primary Function (TPF) scores; 2) Etanercept improves hearing; and 3) Etanercept reduces tinnitus distress by restoring abnormal functional connectivity between auditory and limbic brain structures to physiological levels, as revealed by resting-state fMRI.

In addition, the investigators will test if: 1) Etanercept treatment leads to sustained therapeutic effects over time; 2) Etanercept-induced tinnitus relief is accompanied by restored abnormal functional connectivity between brain centers, extending past cessation of treatment; 3) Etanercept will further improve microvasculature-related neural plasticity after treatment.

The secondary objectives are to test if: 1) Etanercept reduces tinnitus loudness measured by visual numeric scale (VNS) rating; 2) Etanercept decreases TNF-α concentration in blood serum; 3) Etanercept reduces tinnitus distress and/or loudness by improving maladaptive, microvasculature-related neural plasticity.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 310 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Clinical Trial of Etanercept (TNF-α Blocker) for Treatment of Blast-Induced Tinnitus
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Noise Tinnitus
Drug Information available for: Etanercept

Arm Intervention/treatment
Experimental: Etanercept Injection Group
Subjects will receive 2 X 25mg/ 1ml etanercept injection (experimental) weekly for 12 weeks.
Biological: Etanercept
To treat blast or noise induced tinnitus
Other Name: Enbrel

Placebo Comparator: Placebo Injection Group
Subjects will receive 2 X 1ml saline injection (placebo) weekly for 12 weeks.
Biological: Etanercept
To treat blast or noise induced tinnitus
Other Name: Enbrel




Primary Outcome Measures :
  1. The primary outcome for tinnitus severity is the Tinnitus Functional Index (TFI). [ Time Frame: 36 weeks ]

    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.


  2. The primary outcome for tinnitus severity is the Tinnitus Primary Function (TPF). [ Time Frame: 36 weeks ]

    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.


  3. The primary outcome for hearing sensitivity is the change in pure-tone audiometric threshold [ Time Frame: 36 weeks ]

    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.



Secondary Outcome Measures :
  1. Secondary outcome for tinnitus loudness is visual analog scale (VNS) [ Time Frame: 36 weeks ]

    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.


  2. The secondary outcome for hearing sensitivity is the change in word recognition score. [ Time Frame: 36 weeks ]

    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.


  3. The secondary outcome for hospital anxiety and depression scale (HADS). [ Time Frame: 36 weeks ]

    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.


  4. Secondary outcome for tinnitus loudness is Tinnitus loudness matching [ Time Frame: 36 weeks ]

    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.


  5. Secondary outcome for tinnitus loudness is Minimum masking level (MML) [ Time Frame: 36 weeks ]

    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.



Other Outcome Measures:
  1. Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Age [ Time Frame: 36 weeks ]
    Conduct exploratory investigations to if AGE influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

  2. Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Hearing sensitivity [ Time Frame: 36 weeks ]
    Conduct exploratory investigations to if "Hearing sensitivity" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

  3. Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - History of noise exposure, which can be captured with questionnaires [ Time Frame: 36 weeks ]
    Conduct exploratory investigations to if "History of noise exposure, which can be captured with questionnaires" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

  4. Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Time since blast exposure (and number of blast exposures) [ Time Frame: 36 weeks ]
    Conduct exploratory investigations to if "Time since tinnitus started (tinnitus duration)" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

  5. Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Time since military service ended [ Time Frame: 36 weeks ]
    Conduct exploratory investigations to if "Time since military service ended" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

  6. Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - History of traumatic brain injury (TBI) [ Time Frame: 36 weeks ]
    Conduct exploratory investigations to if "History of traumatic brain injury (TBI)" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Tinnitus associated with blast- or noise-exposure of at least a moderate severity as defined by a score of >25 points or higher on the Tinnitus Functional Index (TFI) questionnaire1, and/or a self-rated visual numeric score (VNS) of at least 5 out of 10 for tinnitus loudness.
  2. Able to provide written informed consent.
  3. Age/Gender: Minimum 18 years of age at the time of enrollment.
  4. Other concurrent treatments: A four-week washout from any other tinnitus treatment or management program is required prior to entering this study.
  5. Psychological status: Stable enough to complete this study per the opinion of the research team.
  6. Hearing function: All degrees of hearing function can be included, recognizing that individuals with profound, bilateral hearing losses 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.
  7. Additional tinnitus characteristics:

    1. Tinnitus history: Onset associated with blast- and/or noise exposure. Subjects will have either recent blast or noise exposure, defined as exposure less than six months ago at time of enrollment, or historical exposure, defined as exposure 6 months or longer ago at time of enrollment.
    2. 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.
    3. Location of tinnitus perception: Unrestricted. Tinnitus may be unilateral, bilateral, or perceived in the head.

