Protection for medication-induced hearing loss: the state of the science

Figures & data

Table 1. List of search terms developed with the assistance of a medical librarian to extract and review any clinical trials to prevent or treat drug-induced ototoxicity with a chemical agent in currently published literature.

1	Hearing loss[mesh:noexp] OR deafness[mesh:noexp] OR hearing loss, bilateral[mesh:noexp] OR hearing loss, conductive[mesh:noexp] OR hearing loss, functional[mesh:noexp] OR hearing loss, high-frequency[mesh:noexp] OR hearing loss, mixed conductive-sensorineural[mesh:noexp] OR hearing loss, sensorineural[mesh:noexp] OR hearing loss, central[mesh:noexp] OR hearing loss, noise-induced[mesh:noexp] OR hearing loss, sudden[mesh:noexp] OR hearing loss, unilateral/OR (deaf[tiab] OR deafness[tiab] OR hearing loss[tiab])
2	Ear[mesh:noexp] OR ear, middle[mesh:noexp] OR ear, inner[mesh:noexp] OR cochlea[mesh:noexp] OR basilar membrane[mesh:noexp] OR cochlear aqueduct[mesh:noexp] OR cochlear duct[mesh:noexp] OR “organ of corti”[mesh:noexp] OR hair cells, auditory[mesh:noexp] OR hair cells, auditory, inner[mesh:noexp] OR hair cells, auditory, outer[mesh:noexp] OR labyrinth supporting cells[mesh:noexp] OR round window, ear[mesh:noexp] OR scala tympani[mesh:noexp] OR scala vestibuli[mesh:noexp] OR spiral ganglion[mesh:noexp] OR spiral lamina[mesh:noexp] OR “spiral ligament of cochlea”/
3	(Ear[tiab] OR cochlea*[tiab])
4	# 1 OR #2 OR #3
5	Cell death[mesh:noexp] OR apoptosis/
6	(Cell death[tiab] OR apopto*[tiab])
7	#5 OR #6
8	#4 AND #7
9	Anibiotic[tiab] OR aminoglycoside[tiab] OR cisplatin[tiab] OR carboplain[tiab] OR plantinum[tiab] OR tobramycin[tiab] OR gentamicin[tiab] OR amikacin[tiab] OR kanamycin[tiab]
10	Ototoxicity[tiab] OR ototoxic[tiab]
11	#9 OR #10
12	#4 AND #11
13	#8 AND #11
14	#12 OR #13
15	“4,5-dihydro-1-(3-(trifluoromethyl)phenyl)-1h-pyrazol-3-amine”[mesh:noexp] OR adalimumab[mesh:noexp] OR adapalene, benzoyl peroxide drug combination[mesh:noexp] OR adapalene[mesh:noexp] OR algestone acetophenide[mesh:noexp] OR ampyrone[mesh:noexp] OR anti-inflammatory agents, non-steroidal[mesh:noexp] OR anti-inflammatory agents[mesh:noexp] OR antioxidants[mesh:noexp] OR antipyrine[mesh:noexp] OR apazone[mesh:noexp] OR aspirin[mesh:noexp] OR beclomethasone[mesh:noexp] OR benzydamine[mesh:noexp] OR betamethasone valerate[mesh:noexp] OR betamethasone[mesh:noexp] OR budesonide[mesh:noexp] OR bufexamac[mesh:noexp] OR celecoxib[mesh:noexp] OR clobetasol[mesh:noexp] OR clofazimine[mesh:noexp] OR clonixin[mesh:noexp] OR corticosterone[mesh:noexp] OR cortisone[mesh:noexp] OR curcumin[mesh:noexp] OR cyclooxygenase 2 inhibitors[mesh:noexp] OR cyclooxygenase inhibitors[mesh:noexp] OR desonide[mesh:noexp] OR desoximetasone[mesh:noexp] OR dexamethasone isonicotinate[mesh:noexp] OR dexamethasone[mesh:noexp] OR diclofenac[mesh:noexp] OR diflucortolone[mesh:noexp] OR diflunisal[mesh:noexp] OR dipyrone[mesh:noexp] OR epirizole[mesh:noexp] OR etanercept[mesh:noexp] OR etodolac[mesh:noexp] OR fenoprofen[mesh:noexp] OR feprazone[mesh:noexp] OR fludrocortisone[mesh:noexp] OR flufenamic acid[mesh:noexp] OR flumethasone[mesh:noexp] OR fluocinolone acetonide[mesh:noexp] OR fluocinonide[mesh:noexp] OR fluocortolone[mesh:noexp] OR fluorometholone[mesh:noexp] OR