Effect of Combined Antioxidant Therapy on Oxidative Stress Markers and Inflammatory Cytokines in Patients With Tinnitus

Study Overview
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Brief Summary
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The main objective of our study is to evaluate the effect of combinated antioxidants therapy with Adepsique® (amitriptyline, perphenazine, and diazepam) on patients with tinnitus chronic symptoms, evaluating the levels of inflammatory cytokines and oxidative stress in blood. The researchers intend to include 58 patients, divided into two intervention groups, who will be randomly assigned a pill with antioxidants or placebo, and the patient must eat one pill per day for 3 months. In the study, the clinical characteristics of tinnitus, inflammatory cytokines and oxidative stress markers will be evaluated, before, during and after the intervention with antioxidant therapy. Subsequently, the clinical and sample results will be evaluated to compare the effects between them.

Detailed Description
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Tinnitus is a pathology defined as the perception of a sound without an external acoustic stimulus. About 15 to 20% of the world population suffers from this pathology.It is classified according to the time of presentation (acute or chronic); in the existence of an internal source measurable and perceptible by the patient and the physician (objective) or where the source does not exist and is only perceived by the patient (subjective), the latter being the most common. And, in the place where they originate, exotic (outside the ear), endotic (within the auditory apparatus), and central (within the cerebral cortex without lesion of the auditory apparatus). As well as the influence it presents in daily life, being mild, moderate, severe or catastrophic. Within the pathophysiology, the influence of different proinflammatory cytokines such as IL-6, TNF-α, β-2GP1, IL-1, among others, is described; as well as markers of oxidative stress and elevated levels of ROS, which annul defense mechanisms against oxidative damage, and induce damage to DNA, lipids, and membrane proteins.ncreased levels of nitric oxide, peroxynitrite, nuclear transcriptional factor Kappa-B (NF-κB), glutamate (N-methyl D-aspartate) receptors, and calcium cause hair cell damage. On the other hand, reduced levels of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase, and glutathione transferase perpetuate cell damage. The diagnosis is based mainly on ruling out etiological factors, associated symptoms or existing comorbidities that cause tinnitus secondarily, as well as a detailed clinical history, measurement of hearing quality, and demonstration of the imbalance of neurotransmitters and proinflammatory molecules. Because it is a multifactorial entity, the definitive treatment has not yet been developed. Extensive pharmacological therapies, from the use of NSAIDs to antidepressant and antipsychotic drugs, have been tried with ambiguous, inconsistent and inconclusive results. Alternative therapies with multivitamins and antioxidants have shown probable utility in the treatment of tinnitus, however, the existing evidence is of poor and conflicting quality.The latter reduce oxidative stress through different means; through the destruction of free radicals by donating electrons to the unpaired states of these radicals. Another means is through the catalysis of free radicals, converting them into harmless molecules (water and oxygen). Lastly, they support reducing chronic inflammation secondarily by decreasing the rate of auditory hairy cell apoptosis.

Official Title
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Effect of Combined Antioxidant Therapy on Oxidative Stress Markers and Inflammatory in Patients With Chronic Subjective Endotic Tinnitus

Conditions
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Tinnitus, Subjective, Tinnitus, Bilateral, Antioxidant Therapy, Psychiatric Drugs, Oxidative Stress, Inflammatory Cytokines, SSRI

Intervention / Treatment
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* Dietary Supplement: Drusen Mega®
* Drug: Sertraline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female with subjective chronic tinnitus (unilateral or bilateral) Patients with normal audiometry or identification of hearing loss up to a medium degree (20-70 dB) Patients with evidence of endotic tinnitus Patients who have or do not have social medical security Females of childbearing age with a negative pregnancy test and use of oral contraceptives Patients under pharmacological management with a period of stable medication (≥3 months) for chronic degenerative diseases and under good metabolic control (according to ADA 2022 criteria) through primary intervention Exclusion Criteria: Presence of tinnitus secondary to head trauma, acoustic trauma, or sudden hearing loss History or presence of Ménière's disease, otosclerosis, acute or chronic otitis media Active gastrointestinal haemorrhagic disease History or presence of cancer (any type) or submission to radio and/or chemotherapy Autoimmune disease (any) History of severe cardiovascular disease (myocardial infarction, stroke, severe peripheral vascular disease) Benign prostatic hyperplasia Blood dyscrasias and/or bleeding diathesis Thyroid disease (any) Temporomandibular joint dysfunction Neurodegenerative processes Hepatic and renal failure Closed or open angle glaucoma Intake of any medication belonging to the following families (Anticoagulants, Benzodiazepines, ASA diuretics, Aminoglycosides, Chemotherapeutics, Acetylsalicylic Acid, Quinine, MAOIs) Intake of antioxidants in the last 6 months Hypersensitivity to vitamins that constitute the antioxidant intervention, or any medication belonging to the Adepsique formulation Pregnancy, lactation History of disease due to COVID-19 infection in the last 6 months Diet rich in antioxidants that exceeds the concentrations of the daily nutritional recommendations of the Dietary Reference Intake Participation in another clinical trial Drug abuse, smoking (daily consumption during the last month of 5 to 10 cigarettes) and/or alcoholism

