A Study on the Effect of Cilostazol in Patients With Chronic Tinnitus (CITI-ESR)

A Randomized, Prospective, Placebo-controlled Double-blind, Pilot Study on the Effect of Cilostazol for 4 Weeks in Patients With Chronic Tinnitus

1. Overview of tinnitus Tinnitus is a noisy sound which is perceived without any external sound source. According to the survey of the US, 10-20% of adult have the symptom of tinnitus and 3-5% of tinnitus patients have severe discomfort of daily life. Severe tinnitus can result in psychiatric problems such as depression and anxiety disorders. Enhancement of environmental sound, hearing aids, sound generators, cognitive therapy, transcranial magnetic therapy, and drug therapy have been tried for treatment of tinnitus. Nitric oxide(NO) is a well-known neurotransmitter acting as a vasodilator through regulation of production of cyclic guanosine monophosphate(cGMP) and can be found in various sites of cochlea. It is reported that cGMP enhances activity of protein kinase A (PKA), a mediator of platelet aggregation inhibition and vasodilatation and results in increase of vascular flow.
2. Characteristics of the clinical research drug, cilostazol Cilostazol inhibits phosphodiesterase type 3 (PDE3) selectively and increases amount of cAMP by inhibition of degradation of cyclic adenosine monophosphate(cAMP). cAMP again by increasing the active form of PKA suppress the production of blood clots and increase blood flow by expanding blood vessels. Anti-platelet activity and vasodilatation effect of cilostazol have been used for improvement of diabetic peripheral vascular disorders and suppression of stroke recurrence. Previous studies reported that by increasing the activity of NO and PKA, the blood flow of stria vascularis and cochlear hair cells can be improved. These studies implies that cilostazol, which causes inhibition of PDE3 and increase of PKA, can have a potential effect on improvement of tinnitus by increase of blood flow to peripheral cochlear cells. Thus, we hypothesized that cilostazol, which has been widely used for enhancing peripheral blood flow, can bring improvement of tinnitus by causing better peripheral blood flow of cochlea.
3. The aim of the study We planned this study to validate the assumptions of the background. The aim of our study is whether administration of cilostazol can improve tinnitus in terms of subjective degree of symptoms in chronic tinnitus patients.

Study Overview

• Status: Completed
• Conditions: Tinnitus
• Intervention / Treatment: Drug: Cilostazol; Drug: Placebo

Detailed Description

1. Clinical research methods

   • Determination of eligibility by history taking, physical examination, pure tone audiometry, speech audiometry, and distortion product otoacoustic emission test.
   • Randomization by random sequence generation
   • Administration : cilostazol 100mg Bid 4 weeks for the study group and placebo tablet Bid 4 weeks for the control group.
   • Evaluation battery: questionnaires (tinnitus handicap inventory, visual analogue scale, Quality of life SF-36)
   • Time of evaluation : pre-administration, 2 weeks after administration, 4 week after administration
   • Monitoring of side effects
2. Evaluation of treatment response - Statistical analysis of scores of questionnaires using SPSS K12.0 (paired t-test for changes of each group and Mann-Whitney U test for comparing the mean scores of two groups)

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults of age over 19
• Unilateral or bilateral tinnitus
• Chronic tinnitus lasting more than 3 months
• Initial visual analogue scale of tinnitus >3

Exclusion Criteria:

• Conductive hearing loss on pure tone audiometry
• Associated other inner ear diseases such as Meniere's disease
• Objective or pulsatile tinnitus
• Contraindication to anti-platelet drug
• Any cardiac disease
• Bleeding tendency and major operation within 3 months
• Breastfeeding
• Pregnancy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cilostazol group; Administration of Cilostazol 100mg twice a day for 4 weeks	Drug: Cilostazol; Administration of Cilostazol 100mg twice a day for 4 weeks; Other Names: Pletaal
Placebo Comparator: Placebo group; placebo drug twice a day for 4 weeks.	Drug: Placebo; placebo one tablet matching for cilostazol twice a day for 4 weeks.; Other Names: Placebo matching for cilostazol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of the tinnitus handicap inventory (THI) score	A Questionnaire for assessing subjective discomfort from chronic tinnitus	within 2 weeks before administration, 2 weeks after administration, 4 week after administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of Quality of Life (SF-36) score	A questionnaire for assessing subjective discomfort from chronic tinnitus	within 2weeks before administration, 2 weeks after administration, 4 weeks after administration
Change of the visual analogue scale (VAS) score	A Questionnaire for assessing subjective discomfort from chronic tinnitus	within 2 weeks before administration, 2 weeks after administration, 4 week after administration

Collaborators and Investigators

• Sponsor: Jong Woo Chung
• Collaborators: Korea Otsuka Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Jong Woo Chung, M.D., Asan Medical Center

Publications and helpful links

General Publications

• Mazurek B, Haupt H, Szczepek AJ, Sandmann J, Gross J, Klapp BF, Kiesewetter H, Kalus U, Stover T, Caffier PP. Evaluation of vardenafil for the treatment of subjective tinnitus: a controlled pilot study. J Negat Results Biomed. 2009 Feb 17;8:3. doi: 10.1186/1477-5751-8-3.
• Ye YL, Shi WZ, Zhang WP, Wang ML, Zhou Y, Fang SH, Liu LY, Zhang Q, Yu YP, Wei EQ. Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries. Eur J Pharmacol. 2007 Feb 14;557(1):23-31. doi: 10.1016/j.ejphar.2006.11.003. Epub 2006 Nov 10.

Helpful Links

• Clinical Research Information Service (CRIS)
• Institutional Review Board of Asan Medical Center

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: June 21, 2011
• First Submitted That Met QC Criteria: June 21, 2011
• First Posted (Estimate): June 22, 2011

Study Record Updates

• Last Update Posted (Estimate): May 22, 2014
• Last Update Submitted That Met QC Criteria: May 21, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Tinnitus; Cilostazol; Medication therapy management; Antiplatelet agents
• 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; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Neuroprotective Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Cilostazol
• Other Study ID Numbers: AMC-2010-0800; KCT0000128 (Registry Identifier: Clinical Research Information Service (CRIS))