DMSO Dual-Route Therapy for Refractory Tinnitus in Long-COVID and Post-COVID-19 Vaccine Injury

Official title

Single-Arm Pilot Study of Compounded DMSO-Based Dual-Route Therapy for Refractory Subjective Tinnitus in PASC and Post-COVID-19 Vaccine Injury

Overview

The goal of this clinical trial is to test a compounded dimethyl sulfoxide (DMSO)-based dual-route therapy for adults with refractory subjective tinnitus linked to long-COVID (post-acute sequelae of SARS-CoV-2) or post-COVID-19 vaccine injury. Participants have bothersome tinnitus that has not improved with at least two prior standard treatments. All participants will receive two study treatments for 30 days: a DMSO-based ear canal liquid and a DMSO-based transdermal cream applied to the skin around the ears and upper neck. The ear drops are used every 4 days, and the cream is applied once daily at bedtime. Both formulations are prepared by a licensed compounding pharmacy. The main question is whether at least half of the participants achieve a 50% or greater reduction in their Tinnitus Handicap Inventory (THI) score from baseline to Day 30. Researchers will also look at changes in tinnitus loudness and annoyance, sleep and concentration, other symptoms such as vertigo, insomnia, headache, and fatigue, and any side effects. After an initial in-person ear, nose, and throat (ENT) evaluation, all study visits are conducted by telemedicine. Participants complete electronic questionnaires through a secure, HIPAA-compliant system over 12 months of follow-up.

Detailed description

Subjective non-pulsatile tinnitus is a common and often debilitating symptom in patients with post-acute sequelae of SARS-CoV-2 (PASC, long-COVID) and post-COVID-19 vaccine injury. Mechanisms are thought to include neuroinflammation, microvascular dysfunction, oxidative stress, and mitochondrial impairment within cochlear and central auditory pathways. A substantial proportion of patients remain highly symptomatic despite standard therapies such as sound therapy, cognitive behavioral approaches, antidepressants, and corticosteroids. No FDA-approved curative pharmacologic therapy exists for chronic subjective tinnitus.

Dimethyl sulfoxide (DMSO) is a tree-derived solvent with anti-inflammatory, antioxidant, vasodilatory, and penetration-enhancing properties. A foundational open-label study in the 1970s reported that DMSO-based formulations combined with vasoactive and anti-inflammatory agents improved or resolved subjective tinnitus in most treated patients, but this approach has not been systematically evaluated in modern refractory PASC or vaccine-injury cohorts. This pilot trial modernizes that historical concept using current compounding standards and telemedicine-enabled follow-up.

This is a prospective, single-arm, open-label pilot study of approximately 20 adults with refractory subjective tinnitus attributed to PASC or post-COVID-19 vaccine injury. All participants receive a dual-route regimen for 30 days: (1) a DMSO-based otic liquid instilled into the external auditory canal every 4 days, and (2) a DMSO-based transdermal cream applied once daily to the bilateral mastoid regions, periauricular skin, and upper posterior neck. Both formulations are compounded by a licensed pharmacy according to protocol specifications. Standard tinnitus counseling and sound therapy are allowed, but no new tinnitus-specific medications may be started during the 30-day treatment window.

The primary objective is to estimate the proportion of participants achieving at least a 50% reduction in Tinnitus Handicap Inventory (THI) score from baseline to Day 30. Secondary objectives include changes in THI score at later time points, visual analog scale (VAS) ratings of tinnitus loudness, annoyance, sleep interference, and concentration, patient global impression of change, and VAS measures of concomitant symptoms such as vertigo, insomnia, headache, and fatigue. Safety and tolerability are assessed by monitoring adverse events, including expected DMSO-related effects such as transient odor or skin irritation. Exploratory measures may include changes in tympanic membrane temperature and audiometric parameters where available.

Screening and informed consent are performed via telemedicine, followed by a required baseline in-person ENT evaluation with otoscopy, audiometry, and completion of the THI and other questionnaires. During the 30-day treatment period, participants have regular telemedicine check-ins and complete electronic questionnaires through a secure, HIPAA-compliant REDCap-based platform. Follow-up assessments occur at approximately 6 and 12 months to evaluate durability of tinnitus response and longer-term safety. As a pilot study, analyses are descriptive and use paired pre- and post-treatment comparisons to generate effect-size estimates and feasibility data for future controlled trials.

