Migraine, Migraine Associated Vertigo, Tinnitus, Vestibular Migraine
Conditions
Keywords
tinnitus, migraine, vestibular migraine, migraine-associated tinnitus, CGRP
Brief summary
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.
Detailed description
Tinnitus affects approximately 15% of the global population, and migraine history is an established risk factor for both its prevalence and severity. Converging preclinical and clinical evidence implicates calcitonin gene-related peptide (CGRP) signaling at the intersection of these two conditions: CGRP and its receptors are expressed in cochlear inner and outer hair cells, the spiral ganglion, and the vestibular end organs; in a chronic migraine mouse model, cochlear CGRP expression is upregulated and CGRP administration attenuates cochlear deficits; and in humans, conventional migraine preventive medications have been shown to reduce tinnitus burden as measured by the TFI. Whether CGRP-targeting agents confer additional or differential benefit for tinnitus - given their direct cochlear and vestibular targets - has not been evaluated in a randomized controlled trial. COMPACT-PM addresses this gap using a randomized, open-label, active-comparator controlled design. A placebo arm is not included because withholding migraine preventive treatment from patients with a clinical indication for preventive therapy would be ethically inappropriate; both arms therefore receive active, clinically indicated migraine treatment, and randomization controls for treatment selection bias. Within each arm, the specific agent is selected by the treating clinician based on clinical appropriateness, patient factors, and insurance coverage; participants must have confirmed insurance access to at least one CGRP-targeting agent prior to randomization.
Interventions
DRUGGalcanezumab
240 mg loading dose, then 120 mg monthly; intramuscular injection. Manufacturer: Eli Lilly.
DRUGErenumab 70 mg
70-140 mg monthly; subcutaneous injection. Manufacturer: Amgen/Novartis.
DRUGEptinezumab
100-300 mg every 3 months; intravenous infusion. Manufacturer: Lundbeck.
DRUGAtogepant
10, 30, or 60 mg daily; oral. Manufacturer: AbbVie.
DRUGAmitriptyline
10-100 mg daily; oral. Generic.
DRUGNortriptyline
10-100 mg daily; oral. Generic.
DRUGpropranolol
10-120 mg daily; oral. Generic.
120-480 mg SR daily; oral. Generic.
DRUGCandesartan
2-32 mg daily; oral. Generic.
DRUGtopiramate
12.5-200 mg daily; oral. Generic.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants are randomized 1:1 to one of two parallel arms: a CGRP-targeting agent arm or a conventional migraine preventive arm. Within each arm, the specific medication is selected by the treating clinician based on clinical appropriateness and patient factors. The conventional arm is organized by pharmacological class: antidepressants (amitriptyline, nortriptyline, venlafaxine), antihypertensives (propranolol, verapamil, candesartan), and anticonvulsants (topiramate).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 * Clinically appropriate candidate for migraine preventive therapy as determined by the treating clinician * Stable medication regimen for at least 3 months prior to enrollment (no new medications started or stopped within 3 months of screening) * Ability to provide written informed consent * Ability to complete self-report questionnaires in English or with certified interpreter assistance * Willingness to attend three in-person study visits over 24 weeks and complete daily symptom diaries
Exclusion criteria
* 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 * Known contraindication to all medications within the assigned study arm * History of serious cardiovascular event (myocardial infarction, stroke, or unstable angina) within 6 months of enrollment * Severe hepatic or renal impairment that would contraindicate study medications * Active psychiatric disorder requiring medication adjustment within 3 months of enrollment * Known hypersensitivity or prior serious adverse reaction to a medication within the assigned study arm * Active malignancy or life expectancy less than 12 months * Inability to complete study procedures or follow-up visits in the judgment of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Tinnitus Functional Index (TFI) Score | Baseline to 24 weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Tinnitus Functional Index (TFI) Score at 12 Weeks | Baseline to 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 | Weeks 4, 8, 16, 20 | 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 | Baseline, 12 weeks, 24 weeks | 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 | Baseline, 12 weeks, 24 weeks | Participant-rated tinnitus loudness on a 0-10 VAS, where 0 = no loudness and 10 = worst imaginable loudness. |
| Change in Visual Analog Scale (VAS) Tinnitus Unpleasantness | Baseline, 12 weeks, 24 weeks | Participant-rated tinnitus unpleasantness on a 0-10 VAS, where 0 = not unpleasant and 10 = worst imaginable unpleasantness. |
| Patient Global Impression of Change (PGIC) | 12 weeks, 24 weeks | Single-item participant-rated global impression of change in tinnitus since starting study treatment, rated on a 7-point scale from 1 (very much worse) to 7 (very much improved). |
| Change in Headache Impact Test-6 (HIT-6) Score | Baseline, 12 weeks, 24 weeks | The HIT-6 is a validated 6-item questionnaire measuring the impact of headaches on daily functioning. Scores range from 36-78; higher scores indicate greater headache impact. |
| Change in Migraine Disability Assessment (MIDAS) Score | Baseline, 12 weeks, 24 weeks | The Migraine Disability Assessment (MIDAS) quantifies headache-related disability over the prior 3 months based on lost productive time, scored in days. Scores range from 0 to unlimited; higher scores indicate greater disability and worse outcome. |