fluprednisolone[mesh:noexp] OR flurandrenolone[mesh:noexp] OR flurbiprofen[mesh:noexp] OR fluticasone[mesh:noexp] OR glycyrrhetinic acid[mesh:noexp] OR glycyrrhizic acid[mesh:noexp] OR halcinonide[mesh:noexp] OR heparinoids[mesh:noexp] OR hydrocortisone[mesh:noexp] OR ibuprofen[mesh:noexp] OR indomethacin[mesh:noexp] OR indoprofen[mesh:noexp] OR ketoprofen[mesh:noexp] OR ketorolac tromethamine[mesh:noexp] OR ketorolac[mesh:noexp] OR meclofenamic acid[mesh:noexp] OR mefenamic acid[mesh:noexp] OR mesalamine[mesh:noexp] OR methylprednisolone hemisuccinate[mesh:noexp] OR methylprednisolone[mesh:noexp] OR mometasone furoate[mesh:noexp] OR naproxen[mesh:noexp] OR nedocromil[mesh:noexp] OR niflumic acid[mesh:noexp] OR olopatadine hydrochloride[mesh:noexp] OR oxyphenbutazone[mesh:noexp] OR paramethasone[mesh:noexp] OR phenylbutazone[mesh:noexp] OR piroxicam[mesh:noexp] OR prednisolone[mesh:noexp] OR prednisone[mesh:noexp] OR salicylates[mesh:noexp] OR sodium salicylate[mesh:noexp] OR steroids[mesh:noexp] OR sulfasalazine[mesh:noexp] OR sulindac[mesh:noexp] OR suprofen[mesh:noexp] OR tilorone[mesh:noexp] OR tolmetin[mesh:noexp] OR triamcinolone acetonide[mesh:noexp] OR triamcinolone[mesh:noexp] 14 adalimumab[tiab] OR adapalene[tiab] OR algestone acetophenide[tiab] OR ampyrone[tiab] OR anti-inflammatory agents[tiab] OR antioxidants [tiab] OR antipyrine[tiab] OR apazone[tiab] OR aspirin[tiab] OR beclomethasone[tiab] OR benzydamine[tiab] OR betamethasone[tiab] OR budesonide[tiab] OR bufexamac[tiab] OR celecoxib[tiab] OR clobetasol[tiab] OR clofazimine[tiab] OR clonixin[tiab] OR corticosterone[tiab] OR cortisone[tiab] OR curcumin[tiab] OR cyclooxygenase 2 inhibitor*[tiab] OR cyclooxygenase inhibitor*[tiab] OR desonide[tiab] OR desoximetasone[tiab] OR dexamethasone[tiab] OR diclofenac[tiab] OR diflucortolone[tiab] OR diflunisal[tiab] OR dipyrone[tiab] OR epirizole[tiab] OR etanercept[tiab] OR etodolac[tiab] OR fenoprofen[tiab] OR feprazone[tiab] OR fludrocortisone[tiab] OR flufenamic acid[tiab] OR flumethasone[tiab] OR fluocinolone acetonide[tiab] OR fluocinonide[tiab] OR fluocortolone[tiab] OR fluorometholone[tiab] OR fluprednisolone[tiab] OR flurandrenolone[tiab] OR flurbiprofen[tiab] OR fluticasone[tiab] OR glycyrrhetinic acid[tiab] OR glycyrrhizic acid[tiab] OR halcinonide[tiab] OR heparinoid*[tiab] OR hydrocortisone[tiab] OR ibuprofen[tiab] OR indomethacin[tiab] OR indoprofen[tiab] OR ketoprofen[tiab] OR ketorolac tromethamine[tiab] OR ketorolac[tiab] OR meclofenamic acid[tiab] OR mefenamic acid[tiab] OR mesalamine[tiab] OR methylprednisolone[tiab] OR mometasone furoate[tiab] OR naproxen[tiab] OR nedocromil[tiab] OR niflumic acid[tiab] OR olopatadine hydrochloride[tiab] OR oxyphenbutazone[tiab] OR paramethasone[tiab] OR phenylbutazone[tiab] OR piroxicam[tiab] OR prednisolone[tiab] OR prednisone[tiab] OR salicylate*[tiab] OR steroid*[tiab] OR sulfasalazine[tiab] OR sulindac[tiab] OR suprofen[tiab] OR tilorone[tiab] OR tolmetin[tiab] OR triamcinolone[tiab]
