Intratympanic N-Acetylcysteine for Prevention of Cisplatin-induced Ototoxicity.

Study Overview
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Brief Summary
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Although many intratympanic agents have been attempted, N-Acetylcysteine (NAC) appears to be the most promising and is a powerful, commonly used anti-oxidant. The goal of this prospective phase 2 randomized controlled trial is to determine the optimal dosage and effectiveness of intratympanic NAC injection in reducing hearing loss in head & neck cancer patients receiving cisplatin chemotherapy with curative intent.

Detailed Description
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A prospective randomized controlled trial phase 1 using a standard 3+3 design, followed by a randomized controlled phase 2 to determine dosage, safety, and efficacy of intratympanic NAC to treat hearing loss in head & neck patients receiving high-dose cisplatin chemotherapy. Participants will complete various pre-treatment hearing tests. One ear will be randomly chosen for the experimental treatment and the other ear will serve as the control ear. Participants will receive intratympanic NAC injections 60 minutes prior to their scheduled chemotherapy sessions in the experimental ear. The control ear will not receive any injection. Follow up hearing tests will be performed 2 months following completion of their primary cancer treatment.

Official Title
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Intratympanic N-Acetylcysteine (NAC) Injections for Prevention of Cisplatin-induced Ototoxicity in Head and Neck Cancer Patients: A Multi-centre Phase II Randomized Controlled Trial.

Conditions
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Ototoxic Hearing Loss

Intervention / Treatment
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* Drug: N-Acetyl Cysteine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced stage head and neck cancer Receiving high dose systemic cisplatin (100mg/m2) with concurrent radiation therapy as part of their curative intent treatment Willing to provide informed consent ECOG performance status 0-2 Histological confirmation of squamous cell carcinoma Exclusion Criteria: Age less than 18 Metastatic disease Tympanic membrane perforation or the presence of tympanostomy tubes as this may impact the retention and absorption of NAC when inserted into the middle ear Preexisting severe to profound sensorineural hearing loss (unilateral or bilateral) Pretreatment interaural discrepancy of greater than 10dB at three frequencies History of Meniere's or fluctuating hearing loss Previous hypersensitivity to NAC Patient unable to follow the protocol for any reason

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental arm with Intratympanic NAC injection<br>One ear will be randomly chosen for the experimental treatment and receive intratympanic NAC injections 60 minutes prior to their scheduled chemotherapy sessions | Drug: N-Acetyl Cysteine<br>* One ear will be randomly chosen for the experimental treatment of intratympanic NAC. The other ear will serve as the control ear which will not receive any injection.<br>* Other names: NAC;|
| No Intervention: Control arm with No injection<br>The control ear will not receive any injections | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of a safe and tolerable dosage for intratympanic NAC injection | The primary end-point of the phase 1 part of this study is the safety and tolerability of intratympanic NAC injections, by determining the causality of adverse events and serious adverse events and grading according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 | Within 1 day | 
| Improvement in hearing threshold with intratympanic NAC injection | The primary outcome measure of this study will be a comparison of hearing loss between the control and NAC-injected ears. More specifically, each ear will be scored as having hearing loss if there is a greater than 10dB hearing loss in three contiguous frequencies. This will be measured via threshold hearing tests. | Within 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in hearing quality with intratympanic NAC injection | The secondary outcome measure of this study will be a comparison of hearing discrimination, subjective tinnitus, otoacoustic emission, speech spatial and quality of hearing between the control and NAC-injected ears. | Within 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hearing Loss, Deafness, Cisplatin-induced Ototoxicity, Sensorineural hearing loss, Ear diseases, Antioxidant, N-acetyl cystein