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Clinical Trial Phase II A, controlled with placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drusen Mega® + Sertraline<br>It will consist of 29 patients with Chronic Subjetive Endotic Tinnitus. Patients will eat one capsule of antioxidant therapy (Drusen Mega®) and one capsule of sertraline per day in the night for 3 months. | Dietary Supplement: Drusen Mega®<br>* It consists of a dietary supplement composed of Vitamin C 60.0mg, Vitamin E 30.0mg, Zinc 12.5mg, Copper 1.0mg, Astaxanthin 4.0mg, Zeaxanthin 2.0mg, Lutein 10.0mg and Omega 3 Acids 500.0mg. It is suggested to consume one capsule per day, preferably with food. This supplement is indicated for nutritional deficiencies and in patients with ophthalmological pathologies.<br>* Other names: Multivitamins;Drug: Sertraline<br>* It consists of a drug capsule composed of Sertraline Hydrochloride 50mg. In adults it is suggested to consume one to four capsule(s) per day, administering (preferably) the highest dose in the evening, before going to bed. This drug is indicated in the treatment of depressive states with anxiety or moderate to severe agitation, which are accompanied by tension, excitement, insomnia, obsessive and hypochondriac traits. It is also indicated in obsessive-compulsive disorder, panic attacks, stress disorder, post-traumatic disorder, social anxiety disorder and used to relieve the symptoms of premenstrual dysphoric disorder.<br>* Other names: Sertraline Hydrochloride;|
| Placebo Comparator: Placebo + Sertraline<br>It will consist of 29 patients with Chronic Subjetive Endotic Tinnitus. Patients will eat one capsule of placebo (Magnesium Oxide 100mg) per day in the morning and one capsule of sertraline per day in the night for 3 months. | Drug: Sertraline<br>* It consists of a drug capsule composed of Sertraline Hydrochloride 50mg. In adults it is suggested to consume one to four capsule(s) per day, administering (preferably) the highest dose in the evening, before going to bed. This drug is indicated in the treatment of depressive states with anxiety or moderate to severe agitation, which are accompanied by tension, excitement, insomnia, obsessive and hypochondriac traits. It is also indicated in obsessive-compulsive disorder, panic attacks, stress disorder, post-traumatic disorder, social anxiety disorder and used to relieve the symptoms of premenstrual dysphoric disorder.<br>* Other names: Sertraline Hydrochloride;Drug: Placebo<br>* It consists of a placebo capsule composed of Magnesium Oxide 100mg. This component is inert in the dose at which it will be administered.<br>* Other names: Magnesium Oxide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in levels of Superoxide Dismutase (SOD) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The enzyme concentration will be determined with multiplex bead immunoassays technique and reported in microunits per milliliter units (mUI/mL) | 90 days | 
| Change from baseline in levels of Catalase (CAT) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The enzyme concentration will be determined with multiplex bead immunoassays technique and reported in microunits per milliliter units (mUI/mL) | 90 days | 
| Change from baseline in levels of Glutathione Peroxidase (GPx) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The enzyme concentration will be determined with multiplex bead immunoassays technique and reported in microunits per milliliter units (mUI/mL) | 90 days | 
| Change from baseline in levels of Malondialdehyde (MDA) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The enzyme concentration will be determined with multiplex bead immunoassays technique and reported in microunits per milliliter units (mUI/mL) | 90 days | 
| Change from baseline in levels of Oxidized Low-Density Lipoprotein LDL (oxLDL) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The enzyme concentration will be determined with multiplex bead immunoassays technique and reported in nanograms per milliliter units (ng/mL) | 90 days | 
| Change from baseline in levels of Tumor Necrosis Factor Alpha (TNF-a) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in picogram per milliliter units (pg/mL) | 90 days | 
| Change from baseline in levels of Interleukin 8 (IL-8) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in picogram per milliliter units (pg/mL) | 90 days | 
| Change from baseline in levels of Interleukin 6 (IL-6) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in picogram per milliliter units (pg/mL) | 90 days | 
| Change from baseline in levels of Gamma Interferon (IFN-γ) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in picogram per milliliter units (pg/mL) | 90 days | 
| Change from baseline in levels of Nuclear Factor Kappa B (NF-κB) | Standard blood sampling will be collected through a catheter in an antecubital vein in tubes without EDTA, centrifuged and serum will placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in nanogram per milliliter units (ng/mL) | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Tinnitus Loudness (db) Assessment | Tinnitus screening tests will be conducted, using psychoacoustic techniques including pitch loudness matching within a soundproof booth. Patients will be given pairs of different tones in the non-tinnitus or less intense ear and will be asked to choose which tone is closest to the perceived tinnitus. This will be continued until a definite match will made. The results will be expressed in decibels | 90 days | 
| Change from baseline in Tinnitus Frecuency (Hz) Assessment | Tinnitus screening tests will be conducted, using psychoacoustic techniques including pitch frequency matching within a soundproof booth. Patients will be given pairs of different tones in the non-tinnitus or less intense ear and will be asked to choose which tone is closest to the perceived tinnitus. This will be continued until a definite match will made. The results will be expressed in hertz. | 90 days | 
| Change from baseline in Audiometric Assessment | Patients will undergo conventional pure tone audiometry and extended high frequency (EHF) audiometry to determine any hearing loss. The degree of hearing loss will be determined using the average of values in four consecutive frequencies (500-1000-2000-4000) and will be classified as normal hearing, little, mild, moderate or severe hearing loss. | 90 days | 
| Change from baseline in Tinnitus Discomfort Assessment | Patients will complete the questionnaire Tinnitus Handicap Inventory (THI) which measure the subjective discomfort a patient experiences because of tinnitus. THI comprises 25 questions which are divided in functional, emotional, and catastrophic subscales. Total scores of THI range from 0 to 100. | 90 days | 
| Change from baseline in levels of Otolin-1 | Otolin-1 is a scaffold glycoprotein that connects the otoliths and matrix proteins of the otoconial nucleus with the sensory epithelium. Under normal conditions it is not found in peripheral blood, but in some hearing diseases it can be measured due to the loss of the blood-cochlear barrier. This will serve as an ear-specific marker. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tinnitus