About this trial
Many people with migraine also experience tinnitus - a persistent ringing, buzzing, or hissing in the ears - and research suggests these conditions share underlying biological mechanisms, including a protein called calcitonin gene-related peptide (CGRP) that is active in both the brain and the inner ear. COMPACT-PM is a randomized trial comparing two classes of migraine preventive medications in adults with bothersome tinnitus and a history of migraine: anti-CGRP therapies (newer injectable or oral agents that block CGRP or its receptor) versus conventional migraine preventives (antidepressants including amitriptyline, nortriptyline, and venlafaxine; antihypertensives including propranolol, verapamil, and candesartan; and the anticonvulsant topiramate). Participants are randomly assigned - like a coin flip - to one of the two treatment groups; neither group receives a placebo, as both receive active migraine treatment. The study's primary outcome is change in the Tinnitus Functional Index (TFI) over 24 weeks, with additional measures including hearing tests, balance assessments, auditory brainstem response testing, and a comprehensive symptom diary. The study is conducted at the Stanford Ear Institute and is funded by a philanthropic gift to the Department of Otolaryngology - Head \& Neck Surgery at Stanford University.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Age 18 years or older
Non-pulsatile, subjective tinnitus present for at least 6 months
Tinnitus Functional Index (TFI) score greater than 25 at screening, indicating at least mild-to-moderate tinnitus burden
Current or past history of migraine, vestibular migraine, or episodic headache disorder, diagnosed by a physician or meeting ICHD-3 criteria
Disqualifiers
Pulsatile tinnitus or objective tinnitus (tinnitus audible to examiner)
Pregnancy, planned pregnancy during the study period, or breastfeeding
Participation in any other interventional tinnitus treatment research protocol during the study period
Currently receiving a CGRP-targeting medication (for participants being considered for the conventional arm) or a conventional migraine preventive medication listed in this protocol (for participants being considered for the CGRP arm) - to avoid within-arm ineligibility at randomization
Trial design
Parallel
Treatments tested in this trial
Galcanezumab
Drug240 mg loading dose, then 120 mg monthly; intramuscular injection. Manufacturer: Eli Lilly.
Erenumab 70 mg
Drug70-140 mg monthly; subcutaneous injection. Manufacturer: Amgen/Novartis.
Eptinezumab
Drug100-300 mg every 3 months; intravenous infusion. Manufacturer: Lundbeck.
Atogepant
Drug10, 30, or 60 mg daily; oral. Manufacturer: AbbVie.
Amitriptyline
Drug10-100 mg daily; oral. Generic.
Nortriptyline
Drug10-100 mg daily; oral. Generic.
propranolol
Drug10-120 mg daily; oral. Generic.
Verapamil SR 120 mg
Drug120-480 mg SR daily; oral. Generic.
Candesartan
Drug2-32 mg daily; oral. Generic.
topiramate
Drug12.5-200 mg daily; oral. Generic.
Treatment groups
Trial outcomes
Primary outcomes
Change in Tinnitus Functional Index (TFI) Score
The TFI is a validated 25-item self-report questionnaire measuring the negative impact of tinnitus on daily life. Scores range from 0-100; higher scores indicate greater tinnitus burden. The minimally important clinical difference is 13 points. The primary endpoint is the between-arm difference in TFI change from baseline to 24 weeks. The Tinnitus Functional Index (TFI) is a validated 25-item self-report questionnaire measuring the negative impact of tinnitus on daily life. Scores range from 0-100; higher scores indicate greater tinnitus burden. The minimally important clinical difference is 13 points. The primary endpoint is the between-arm difference in TFI change from baseline to 24 weeks, with a greater reduction indicating better outcome.
Secondary outcomes
Change in Tinnitus Functional Index (TFI) Score at 12 Weeks
Between-arm difference in TFI change from baseline to 12 weeks, to characterize early treatment response. The Tinnitus Functional Index (TFI) is a validated 25-item self-report questionnaire measuring the negative impact of tinnitus on daily life. Scores range from 0-100; higher scores indicate greater tinnitus burden. The minimally important clinical difference is 13 points. The primary endpoint is the between-arm difference in TFI change from baseline to 24 weeks, with a greater reduction indicating better outcome.
TFI Score Trajectory
Within- and between-arm TFI change at weeks 4, 8, 16, and 20 to characterize the time course of tinnitus response. The Tinnitus Functional Index (TFI) is a validated 25-item self-report questionnaire measuring the negative impact of tinnitus on daily life. Scores range from 0-100; higher scores indicate greater tinnitus burden. The minimally important clinical difference is 13 points. The primary endpoint is the between-arm difference in TFI change from baseline to 24 weeks, with a greater reduction indicating better outcome.
Change in Tinnitus Handicap Inventory (THI) Score
The THI is a validated 25-item questionnaire measuring tinnitus-related handicap across functional, emotional, and catastrophic subscales. Scores range from 0-100. The Tinnitus Handicap Inventory (THI) is a validated 25-item questionnaire measuring tinnitus-related handicap across functional, emotional, and catastrophic subscales. Scores range from 0-100; higher scores indicate greater handicap and worse outcome.
Change in Visual Analog Scale (VAS) Tinnitus Loudness
Participant-rated tinnitus loudness on a 0-10 VAS, where 0 = no loudness and 10 = worst imaginable loudness.
Other outcomes
Change in Hyperacusis Questionnaire (HQ) Score
The Hyperacusis Questionnaire (HQ) is a 14-item questionnaire measuring hyperacusis severity and impact. Scores range from 0-42; higher scores indicate greater hyperacusis severity and worse outcome. Included as an exploratory outcome given the frequent co-occurrence of hyperacusis and tinnitus in this population.
Pupillometry Changes
Change in sound-evoked pupil dilation amplitude and latency from baseline, as a measure of olivocochlear and autonomic auditory pathway function. Change in resting pupil diameter from baseline as a measure of baseline autonomic tone. Exploratory mechanistic outcome.
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