A Study on the Effectiveness of Antioxidant Supplementation in Tinnitus

A Phase-II Clinical Trial on the Effectiveness of Antioxidant Supplementation in Idiopathic Tinnitus Patients

The purpose of this study is to assess the effectiveness of antioxidant supplementation in idiopathic tinnitus patients.

To investigate this, a double-blind, randomized, and placebo-controlled clinical trial was conducted to assess the impact of a multivitamin-multimineral supplement with phytochemicals combined with a-lipoic acid supplements on serum oxidative stress, serum antioxidant capacity and tinnitus parameters in patients with idiopathic tinnitus.

Subjective, idiopathic, non-pulsatile tinnitus ("tinnitus") is perception of sound without the presence of an external acoustic stimulus. Causes of idiopathic tinnitus remain unknown and the pathological mechanisms are not fully understood. Currently, effective therapies for tinnitus remain limited. Previous research has demonstrated that oxidative stress is possibly involved in the pathogenesis of idiopathic tinnitus and some studies have shown beneficial effects of antioxidant therapy in tinnitus patients. Moreover, many studies have shown the beneficial effect of antioxidant supplementation on the reduction of oxidative stress and the increase of endogenous antioxidant enzymes and antioxidant capacity.

Seventy patients with idiopathic tinnitus were enrolled based on certain inclusion and exclusion criteria. Subsequently, they were informed regarding the aims, methods, anticipated benefits, and potential hazards of the study, and were provided with the information leaflet of the study. Each patient who agreed to take part in the study, signed an informed consent form, a copy of which was given to them.

Participants were allocated to either antioxidant or placebo group. Randomisation was conducted by someone who was not involved in the study and blinding was strictly maintained to researchers and participants.

The antioxidant group received one multivitamin and multimineral tablet with grape seed extract once a day together with one tablet of alpha-lipoic acid twice a day, whereas the placebo group received identical placebo tablets. Supplements were kindly donated by Lamberts. The intervention lasted 3 months. Both groups kept their usual medical treatment and their diet and exercise habits stable during the intervention.

Patients were assessed after randomisation according to the following tools:

• Medical history
• Audiometric and Tinnitus assessment: Basic audiometric tests, pitch match, loudness match, minimum masking level (MML)
• Tinnitus questionnaires: Tinnitus Handicap Inventory (THI), Tinnitus Functional Index (TFI) and Visual Analogue Scale (VAS)
• anthropometrics: body weight , height, Body Mass Index, waist and hip circumferences
• Nutrition and physical activity evaluation
• Adherence to the Mediterranean dietary pattern (MedDietScore)
• Psychological assessment
• Biochemical measurements: Complete blood count, lipid profile, glucose, electrolytes, liver enzymes, thyroid hormones
• Vitamin laboratory tests
• Oxidative stress assessment in serum samples: Total Antioxidant Capacity (TAC), Superoxide Dismutase (SOD) activity and Oxidized LDL are quantified.

Compliance and any side effects were checked with a weekly telephone contact with the patients. The consumption of tablets was checked with a diary completed by patients. At the end of the intervention, all baseline parameters were assessed.

Study Overview

• Status: Completed
• Conditions: Tinnitus
• Intervention / Treatment: Dietary supplement: Antioxidants; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece
    • General Hospital of Athens "Hippocratio", Department of Otorhinolaryngology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 25-75 years old
• Unilateral or bilateral chronic idiopathic persistent tinnitus of at least 6 months' duration
• Tinnitus Handicap Inventory score rated ≥ 4 at baseline
• With a normal audiogram or up to medium-grade neurosensory hearing loss.
• Tinnitus maskable (by noise masking) with noise at least 5 decibel
• Childbearing age with a negative pregnancy test at eligibility and baseline assessment
• Stable medication during the whole period of the 3-month intervention
• Willing and able to attend the on-study visits
• Able to read and understand the relevant study documents and rating scales and follow investigator instructions during audiologic measurements

Exclusion Criteria:

