Otology & Neurotology - DOD Hearing Center of Excellence: Pharmaceutical Interventions for Hearing Loss (PIHL) Clinical Research Guidance Papers

Introduction to the Pharmaceutical Interventions for Hearing Loss Clinical Research Guidance Papers No abstract available

The Genomic Basis of Noise-induced Hearing Loss: A Literature Review Organized by Cellular Pathways Objective: Using Reactome, a curated Internet database, noise-induced hearing loss studies were aggregated into cellular pathways for organization of the emerging genomic and epigenetic data in the literature. Data Sources: PubMed and Reactome.org, a relational data base program systematizing biological processes into interactive pathways and subpathways based on ontology, cellular constituents, gene expression, and molecular components. Study Selection: Peer-reviewed population and laboratory studies for the previous 15 years relating genomics and noise and hearing loss were identified in PubMed. Criteria included p values <0.05 with correction for multiple genes, a fold change of >1.5, or duplicated studies. Data Extraction and Synthesis: One-hundred fifty-eight unique HGNC identifiers from 77 articles met the selection criteria, and were uploaded into the analysis program at http://reactome.org. These genes participated in a total of 621 cellular interactions in 21 of 23 pathways. Cellular response to stress with its attenuation phase, particularly in response to heat stress, detoxification of ROS, and specific areas of the immune system are predominant pathways identified as significantly "overrepresented" (p values <0.1e-5 and false discovery rates <0.01). Conclusion: Twenty-one of 23 of the designated pathways in Reactome have significant influence on noise-induced hearing loss, signifying a confluence of molecular pathways in reaction to acoustic trauma; however, cellular response to stress, including heat shock response, and other small areas of immune response were highly overrepresented. Yet-to-be-explored genomics areas include miRNA, lncRNA, copy number variations, RNA sequencing, and human genome-wide association study.

Oxidative Damage and Inflammation Biomarkers: Strategy in Hearing Disorders Importance: Excess free radical-induced oxidative stress and inflammatory processes are increasingly recognized as causative factors in hearing and balance disorders. Antioxidant micronutrients neutralize free radicals and, at adequate doses, reduce inflammation and demonstrate benefits in animal models and human trials. Therefore, it is reasonable to expect that biomarkers of oxidative damage and inflammation are appropriate correlative biological outcome parameters in clinical hearing intervention studies. Objective: To provide the otology investigator a selected panel of biomarkers from the large universe of available tests that can be used as reasonable secondary endpoints in hearing and balance research. Background Setting: The tenets of antioxidant science dictate that there are a great variety of free radicals and that they impact different cellular targets. They also demonstrate varying functions in different cellular environments. In addition, oxidative stress and inflammation may cause direct injury to tissues, cell membrane lipids, proteins and mitochondrial, and nuclear DNA. To accommodate these many pathways, the useful categories of potential biomarkers become extensive. The degree of injury is also reflected by separate markers of inflammation and measures of antioxidant levels. Therefore, to provide a reliable indication of oxidative damage, inflammation and antioxidant level, it is necessary to determine a broad spectrum of lipid peroxidation markers, adducts of DNA, oxidation levels of proteins and pro-inflammatory cytokines. Conclusion: This report highlights some of the most clinically relevant and well-studied biomarkers in each category of tissue damage. It also includes those markers with which the authors have had direct positive clinical experience. The outcome from these studies is intended to provide a list of adjunctive measures that can be recommended as a relevant biomarker panel in hearing disorder clinical trials.

Speech-in-Noise Tests and Supra-threshold Auditory Evoked Potentials as Metrics for Noise Damage and Clinical Trial Outcome Measures Objective: In humans, the accepted clinical standards for detecting hearing loss are the behavioral audiogram, based on the absolute detection threshold of pure-tones, and the threshold auditory brainstem response (ABR). The audiogram and the threshold ABR are reliable and sensitive measures of hearing thresholds in human listeners. However, recent results from noise-exposed animals demonstrate that noise exposure can cause substantial neurodegeneration in the peripheral auditory system without degrading pure-tone audiometric thresholds. It has been suggested that clinical measures of auditory performance conducted with stimuli presented above the detection threshold may be more sensitive than the behavioral audiogram in detecting early-stage noise-induced hearing loss in listeners with audiometric thresholds within normal limits. Methods: Supra-threshold speech-in-noise testing and supra-threshold ABR responses are reviewed here, given that they may be useful supplements to the behavioral audiogram for assessment of possible neurodegeneration in noise-exposed listeners. Conclusion: Supra-threshold tests may be useful for assessing the effects of noise on the human inner ear, and the effectiveness of interventions designed to prevent noise trauma. The current state of the science does not necessarily allow us to define a single set of best practice protocols. Nonetheless, we encourage investigators to incorporate these metrics into test batteries when feasible, with an effort to standardize procedures to the greatest extent possible as new reports emerge.

