Clinical trial NCT05646693: Effect of Combined Antioxidant Therapy on Oxidative Stress Markers and Inflammatory Cytokines in Patients With Tinnitus
Official title: Effect of Combined Antioxidant Therapy on Oxidative Stress Markers and Inflammatory in Patients With Chronic Subjective Endotic Tinnitus
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Tinnitus, Subjective
Tinnitus, Bilateral
Antioxidant Therapy
Psychiatric Drugs
Oxidative Stress
Inflammatory Cytokines
SSRI
Keywords: Tinnitus
Lead sponsor: University of Guadalajara
Sponsor class: OTHER
Collaborators: name: Institute of Experimental and Clinical Therapeutics
name: Hospital Civil de Guadalajara
First posted: 2022-12-12
Enrollment: 58
Sex: ALL
Minimum age (years): 25
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Clinical Trial Phase II A, controlled with placebo
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from baseline in levels of Superoxide Dismutase (SOD)
timeFrame: 90 days
measure: Change from baseline in levels of Catalase (CAT)
timeFrame: 90 days
measure: Change from baseline in levels of Glutathione Peroxidase (GPx)
timeFrame: 90 days
measure: Change from baseline in levels of Malondialdehyde (MDA)
timeFrame: 90 days
measure: Change from baseline in levels of Oxidized Low-Density Lipoprotein LDL (oxLDL)
timeFrame: 90 days
measure: Change from baseline in levels of Tumor Necrosis Factor Alpha (TNF-a)
timeFrame: 90 days
measure: Change from baseline in levels of Interleukin 8 (IL-8)
timeFrame: 90 days
measure: Change from baseline in levels of Interleukin 6 (IL-6)
timeFrame: 90 days
measure: Change from baseline in levels of Gamma Interferon (IFN-γ)
timeFrame: 90 days
measure: Change from baseline in levels of Nuclear Factor Kappa B (NF-κB)
timeFrame: 90 days
Secondary outcomes:
measure: Change from baseline in Tinnitus Loudness (db) Assessment
timeFrame: 90 days
measure: Change from baseline in Tinnitus Frecuency (Hz) Assessment
timeFrame: 90 days
measure: Change from baseline in Audiometric Assessment
timeFrame: 90 days
measure: Change from baseline in Tinnitus Discomfort Assessment
timeFrame: 90 days
measure: Change from baseline in levels of Otolin-1
timeFrame: 90 days
Other outcomes:
Locations:
city: Guadalajara
country: Mexico
facility: Institute of Experimental and Clinical Therapeutics,
state: Jalisco
Study officials:
affiliation: University of Guadalajara
name: Adolfo D Rodríguez-Carrizalez, MD / PhD
role: PRINCIPAL_INVESTIGATOR
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