16	Acetaminophen[tiab] OR adalimumab[tiab] OR adapalene[tiab] OR algestone acetophenide[tiab] OR ampyrone[tiab] OR anti-inflammatory agents[tiab] OR antioxidants [tiab] OR antipyrine[tiab] OR apazone[tiab] OR aspirin[tiab] OR beclomethasone[tiab] OR benzydamine[tiab] OR betamethasone[tiab] OR budesonide[tiab] OR bufexamac[tiab] OR celecoxib[tiab] OR clobetasol[tiab] OR clofazimine[tiab] OR clonixin[tiab] OR corticosterone[tiab] OR cortisone[tiab] OR curcumin[tiab] OR cyclooxygenase 2 inhibitor*[tiab] OR cyclooxygenase inhibitor*[tiab] OR desonide[tiab] OR desoximetasone[tiab] OR dexamethasone[tiab] OR diclofenac[tiab] OR diflucortolone[tiab] OR diflunisal[tiab] OR dipyrone[tiab] OR epirizole[tiab] OR etanercept[tiab] OR etodolac[tiab] OR fenoprofen[tiab] OR feprazone[tiab] OR fludrocortisone[tiab] OR flufenamic acid[tiab] OR flumethasone[tiab] OR fluocinolone acetonide[tiab] OR fluocinonide[tiab] OR fluocortolone[tiab] OR fluorometholone[tiab] OR fluprednisolone[tiab] OR flurandrenolone[tiab] OR flurbiprofen[tiab] OR fluticasone[tiab] OR glycyrrhetinic acid[tiab] OR glycyrrhizic acid[tiab] OR halcinonide[tiab] OR heparinoid*[tiab] OR hydrocortisone[tiab] OR ibuprofen[tiab] OR indomethacin[tiab] OR indoprofen[tiab] OR ketoprofen[tiab] OR ketorolac tromethamine[tiab] OR ketorolac[tiab] OR meclofenamic acid[tiab] OR mefenamic acid[tiab] OR mesalamine[tiab] OR methylprednisolone[tiab] OR mometasone furoate[tiab] OR naproxen[tiab] OR nedocromil[tiab] OR niflumic acid[tiab] OR olopatadine hydrochloride[tiab] OR oxyphenbutazone[tiab] OR paramethasone[tiab] OR phenylbutazone[tiab] OR piroxicam[tiab] OR prednisolone[tiab] OR prednisone[tiab] OR salicylate*[tiab] OR steroid*[tiab] OR sulfasalazine[tiab] OR sulindac[tiab] OR suprofen[tiab] OR tilorone[tiab] OR tolmetin[tiab] OR triamcinolone[tiab]
17	“24,25-dihydroxyvitamin d 3”[mesh:noexp] OR “25-hydroxyvitamin d 2”[mesh:noexp] OR acetylcarnitine[mesh:noexp] OR acetylcysteine[mesh:noexp] OR alpha-tocopherol[mesh:noexp] OR ascorbic acid[mesh:noexp] OR beta carotene[mesh:noexp] OR beta-tocopherol[mesh:noexp] OR biotin[mesh:noexp] OR calcifediol[mesh:noexp] OR calcitriol[mesh:noexp] OR carnitine[mesh:noexp] OR cholecalciferol[mesh:noexp] OR cobamides[mesh:noexp] OR cod liver oil[mesh:noexp] OR dehydroascorbic acid[mesh:noexp] OR dihydrotachysterol[mesh:noexp] OR dihydroxycholecalciferols[mesh:noexp] OR ergocalciferols[mesh:noexp] OR flavin mononucleotide[mesh:noexp] OR folic acid[mesh:noexp] OR formyltetrahydrofolates[mesh:noexp] OR fursultiamin[mesh:noexp] OR gamma-tocopherol[mesh:noexp] OR hydroxocobalamin[mesh:noexp] OR hydroxycholecalciferols[mesh:noexp] OR inositol 1,4,5-trisphosphate[mesh:noexp] OR inositol phosphates[mesh:noexp] OR inositol[mesh:noexp] OR leucovorin[mesh:noexp] OR magnesium[mesh:noexp] OR niacin[mesh:noexp] OR niacinamide[mesh:noexp] OR nicorandil[mesh:noexp] OR nicotinic acids[mesh:noexp] OR palmitoylcarnitine[mesh:noexp] OR palmitoylcarnitine[mesh:noexp] OR panax notoginseng[mesh:noexp] OR panax[mesh:noexp] OR pantothenic acid[mesh:noexp] OR phytic acid[mesh:noexp] OR pteroylpolyglutamic acids[mesh:noexp] OR pyridoxal phosphate[mesh:noexp] OR pyridoxal[mesh:noexp] OR pyridoxamine[mesh:noexp] OR pyridoxine[mesh:noexp] OR riboflavin[mesh:noexp] OR superoxide dismutase[mesh:noexp] OR tetrahydrofolates[mesh:noexp] OR thiamine monophosphate[mesh:noexp] OR thiamine pyrophosphate[mesh:noexp] OR thiamine triphosphate[mesh:noexp] OR thiamine[mesh:noexp] OR thioctic acid[mesh:noexp] OR tocopherols[mesh:noexp] OR tocotrienols[mesh:noexp] OR tocotrienols[mesh:noexp] OR vitamin a[mesh:noexp] OR vitamin b 12[mesh:noexp] OR vitamin b 6[mesh:noexp] OR vitamin b complex[mesh:noexp] OR vitamin d[mesh:noexp] OR vitamin e[mesh:noexp] OR vitamin k 1[mesh:noexp] OR vitamin k 2[mesh:noexp] OR vitamin k 3[mesh:noexp] OR vitamin k[mesh:noexp] OR vitamin u[mesh:noexp] OR vitamins[mesh:noexp] OR xanthopterin[mesh:noexp]