Serial Monitoring of Otoacoustic Emissions in Clinical Trials The purpose of this report is to provide guidance on the use of otoacoustic emissions (OAEs) as a clinical trial outcome measure for pharmaceutical interventions developed to prevent acquired hearing loss secondary to cochlear insult. OAEs are a rapid, noninvasive measure that can be used to monitor cochlear outer hair cell function. Serial monitoring of OAEs is most clearly established for use in hearing conservation and ototoxicity monitoring programs in which they exhibit more frequent and earlier changes compared with pure-tone audiometry. They also show promise in recent human trials of otoprotectants. Questions remain, however, concerning the most appropriate OAE protocols to use and what constitutes a "significant" OAE response change. Measurement system capabilities are expanding and test efficacy will vary across locations and patient populations. Yet, standardizing minimal measurement criteria and reporting of results is needed including documentation of test-retest variability so that useful comparisons can be made across trials. It is also clear that protocols must be theoretically sound based on known patterns of damage, generate valid results in most individuals tested, be accurate, repeatable, and involve minimal time. Based on the potential value added, OAEs should be included in clinical trials when measurement conditions and time permit.

"Measurement" of Tinnitus Chronic tinnitus is the persistent sensation of hearing a sound that exists only inside the head. The prevalence of tinnitus in adults in the United States is estimated at 10 to 15%. For about 20% of these individuals the tinnitus is significantly bothersome. Although myriad therapies for tinnitus are offered (often at significant cost), most are not evidence based. Difficulty in the assessment and further development of interventions for tinnitus stems from the limitations of techniques used to evaluate these interventions. Questionnaires are widely available to "measure" (tinnitus can only be indirectly measured) functional effects of tinnitus, such as difficulty sleeping and concentrating, and negative emotions such as anxiety, depression, and annoyance. Questionnaires have recently been documented for sensitivity to change in response to intervention (i.e., "responsiveness"). All of these questionnaires function well to assess the overall impact of tinnitus. The limitations mentioned pertain primarily to measures of tinnitus perception, which typically include the psychoacoustic measures of tinnitus loudness and pitch matches, tinnitus spectral content, minimum masking levels, and residual inhibition. These measures, which are obtained routinely in many clinics and as part of research studies, have not been validated for being diagnostic, prognostic, discriminative, or responsive. In order for these measures to become clinically meaningful, normative standards are needed, both for baseline measures and for repeated measures of tinnitus perception. Evidence-based intervention for tinnitus requires accurately measuring both the perception of, and reactions to, tinnitus.

Temporary and Permanent Noise-induced Threshold Shifts: A Review of Basic and Clinical Observations Objective: To review basic and clinical findings relevant to defining temporary (TTS) and permanent (PTS) threshold shifts and their sequelae. Data Sources: Relevant scientific literature and government definitions were broadly reviewed. Data Synthesis: The definitions and characteristics of TTS and PTS were assessed and recent advances that expand our knowledge of the extent, nature, and consequences of noise-induced hearing loss were reviewed. Conclusion: Exposure to intense sound can produce TTS, acute changes in hearing sensitivity that recover over time, or PTS, a loss that does not recover to preexposure levels. In general, a threshold shift ≥10 dB at 2, 3, and 4 kHz is required for reporting purposes in human studies. The high-frequency regions of the cochlea are most sensitive to noise damage. Resonance of the ear canal also results in a frequency region of high-noise sensitivity at 4 to 6 kHz. A primary noise target is the cochlear hair cell. Although the mechanisms that underlie such hair cell damage remain unclear, there is evidence to support a role for reactive oxygen species, stress pathway signaling, and apoptosis. Another target is the synapse between the hair cell and the primary afferent neurons. Large numbers of these synapses and their neurons can be lost after noise, even though hearing thresholds may return to normal. This affects auditory processing and detection of signals in noise. The consequences of TTS and PTS include significant deficits in communication that can impact performance of military duties or obtaining/retaining civilian employment. Tinnitus and exacerbation of posttraumatic stress disorder are also potential sequelae.

Guidelines for Auditory Threshold Measurement for Significant Threshold Shift The purpose of this article is to provide guidelines for determining a Significant Noise-Induced Threshold Shift in clinical trials involving human populations. The article reviews recommendations for the standards to be referenced for human subjects, equipment, test environment, and personnel. Additional guidelines for military populations are provided. Guidelines for the calibration of audiometers, sound booth noise levels, and immitance equipment are provided. In addition the guidance provides specific suggestions for the subjects history before study onset, and otoscopy. Test frequencies for threshold determination and methods of threshold determination are reviewed for both air conduction and bone conduction for both baseline testing and later determination of either a temporary (TTS) or permanent threshold shift (PTS). Once a Significant Noise-Induced Threshold Shift has been determined, subjects should be retested, conductive component should be ruled out or addressed, and the subject should be counseled or referred for additional medical evaluation. Guidance for reporting procedures and the computerized study database are described. Finally, experimental designs suggested for noise-induced otoprotection clinical trials are described.

Alexandros Sfakianakis
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