Study Design and participants
This study reports a monocentric, randomized, triple-blind, placebo-controlled, parallel-group trial, following the SPIRIT guideline and CONSORT statement, and was performed between November 1, 2018, and July 4, 2021. Clinical evaluation and visits were performed at the Institutional Clinical Research Center of our Hospital, and examinations at the Institutional Otorhinolaryngology Service and Laboratory. The initial and follow-up visits were scheduled before and after the intervention, on days 0 and 90, respectively. Participants were contacted an additional three times by phone during the treatment, on days 15, 45, and 75, to ensure adherence and monitor adverse events.
The Tinnitus Research Initiative case history questionary, audiometry (Interacoustics, model AC40 with phone model TDH 39, Middelfart, Denmark), immittance testing (Madsen, model Zodiac 901, Copenhagen, Denmark), otolaryngology examination, magnetic resonance exam (when retrocochlear pathology was suspected),12 and laboratory tests were performed during the participants’ eligibility evaluation.
Qualified participants were further evaluated to recheck their baseline characteristics and to measure the first Tinnitus Handicap Inventory score (THI) – primary endpoint (initial visit). The final THI and secondary endpoints were measured in the follow-up visit. The principal investigator managed these visits; no other investigators were involved. Adverse events and adherence were monitored by a pharmacist. Future treatment was guaranteed for the placebo group in case of proof of drug efficacy.
Participants were recruited between November 2018 and March 2020 using social media, and radio as well as a healthcare provider-based clinical invitation. No financial compensation was offered. Adult participants aged 18 to 70 years with non-pulsatile tinnitus for at least six months of both sexes, and a THI score superior or equal to 18 before randomization were eligible.
Exclusion criteria were: middle ear disease; moderate hearing loss or higher; hearing aids use; hearing asymmetry or retrocochlear pathology; vestibular symptoms and Ménière’s disease; incapacities to fill the THI; temporomandibular dysfunction; unstable cardiovascular, metabolic or psychiatric diseases; neurodegenerative, rheumatic and autoimmune diseases; pregnancy and breastfeeding; and betahistine use contra-indication. Participants were advised not to use any other treatment for tinnitus, with a wash-out period of six months.