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.