18	“24,25-dihydroxyvitamin d 3”[tiab] OR “25-hydroxyvitamin d 2”[tiab] OR ginseng[tiab] OR acetylcarnitine[tiab] OR acetylcysteine[tiab] OR acetyl-l-carnitine[tiab] OR alpha-tocopherol[tiab] OR anti-apoptotic[tiab] OR ascorbic acid[tiab] OR Astragaloside[tiab] OR beta carotene[tiab] OR beta-tocopherol[tiab] OR biotin[tiab] OR calcifediol[tiab] OR calcitriol[tiab] OR carnitine[tiab] OR cholecalciferol[tiab] OR cobamides[tiab] OR cod liver oil[tiab] OR dehydroascorbic acid[tiab] OR dihydrotachysterol[tiab] OR dihydroxycholecalciferols[tiab] OR ergocalciferols[tiab] OR flavin mononucleotide[tiab] OR folic acid[tiab] OR formyltetrahydrofolates[tiab] OR fursultiamin[tiab] OR gamma-tocopherol[tiab] OR gene expression inhibitor[tiab] OR hydroxocobalamin[tiab] OR hydroxycholecalciferols[tiab] OR inositol 1,4,5-trisphosphate[tiab] OR inositol phosphates[tiab] OR inositol[tiab] OR leucovorin[tiab] OR magnesium[tiab] OR neuron regulation[tiab] OR niacin[tiab] OR niacinamide[tiab] OR nicorandil[tiab] OR nicotinic acids[tiab] OR palmitoylcarnitine[tiab] OR palmitoylcarnitine[tiab] OR panax notoginseng[tiab] OR panax[tiab] OR pantothenic acid[tiab] OR peptide*[tiab] OR phytic acid[tiab] OR pteroylpolyglutamic acids[tiab] OR pyridoxal phosphate[tiab] OR pyridoxal[tiab] OR pyridoxamine[tiab] OR pyridoxine[tiab] OR riboflavin[tiab] OR ROS scavenger*[tiab] OR Src Inhibitor*[tiab] OR superoxide dismutase[tiab] OR tetrahydrofolates[tiab] OR thiamine monophosphate[tiab] OR thiamine pyrophosphate[tiab] OR thiamine triphosphate[tiab] OR thiamine[tiab] OR thioctic acid[tiab] OR TLR signalling modulator[tiab] OR tocopherols[tiab] OR tocotrienols[tiab] OR tocotrienols[tiab] OR vitamin a[tiab] OR vitamin b 12[tiab] OR vitamin b 6[tiab] OR vitamin b complex[tiab] OR vitamin d[tiab] OR vitamin e[tiab] OR vitamin k 1[tiab] OR vitamin k 2[tiab] OR vitamin k 3[tiab] OR vitamin k[tiab] OR vitamin u[tiab] OR vitamins[tiab] OR xanthopterin[tiab]
19	3-hydroxyanthranilic acid[mesh:noexp] OR allopurinol[mesh:noexp] OR antioxidants[mesh:noexp] OR bilirubin[mesh:noexp] OR butylated hydroxyanisole[mesh:noexp] OR butylated hydroxytoluene[mesh:noexp] OR canthaxanthin[mesh:noexp] OR carotenoids[mesh:noexp] OR catalase[mesh:noexp] OR dimethyl sulfoxide[mesh:noexp] OR ergothioneine[mesh:noexp] OR free radical scavengers[mesh:noexp] OR grape seed extract[mesh:noexp] OR masoprocol[mesh:noexp] OR melatonin[mesh:noexp] OR nitric oxide[mesh:noexp] OR pentoxifylline[mesh:noexp] OR probucol[mesh:noexp] OR propyl gallate[mesh:noexp] OR pyrogallol[mesh:noexp] OR quercetin[mesh:noexp] OR selenic acid[mesh:noexp] OR silymarin[mesh:noexp] OR superoxide dismutase[mesh:noexp] OR uric acid[mesh:noexp] OR zeta carotene[mesh:noexp]