| Change in Vestibular Migraine Patient Assessment Tool and Handicap Inventory (VM-PATHI) Score | Baseline, 12 weeks, 24 weeks | The Vestibular Migraine Patient Assessment Tool and Handicap Inventory (VM-PATHI) is a validated 25-item patient-reported outcome measure specific to vestibular migraine, assessing symptom frequency, severity, and impact. Scores range from 0-100; higher scores indicate greater disease burden and worse outcome. Administered to all participants; subgroup analysis planned for those with confirmed vestibular migraine diagnosis. |
| Change in Dizziness Handicap Inventory (DHI) Score | Baseline, 12 weeks, 24 weeks | The Dizziness Handicap Inventory (DHI) is a validated 25-item questionnaire measuring the self-perceived handicap imposed by dizziness and unsteadiness. Scores range from 0-100; higher scores indicate greater handicap and worse outcome. |
| Monthly Headache Days | Baseline through 24 weeks | Number of headache days per month recorded in participant daily diary, averaged over each 4-week interval between study visits. |
| Monthly Dizzy Days | Baseline through 24 weeks | Number of days with dizziness or vertigo per month recorded in participant daily diary, averaged over each 4-week interval between study visits. |
| Monthly Nausea Days | Baseline through 24 weeks | Number of days with nausea per month recorded in participant daily diary, averaged over each 4-week interval between study visits. |
| Acute Medication Use | Baseline through 24 weeks | Number of days per month with acute migraine or vestibular rescue medication use, recorded in participant daily diary. |
| Change in Pure Tone Audiometric Thresholds | Baseline, 12 weeks, 24 weeks | Change in air conduction pure tone thresholds at 250-8000 Hz from baseline, assessed by standard audiogram. |
| Change in Speech-in-Noise Performance (QuickSIN) | Baseline, 12 weeks, 24 weeks | Change in signal-to-noise ratio loss from baseline as measured by the Quick Speech-in-Noise (QuickSIN) test, reflecting auditory processing in noise. |
| Change in Auditory Brainstem Response (ABR) | Baseline, 12 weeks, 24 weeks | Change in ABR wave latencies and amplitudes from baseline, reflecting peripheral and central auditory pathway integrity. |
| Change in Tinnitus Pitch and Loudness Characteristics | Baseline, 12 weeks, 24 weeks | Change in psychoacoustic tinnitus pitch match (Hz) and loudness match (dB SL) from baseline. |
| Change in Video Head Impulse Test (vHIT) | Baseline, 12 weeks, 24 weeks | Change in semicircular canal vestibulo-ocular reflex (VOR) gain and saccades from baseline, assessed by vHIT across all six semicircular canals. |
| Rotary Chair - VOR Gain | Baseline, 12 weeks, 24 weeks | Change in vestibulo-ocular reflex (VOR) gain from baseline, assessed by sinusoidal harmonic acceleration rotary chair testing across multiple frequencies. Gain is a unitless ratio (eye velocity / chair velocity); values closer to 1.0 indicate better vestibular function. |
| Change in Cervical and Ocular Vestibular Evoked Myogenic Potentials (cVEMP/oVEMP) | Baseline, 12 weeks, 24 weeks | Change in cVEMP and oVEMP amplitude, threshold, and latency from baseline, reflecting saccular, utricular, and inferior/superior vestibular nerve function. |
| VNG - Ocular Motor Testing | Baseline, 12 weeks, 24 weeks | Change in ocular motor parameters from baseline assessed by videonystagmography (VNG), including gaze stability, saccade accuracy and latency, smooth pursuit gain, and optokinetic response gain. Each parameter is reported in its respective unit (degrees/second, milliseconds, or unitless ratio); values will be analyzed individually. |
| Adverse Event Rate | Baseline through 24 weeks plus 30-day safety follow-up | Frequency and severity of adverse events and serious adverse events in each arm, assessed throughout the study period and graded by CTCAE criteria. |
| TFI Responder Rate | 24 weeks | Proportion of participants in each arm achieving a clinically meaningful reduction of 13 or more points from baseline on the Tinnitus Functional Index (TFI) at 24 weeks, representing the minimum important clinical difference established by Meikle et al. (2012). |
| Rotary Chair - VOR Phase | Time Frame: Baseline, 12 weeks, 24 weeks | Change in vestibulo-ocular reflex (VOR) phase lead from baseline, assessed by sinusoidal harmonic acceleration rotary chair testing. Phase is reported in degrees; lower phase lead at low frequencies indicates better vestibular compensation. |
| Rotary Chair - VOR Symmetry | Time Frame: Baseline, 12 weeks, 24 weeks | Change in vestibulo-ocular reflex (VOR) directional preponderance/symmetry from baseline, assessed by sinusoidal harmonic acceleration rotary chair testing. Symmetry is reported as a percentage asymmetry; values closer to 0% indicate better symmetry. |
| VNG - Positional and Positioning Nystagmus | Time Frame: Baseline, 12 weeks, 24 weeks | Change in nystagmus slow-phase velocity (SPV) from baseline during positional and positioning maneuvers assessed by videonystagmography (VNG). SPV is reported in degrees/second; lower values indicate less nystagmus. |
| VNG - Caloric Testing | Time Frame: Baseline, 12 weeks, 24 weeks | Change in unilateral weakness and directional preponderance from baseline assessed by caloric irrigation during videonystagmography (VNG). Unilateral weakness and directional preponderance are reported as percentages; values closer to 0% indicate better symmetry. |
Contacts
CONTACTJwala P Rejimon, AuD
CONTACTResearch Coordinator
PRINCIPAL_INVESTIGATORKristen K. Steenerson
Stanford University
PRINCIPAL_INVESTIGATORMatthew Fitzgerald
Stanford University
Outcome results
None listed