• Tinnitus following acute acoustic trauma, sudden deafness or traumatic head or neck injury
• Intermittent tinnitus
• Meniere's Disease, otosclerosis, acute or chronic otitis media
• Head and neck radiotherapy
• Active GI disease; active malignant diseases; autoimmune diseases; cardiovascular disease; renal or hepatic disorders; haemorrhagic diathesis
• Intake of anticoagulants; ototoxic medications; tinnitus-inducing medication (e.g. aminoglycosides, chemotherapeutics, loop diuretics, high doses of aspirin or quinine)
• Psychiatric disorders
• Unregulated diabetes mellitus, hypertension or thyroid disease
• Alcohol or drug abuse
• Vitamin or inorganic supplements, vegan or macrobiotic diet before and during the trial
• Pregnancy, lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Antioxidants; This arm of patients received one multivitamin and multimineral tablet with 500 mg grape seed extract once a day and one tablet of alpha-lipoic acid (300 mg ALA) twice a day for 3 months.	Dietary supplement: Antioxidants; one multivitamin and multimineral tablet with 500 mg grape seed extract once a day and one tablet of alpha-lipoic acid (300 mg ALA) twice a day for 3 months.
Placebo Comparator: Placebo; This arm of patients received placebo for 3 months.	Dietary supplement: Placebo; one placebo tablet three times per day for 3 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tinnitus loudness (in decibel) assessed by loudness matching test	Mean Change from Baseline in Tinnitus loudness at three months assessed by Loudness matching audiometric test	Change in tinnitus loudness was assessed at 3 months from baseline in tinnitus patients
Tinnitus Handicap Inventory Questionnaire score (ranging from 0 to 100) which assesses the impact of tinnitus on daily life	Mean Change from Baseline in Tinnitus Handicap Inventory Questionnaire at three months	Change in Tinnitus Handicap Inventory score was assessed at 3 months from baseline in tinnitus patients

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tinnitus frequency (in Hz) assessed by pitch match test	Mean Change from Baseline in Tinnitus frequency at three months	Change in Tinnitus frequency was assessed at 3 months from baseline in tinnitus patients
Tinnitus Functional Index questionnaire score (ranging from 0 to 100) which assesses the impact of tinnitus on daily life	Mean Change from Baseline in Tinnitus Functional Index score at three months	Change in Tinnitus Functional Index score was assessed at 3 months from baseline in tinnitus patients
serum Total Antioxidant Capacity (mM)	Mean Change from Baseline in Serum Total Antioxidant Capacity at three months	Change in Serum Total Antioxidant Capacity was assessed at 3 months from baseline in tinnitus patients
Vitamins B12, E, C, B2, B1, B6 and folic acid in blood	Mean Change from Baseline in vitamin levels at three months	Change in vitamin levels were assessed at 3 months from baseline in tinnitus patients
Tinnitus Minimum Masking Level (in decibel)	Mean Change from Baseline in Tinnitus Minimum Masking Level at three months	Change in Tinnitus Minimum Masking Level was assessed at 3 months from baseline in tinnitus patients
Visual Analogue Scale Score (ranging from 0 to 10) which assesses tinnitus annoyance	Mean Change from Baseline in Visual Analogue Scale Score at three months	Change in Visual Analogue Scale Score was assessed at 3 months from baseline in tinnitus patients
serum Superoxide Dismutase (U/ml)	Mean Change from Baseline in serum Superoxide Dismutase at three months	Change in serum Superoxide Dismutase was assessed at 3 months from baseline in tinnitus patients
serum Oxidized LDL (ng/ml)	Mean Change from Baseline in serum Oxidized LDL at three months	Change in serum Oxidized LDL was assessed at 3 months from baseline in tinnitus patients

Collaborators and Investigators

• Sponsor: National and Kapodistrian University of Athens
• Investigators: Study Director: Ioannis Xenelis, Professor, General Hospital of Athens "Hippocratio", Department of Otorhinolaryngology

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2019
• Primary Completion (Actual): May 25, 2019
• Study Completion (Actual): May 25, 2019

Study Registration Dates

• First Submitted: September 23, 2019
• First Submitted That Met QC Criteria: September 24, 2019
• First Posted (Actual): September 26, 2019

Study Record Updates

• Last Update Posted (Actual): November 13, 2019
• Last Update Submitted That Met QC Criteria: November 11, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Otorhinolaryngologic Diseases; Ear Diseases; Sensation Disorders; Hearing Disorders; Tinnitus; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants
• Other Study ID Numbers: 4354

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No