20	3-hydroxyanthranilic acid[tiab] OR allopurinol[tiab] OR antioxidant*[tiab] OR bilirubin[tiab] OR butylated hydroxyanisole[tiab] OR butylated hydroxytoluene[tiab] OR canthaxanthin[tiab] OR carotenoid*[tiab] OR catalase[tiab] OR dimethyl sulfoxide[tiab] OR ergothioneine[tiab] OR free radical scavenger*[tiab] OR grape seed extract[tiab] OR masoprocol[tiab] OR melatonin[tiab] OR nitric oxide[tiab] OR pentoxifylline[tiab] OR probucol[tiab] OR propyl gallate[tiab] OR pyrogallol[tiab] OR quercetin[tiab] OR selenic acid[tiab] OR silymarin[tiab] OR superoxide dismutase[tiab] OR uric acid[tiab] OR zeta carotene[tiab]
21	“Lymphocyte specific protein tyrosine kinase p56(lck)”[mesh:noexp] OR “oncogene protein pp60(v-src)”[mesh:noexp] OR “proto-oncogene proteins pp60(c-src)”[mesh:noexp] OR cell-penetrating peptides[mesh:noexp] OR glutathione peroxidase[mesh:noexp] OR glutathione[mesh:noexp] OR hydroxyl radical[mesh:noexp] OR hypochlorous acid[mesh:noexp] OR jnk mitogen-activated protein kinases[mesh:noexp] OR mitogen-activated protein kinase 10[mesh:noexp] OR mitogen-activated protein kinase 8[mesh:noexp] OR mitogen-activated protein kinase 9[mesh:noexp] OR peptides[mesh:noexp] OR peroxides[mesh:noexp] OR proto-oncogene proteins c-fyn[mesh:noexp] OR proto-oncogene proteins c-hck[mesh:noexp] OR proto-oncogene proteins c-yes[mesh:noexp] OR reactive oxygen species[mesh:noexp] OR singlet oxygen[mesh:noexp] OR src-family kinases[mesh:noexp] OR toll-like receptor 1[mesh:noexp] OR toll-like receptor 10[mesh:noexp] OR toll-like receptor 2[mesh:noexp] OR toll-like receptor 3[mesh:noexp] OR toll-like receptor 4[mesh:noexp] OR toll-like receptor 5[mesh:noexp] OR toll-like receptor 6[mesh:noexp] OR toll-like receptor 7[mesh:noexp] OR toll-like receptor 8[mesh:noexp] OR toll-like receptor 9[mesh:noexp] OR toll-like receptors[mesh:noexp]
22	Carbamathione[tiab] OR glutathione peroxidase[tiab] OR glutathione[tiab] OR hydroxyl radical[tiab] OR hypochlorous acid[tiab] OR jnk inhibitor*[tiab] OR kinase*[tiab] OR oncogene protein*[tiab] OR peptide*[tiab] OR peroxide*[tiab] OR reactive oxygen species[tiab] OR ROS scavenger*[tiab] OR singlet oxygen[tiab] OR toll-like receptor*[tiab]
23	“Coenzyme Q10”[tiab] OR Q10[tiab] OR methionine OR “sodium thiosulphate”[tiab] OR ebselen[tiab] OR Ginko[tiab] OR amifostine[tiab] OR pantoprazole[tiab]
24	#15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 or #23
25	#14 AND #24
26	“Clinical Trial” [PT:NoExp] OR “clinical trial, phase i”[pt] OR “clinical trial, phase ii”[pt] OR “clinical trial, phase iii”[pt] OR “clinical trial, phase iv”[pt] OR “controlled clinical trial”[pt] OR “multicenter study”[pt] OR “randomized controlled trial”[pt] OR “Clinical Trials as Topic”[mesh:noexp] OR “clinical trials, phase i as topic”[MeSH Terms:noexp] OR “clinical trials, phase ii as topic”[MeSH Terms:noexp] OR “clinical trials, phase iii as topic”[MeSH Terms:noexp] OR “clinical trials, phase iv as topic”[MeSH Terms:noexp] OR “controlled clinical trials as topic”[MeSH Terms:noexp] OR “randomized controlled trials as topic”[MeSH Terms:noexp] OR “early termination of clinical trials”[MeSH Terms:noexp] OR “multicenter studies as topic”[MeSH Terms:noexp] OR “Double-Blind Method”[Mesh] OR ((randomised[TIAB] OR randomized[TIAB]) AND (trial[TIAB] OR trials[tiab])) OR ((single[TIAB] OR double[TIAB] OR doubled[TIAB] OR triple[TIAB] OR tripled[TIAB] OR treble[TIAB] OR treble[TIAB]) AND (blind*[TIAB] OR mask*[TIAB])) OR (“4 arm”[tiab] OR “four arm”[tiab])
27	#25 AND #26
28	#27 AND english[la]