Interventions

• Drug DMSO-based otic solution with betahistine, dexamethasone, and lidocaine
  Compounded otic liquid containing dimethyl sulfoxide (DMSO) 50% (v/v), betahistine dihydrochloride 8 mg/mL, dexamethasone sodium phosphate 0.2 mg/mL, and lidocaine hydrochloride 1%. Instill 2 mL into the external auditory canal of the affected ear(s) every 4 days (total of 8 applications over 30 days). Formulation is prepared by a licensed compounding pharmacy according to protocol specifications.
• Drug DMSO-based transdermal cream with levocarnitine and N-acetylcysteine
  Compounded transdermal cream containing dimethyl sulfoxide (DMSO) 60% (w/w), levocarnitine 10% (w/w), and N-acetylcysteine 10% (w/w). Apply approximately 1.5 mL (pea- to quarter-sized amount) once daily at bedtime to the bilateral mastoid regions, periauricular skin, and upper posterior neck, with occlusion for 60 minutes or overnight, then wash off in the morning. Formulation is prepared by a licensed compounding pharmacy according to protocol specifications.

Primary outcome measures

• Proportion of participants with at least 50% reduction in Tinnitus Handicap Inventory (THI) score [Time frame: Baseline to Day 30]

Secondary outcome measures (9)

• Change in Tinnitus Handicap Inventory (THI) score over time [Time frame: Baseline to Day 30, Month 6, and Month 12]
• Change in tinnitus loudness on visual analog scale (VAS) [Time frame: Baseline to Day 30, Month 6, and Month 12]
• Change in tinnitus annoyance/distress on visual analog scale (VAS) [Time frame: Baseline to Day 30, Month 6, and Month 12]
• Change in sleep interference due to tinnitus on visual analog scale (VAS) [Time frame: Baseline to Day 30, Month 6, and Month 12]
• Change in concentration difficulty due to tinnitus on visual analog scale (VAS) [Time frame: Baseline to Day 30, Month 6, and Month 12]
• Patient Global Impression of Change (PGIC) in tinnitus symptoms [Time frame: Day 30, Month 6, and Month 12]
• Change in concomitant symptom scores (vertigo, insomnia, headache, fatigue) on visual analog scales (VAS) [Time frame: Baseline to Day 30]
• Incidence of treatment-emergent adverse events [Time frame: From first dose through Day 30]
• Change in tympanic membrane temperature [Time frame: Baseline to Day 30 (where measured)]

Eligibility criteria

Inclusion criteria

• Inclusion Criteria:

Adults 18 to 70 years of age.

Chronic subjective non-pulsatile tinnitus for at least 6 months.

Bothersome tinnitus defined by a Tinnitus Handicap Inventory (THI) score ≥ 20 at screening.

Documented history of post-acute sequelae of SARS-CoV-2 (PASC, long COVID) or post-COVID-19 vaccine injury, with tinnitus onset or clear worsening temporally associated with that event.

Failure of at least two prior tinnitus therapies (for example, sound therapy, counseling or cognitive-behavioral approaches, pharmacologic treatments, or steroid therapy).

Willing and able to provide informed consent.

Able to complete telemedicine visits and electronic questionnaires in English and to attend a baseline in-person otolaryngology (ENT) evaluation.

Exclusion criteria

Objective or pulsatile tinnitus, or tinnitus primarily synchronous with the heartbeat.

Active middle-ear infection, acute otitis media, tympanic membrane perforation, or current otorrhea.

Recent exposure (within the past 3 months) to known ototoxic medications associated with new or rapidly worsening tinnitus.

Known hypersensitivity or allergy to dimethyl sulfoxide (DMSO) or any component of the study formulations (betahistine, dexamethasone, lidocaine, levocarnitine, N-acetylcysteine, or excipients).

Pregnancy or breastfeeding.

Uncontrolled or severe psychiatric illness (for example, active psychosis, acute suicidality) that, in the opinion of the investigator, would interfere with participation or completion of questionnaires.

Inability to comply with study procedures, including telemedicine visits, electronic data capture, or topical/otic dosing instructions.

Any other otologic or neurologic condition judged by the investigator to confound tinnitus assessment or pose unacceptable risk with DMSO-based therapy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Nationwide Telemedicine Study (Leading Edge Clinic) — Ithaca

Publications

• Newman CW, Jacobson GP, Spitzer JB. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg. 1996 Feb;122(2):143-8. doi: 10.1001/archotol.1996.01890140029007. PMID 8630207
• Caro AZ. Dimethyl sulfoxide therapy in subjective tinnitus of unknown origin. Ann N Y Acad Sci. 1975 Jan 27;243:468-74. doi: 10.1111/j.1749-6632.1975.tb25389.x. PMID 1055561

Identifiers

NCT: NCT07567274 · IMIRB-202600105

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