Tinnitus represents one of the most common and distressing otologic problems, and it causes various somatic and psychological disorders that interfere with the quality of life. In addition, it contributes significant costs to the healthcare system. However, the mechanisms of tinnitus are poorly understood. and there is currently no FDA-approved medication to treat this condition. Current pharmacological treatment options address the stress, anxiety, and depression that are caused by tinnitus. There is an increased evidence of an epidemiological and mechanistic association between tinnitus and migraine. Therefore, in this study, we intended to evaluate the effectiveness of two combinations of migraine medications on patients with moderate to severe tinnitus by comparing them to placebo.
This is an 8-week double-blind, randomized (1:1:1), placebo controlled clinical trial, including adult participants with moderate to severe tinnitus (Tinnitus Functional Index (TFI) \>25). After consenting, the participants will be randomized into one of the three arms: the first is nortriptyline (7.5 mg) plus topiramate (10 mg), the second is verapamil (30 mg) plus paroxetine (4 mg), and the third is a placebo group (Microcrystalline Cellulose; PH105). The capsules are in same color and shape and will be supplied by the UCI medical center on-site pharmacy, each containing the initial dosage of medications. All 3 treatments groups might include dose escalation from initial dosage during the study. Nortriptyline may be increased by 7.5mg weekly (to a maximum of 60mg), topiramate by 10mg weekly (maximum 80mg), verapamil by 30mg weekly (maximum 240mg), and paroxetine by 4mg weekly (maximum 32mg). Participants will be contacted by a blinded physician via telephone once per week and in-person visits will be scheduled for week 0, 4, and 8. If during these weekly contacts, the participant reports less than 20% improvement in tinnitus compared to the baseline Visual Analog Scale (VAS) obtained at the beginning of the trial, the physician will instruct the participant to increase the dosage for that week. Conversely, if a participant reports more than or equal to 20% improvement as compared to the baseline VAS, the team member will advise the participant to maintain the same dosage of medication for 1 week until the next weekly check-in. Furthermore, at the clinical assessment visits, participants will complete a tablet-based assessment of tinnitus symptoms. The questionnaire results will be securely transferred to a REDCap database. A data safety monitor will address any reported side effects throughout the study. The within-arm analyses will be based on per-protocol estimand and tested with paired 2-tailed t tests. The between-arm analyses will be based on a per-protocol estimand and tested with analysis of variance (ANOVA) analysis. In addition, an intention-to-treat analysis will be also conducted with identical methods and analyses.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
78
University of California, Irvine Medical Center ENT Clinic (Pavilion 2)
Orange, California, United States
Tinnitus Functional Index (TFI)
The TFI is a 25 item questionnaire rated on a 0 to 10 scale evaluating the negative impact of tinnitus across 8 domains: Intrusive, Sense of control, Cognitive, Sleep, Auditory, Relaxation, Quality of life, and Emotional. A 0 score indicates low to no impact where a 10 would indicate distress or great impact. The overall TFI score is calculated by dividing the sum of the responses (max possible 250) by the number of responses to get the mean, then multiplying the mean by 10 to obtain the overall TFI score. Overall TFI score can range from 0 to 100. Scores \> 31 indicate tinnitus is a moderate to significant problem. A reduction of 13 points in TFI is considered the Minimal Clinically Important Difference (MCID).
Time frame: Baseline and 8 weeks (end of trial)
Patient Health Questionnaire (PHQ)
Change in depression symptoms based on the Patient Health Questionnaire-9 (PHQ-9), scored from 0 to 27. Higher scores indicate greater symptom severity. A negative change reflects improvement. Mean changes from baseline to Week 8 were analyzed using paired t-tests (per-protocol). A ≥5-point improvement was considered the minimal clinically important difference (MCID).
Time frame: Baseline and 8 weeks
Perceived Stress Scale (PSS)
Change in perceived stress symptoms based on the Perceived Stress Scale (PSS), scored from 0 to 40. The PSS is a 10 question Likert-type scale with answers ranging from (0) "Never" to (4) "Very often". Four questions with positive statements are scored in reverse (0 = 4, 1 = 3, 2 = 2, 3 = 1, 4 = 0). Higher scores indicate greater stress. A negative change reflects improvement. Mean changes from baseline to Week 8 were analyzed using paired t-tests (per-protocol). A ≥11-point improvement was considered the minimal clinically important difference (MCID).
Time frame: Baseline and 8 weeks
Pittsburgh Sleep Quality Index (SQI)
Change in sleep quality based on the Pittsburgh Sleep Quality Index (PSQI), scored from 0 to 21. Higher scores indicate poorer sleep quality. A negative change reflects improvement. Mean changes from baseline to Week 8 were analyzed using paired 2-tailed t-tests (per-protocol). Standard error was calculated using end-of-trial SD and sample size. A ≥3-point improvement was considered the minimal clinically important difference (MCID).
Time frame: Baseline and 8 weeks
Generalized Anxiety Disorder (GAD-7)
Change in anxiety symptoms based on the Generalized Anxiety Disorder-7 (GAD-7) scale, scored from 0 to 21. Higher scores indicate greater anxiety. A negative change reflects improvement. Mean changes from baseline to Week 8 were analyzed using paired 2-tailed t-tests (per-protocol). Standard error was calculated using end-of-trial SD and sample size. A ≥4-point improvement was considered the minimal clinically important difference (MCID).
Time frame: Baseline and 8 weeks
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