Pharmaceutical interventions for drug-induced ototoxicity in clinical trials search terms.

Table 2. Summary of agents investigated for prevention or treatment of medication-induced ototoxicity in clinical trials to date (in bold font), including other pertinent pre-clinical targets for ototoxic damage (not in bold font).

Investigated agent	Ototoxicity injury-inducing target(s)	ClinicalTrial(s).gov identifier*	Evidence for safety and efficacy
Alpha-lipoic acid	– Aminoglycosides – Carboplatin – Cisplatin	NCT00477607	Conlon et al. (1999), Rybak, Whitworth, and Somani (1999), Husain et al. (2005) and Martin (2014)
Amifostine	– Cisplatin	NCT00003269	Duval and Daniel (2012), Hensley et al. (2009) and Mason (1999).
Co-enzyme Q10	– Cisplatin – Gentamicin – Tinnitus	NCT02353650	Fetoni et al. (2012), Astolfi et al. (2016) and Rabau (2015)
d-methionine (d-met)	– Amikacin – Carboplatin – Cisplatin – Gentamicin – Kanamycin – Noise – Platinum – Tobramycin	NCT00427102	Hamstra et al. (2010), Sha and Schacht (2000), Fox et al. (2016), Campbell et al. (1996, 1999, 2007, 2009, 2016), Lockwood et al. (2000), Cloven et al. (2000) and Korver et al. (2002)
Ebselen (SPI-1005)	– Cisplatin or – Carboplatin – Gentamicin – Noise – Platinum – Tobramycin	NCT01451853 NCT02819856	Rybak et al. (2000), Lorito et al. (2011), Kim et al. (2009), Takumida, Popa, and Anniko (1999), Lynch and Kil (2009) and Kil et al. (2017)
Ginkgo Biloba	– Aminoglycosides – Noise	NCT01139281	Le Bars and Kastelan (2000), McKenna, Jones, and Hughes (2001), Cakil et al. (2012), Dias et al. (2015), Dias (2010), Huang, Whitworth, and Rybak (2007), Finkler et al. (2012), Fukaya and Kanno, (1999) and Ma et al. (2015)
N-acetylcysteine (NAC)	– Aminoglycosides – Cisplatin – Noise	NCT01271088	Bock et al. (1983), Kramer et al. (2006), Kocyigit (2011), Tokgoz et al. (2011), Kranzer et al. (2015), Yoo et al. (2014) and Riga et al. (2013)
Pantoprazole	– Cisplatin	NCT01848457	Balis (2016), Huang et al. (2013) and Luciani et al. (2004)
Salicylate (aspirin)	– Gentamicin	None found	Crabb et al. (2017), Chen et al. (2007) and Sha, Qiu, and Schacht (2006)
SENS-401	– Cisplatin	None found	Petremann et al. (2017)
Sodium thiosulphate	– Cisplatin – Gentamicin – Noise	NCT02281006 NCT00716976	Otto et al. (1988), Neuwelt et al. (1996), Meyer (2016), Muldoon et al. (2000), Harned et al. (2008), Freyer et al. (2017), Pouyatos et al. (2007) and Hochman et al. (2006)
Steroids	– Cisplatin – Gentamicin – Noise	NCT01372904	Özel et al. (2016), Waissbluth et al. (2013), Sun et al. (2016), Marshak et al. (2014) and Marshak (2015)
Vitamins with magnesium	– Aminoglycosides – Cisplatin – Noise	None found	Le Prell, Hughes, and Miller (2007), Le Prell et al. (2014), Omenn (1998, 2007) and Villani et al. (2016)