Exclusion Criteria:

A subject will be ineligible for this study if any one of the following criteria is met:

  1. History or evidence of significant brain malformation or neoplasm, 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.
  2. History of seizures or epileptic activity.
  3. Subjects with cardiac pace makers, other electronic implants (including cochlear implants), or intracranial or intraocular metallic particles.
  4. Subjects who currently have an active infection, including tuberculosis and chicken pox.
  5. Diagnosis of active neurologic disease, auto-immune disease, a weak immune system, diabetes, HIV, hepatitis B, or current or past heart failure.
  6. Ongoing treatment with one of the following contraindicated medications: abatacept, cyclophosphamide or sulfasalazine.
  7. Subjects who cannot communicate reliably with research team members or who are not likely to cope with the requirements of the trial.
  8. Subjects who have participated in a drug clinical trial within the last 30 days before the start of this one.
  9. Current substance abuse (defined as a score of 2 or greater on the CAGE Substance Abuse Screening Tool)
  10. Pregnancy or planned pregnancy during the study.
  11. Women who are lactating or are of child-bearing-age without use of contraception.
  12. Participation in greater than two previous clinical drug-trials for tinnitus.
  13. MMSE score < 24

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04066348


Contacts
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Contact: Jackie Parker (313) 577-1001 jparker@med.wayne.edu
Contact: Amy Stolinkski (313) 745-0148 astolins@med.wayne.edu

Locations
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United States, Arizona
University of Arizona-AHSC Bldg Not yet recruiting
Tucson, Arizona, United States, 85721
Principal Investigator: Shaowen Bao, Ph.D.         
Sub-Investigator: Faydyeh Barakat         
United States, Florida
University of Miami Not yet recruiting
Coral Gables, Florida, United States, 33124
Principal Investigator: Michael Hoffer, MD         
United States, Illinois
University of Illinois at Urbana-Champaign Not yet recruiting
Champaign, Illinois, United States, 61820
Principal Investigator: Fatima Husain, Ph.D.         
United States, Iowa
University of Iowa Not yet recruiting
Iowa City, Iowa, United States, 52242
Principal Investigator: Richard Tyler, Ph.D./CCC-A         
United States, Michigan
John D. Dingell VA Medical Center Not yet recruiting
Detroit, Michigan, United States, 48201
Principal Investigator: Michael Carron, MD         
Wayne State University Not yet recruiting
Detroit, Michigan, United States, 48201
Principal Investigator: Jinsheng Zhang, Ph.D.         
Michigan Ear Institute Not yet recruiting
Farmington Hills, Michigan, United States, 48334
Principal Investigator: Robert Hong, MD/Ph.D.         
Sub-Investigator: Dennis Bojrab         
United States, Oregon
VA Portland Health Care System Not yet recruiting
Portland, Oregon, United States, 97239
Principal Investigator: Robert Folmer, Ph.D         
Sub-Investigator: Sara Theodoroff, Ph.D./CCC-A         
United States, Texas
Brooke Army Medical Center Not yet recruiting
Fort Sam Houston, Texas, United States, 78234
Principal Investigator: Brent J Wilkerson, MD         
Sponsors and Collaborators
Wayne State University
Brooke Army Medical Center
Portland VA Medical Center
John D. Dingell VA Medical Center
University of Arizona
University of Iowa
University of Miami
University of Illinois at Urbana-Champaign
Investigators
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Principal Investigator: Jinsheng Zhang, Ph. D. Wayne State University
  Study Documents (Full-Text)

Documents provided by Dr. Jinsheng Zhang, Wayne State University:
Study Protocol  [PDF] April 17, 2019


Publications:
VBA. VA Annual Benefits Report: Fiscal Year 2012. In: VA US, ed. 810 Vermont Avenue N. W. , Washington, D.C., 20420: Veterans Benefits Administration, 2013:82.

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Responsible Party: Dr. Jinsheng Zhang, Principle Investigator, Wayne State University
ClinicalTrials.gov Identifier: NCT04066348     History of Changes
Other Study ID Numbers: PR172190
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: August 26, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

In cases where the human subject could possibly benefit medically or otherwise from the information, explain whether or not the results of screening and/or study participation will be shared with human subjects or their primary care provider, to include results from any screening or diagnostic tests performed as part of the study.

The PI plans to disseminate abstracts in National and International Conferences, and the PI plans to publish manuscripts in peer-reviewed journals (national and international) to share the knowledge obtained from the study's data with the research team of this study. Any research team member planning to disseminate results from this study needs the permission of the PI and must follow FDA guidelines.Additionally, data collected during the proposed study period will be shared with the NIH, the Department of Veterans Affairs, the National Science Foundation, and the Department of Health Human.

Supporting Materials: Clinical Study Report (CSR)
Time Frame: Sharing will be available 6 months after the study has concluded and data analysis in completed.
Access Criteria: To follow FDA and IRB guidelines, as well as obtain permission from the PI.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr. Jinsheng Zhang, Wayne State University:
tinnitus
etanercept
tinnitus function index
tinnitus primary function
functional MRI
audiological evaluation
Additional relevant MeSH terms:
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Tinnitus
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Etanercept
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gastrointestinal Agents
Immunosuppressive Agents
Immunologic Factors