NIHL clinical trials were included where they are the only study design for cochlear protection to date but (*) their corresponding ClinicalTrials.gov NCT numbers were not included.

Conlon, B.J., J.M. Aran, J.P. Erre, and D.W. Smith. 1999. “Attenuation of Aminoglycoside-Induced Cochlear Damage with the Metabolic Antioxidant Alpha-Lipoic Acid.” Hearing Research 128 (1–2): 40–44. doi:10.1016/S0378-5955(98)00195-6.

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Rybak, L.P., C. Whitworth, S. Somani. 1999. “Application of Antioxidants and Other Agents to Prevent Cisplatin Ototoxicity.” Laryngoscope 109 (11): 1740–1744. doi:10.1097/00005537-199911000-00003.

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Husain, K., C. Whitworth, S.M. Somani, and L.P. Rybak. 2005. “Partial Protection by Lipoic Acid Against Carboplantin-Induced Ototoxicity in Rats.” Biomedical and Environmental Sciences 18 (3): 198–206.

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Martin, D.L. 2014. Alpha-lipoic acid in preventing hearing loss in cancer patients undergoing treatment with cisplatin. https://clinicaltrials.gov (Identification No. NCT00477607).

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Duval, M., and S.J. Daniel. 2012. “Meta-Analysis of the Efficacy of Amifostine in the Prevention of Cisplatin Ototoxicity.” Journal of Otolaryngology – Head & Neck Surgery 41 (5): 309–315.

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Hensley, M.L., K.L. Hagerty, T. Kewalramani, D.M. Green, N.J. Meropol, T.H. Wasserman, G.I. Cohen, et al. 2009. “American Society of Clinical Oncology 2008 Clinical Practice Guideline Update: Use of Chemotherapy and Radiation Therapy Protectants.” Journal of Clinical Oncology 27 (1): 127–145. doi:10.1200/JCO.2008.17.2627.

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Mason, J.R. 1999. Amifostine Followed by High Dose Chemotherapy in Treating Patients With Hematologic Cancer or Solid Tumors. https://clinicaltrials.gov (Identification No. NCT 00003269).

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Fetoni, A.R., S.L. Eramo, R. Rolesi, D. Troiani, and G. Paludetti. 2012. “Antioxidant Treatment with Coenzyme Q-ter in Prevention of Gentamycin Ototoxicity in An Animal Model.” Acta Otorhinolaryngologica Italica 32 (2): 103–110.

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Astolfi, L., E. Simoni, F. Valente, S. Ghiselli, S. Hatzopoulos, M. Chicca, and A. Martini. 2016. “Coenzyme Q10 Plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats.” PLoS One 11 (9): e0162106. doi:10.1371/journal.pone.0162106.

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Rabau, S. 2015. The Effect of Coenzyme Q10 on Hearing and Tinnitus Characteristics of Chronic Tinnitus Patients. https://clinicaltrials.gov (Identification No. NCT02353650).

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