Omega-3-Based Nutraceutical Supplementation as Adjunctive Therapy in Adults With Otitis Media With Effusion: A Multicenter, Double-Blind, Randomized Placebo-Controlled Trial

Detailed Description - OMENUTS Trial BACKGROUND AND RATIONALE Otitis media with effusion (OME) is defined as the presence of fluid in the middle ear cavity without signs or symptoms of acute infection. It is a leading cause of conductive hearing loss and represents one of the most prevalent conditions in paediatric otolaryngology, affecting up to 90% of children by age 10. Although considerably less prevalent in adults, OME in the adult population represents a clinically relevant and frequently under-investigated entity, estimated to affect approximately 3.2% of adults presenting with conductive hearing impairment. In adults, OME is more frequently associated with Eustachian tube dysfunction, chronic rhinosinusitis, and allergic inflammation rather than adenoidal hypertrophy, and its clinical presentation - including ear fullness, conductive hearing loss, tinnitus, and impaired Eustachian tube patency - can significantly affect quality of life and psychosocial functioning. The pathophysiology of OME is multifactorial and incompletely understood. Eustachian tube dysfunction, impaired mucociliary clearance, and persistent low-grade inflammatory activity of the middle ear and nasopharyngeal mucosa are considered the principal underlying mechanisms, further perpetuated by factors such as allergic sensitization, viral upper respiratory infections, and biofilm formation. The chronic inflammatory component of OME pathogenesis - involving NF-κB-mediated cytokine production, mast cell activation, histamine release, and impaired resolution of inflammation - provides a mechanistically coherent rationale for the use of anti-inflammatory nutraceutical compounds as adjunctive therapy. Management strategies for adult OME remain heterogeneous and controversial. Watchful waiting is recommended for uncomplicated cases, while surgical intervention - tympanostomy tube placement, with or without adenoidectomy - is reserved for chronic or symptomatic disease. Medical therapy, including antibiotics, corticosteroids, antihistamines, and mucolytics, has shown inconsistent efficacy in clinical trials. Antihistamines in particular have been shown to be ineffective in treating OME and may prolong effusion duration. No well-tolerated pharmacological option is currently established for adult patients, representing a significant unmet clinical need. Omega-3 polyunsaturated fatty acids (PUFAs) - particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) - exert well-characterised anti-inflammatory effects through multiple pathways, including inhibition of NF-κB-mediated cytokine transcription, reduction of prostaglandin E2 and leukotriene B4 synthesis, and generation of specialised pro-resolving mediators including resolvins and protectins. Omega-3 fatty acids have also been shown to modulate inflammatory pathways through nutrigenomic mechanisms that influence the expression of cytokine-encoding genes, and dietary omega-3 supplementation has been shown to dampen allergic inflammation in the upper respiratory tract through eosinophilic production of 15-hydroxyeicosapentaenoic acid, a metabolite of EPA that inhibits mast cell degranulation via peroxisome proliferator-activated receptor gamma. DHA may additionally play a protective role in auditory neural conduction, with high plasma omega-3 concentrations associated with reduced hearing impairment. The nutraceutical combination evaluated in this trial (Otoair Flogo, Shedirpharma s.r.l., Piano di Sorrento, Naples, Italy) also contains Spirulina algae, magnesium, and vitamin B6. Spirulina has documented anti-inflammatory properties mediated primarily through C-phycocyanin, a selective cyclooxygenase-2 inhibitor that also inhibits histamine release from mast cells and has been shown to reduce IL-4 levels in patients with allergic rhinitis. Magnesium plays a recognized role in modulating immune cell function, attenuating NF-κB signalling, and reducing the production of pro-inflammatory cytokines including TNF-α and IL-6. Vitamin B6 is an essential cofactor in cytokine metabolism and T-lymphocyte function, with deficiency states associated with impaired immune responses. The synergistic anti-inflammatory and immunomodulatory activity of this combination provides a coherent mechanistic framework for its potential efficacy in OME. A multicenter, double-blind, randomized placebo-controlled trial using the same nutraceutical combination previously demonstrated significant improvements in VAS scores, endoscopic findings, and quality of life in patients with allergic rhinitis - a condition sharing key pathophysiological features with OME, including Eustachian tube dysfunction, IgE-mediated immune activation, and chronic mucosal inflammation. To our knowledge, no randomized controlled trial has evaluated nutraceutical supplementation as adjunctive therapy in adults with OME prior to the OMENUTS trial. STUDY DESIGN The OMENUTS trial is a multicenter, double-blind, randomized placebo-controlled trial with three parallel arms conducted across three tertiary referral centres in Italy: Isola Tiberina - Gemelli Isola Hospital, Rome, Italy University of Catanzaro, Catanzaro, Italy Tortorella Clinic, Salerno, Italy The study was conducted from September 2025 to March 2026, in accordance with the CONSORT guidelines for randomized controlled trials and the Declaration of Helsinki. All centres followed a pre-specified, standardized protocol and identical procedures throughout the trial. The trial was approved by the Institutional Review Board of the Region of Calabria, Italy (approval code: 177/2026), which served as the central ethics committee for all participating sites. All participants provided written informed consent prior to enrollment. PARTICIPANTS Inclusion criteria: Eligible participants were adults aged 18 to 70 years with a confirmed diagnosis of unilateral or bilateral OME, established by otoscopic examination and tympanometry (type B curve), with a duration of symptoms of at least 4 weeks prior to enrollment. Exclusion criteria: Pregnancy or breastfeeding Uncontrolled asthma Chronic obstructive or restrictive pulmonary disease Autoimmune or connective tissue disease Acute sinusitis or acute upper respiratory tract infection at the time of enrollment Cardiovascular, hepatic, or renal disease Use of medications known to affect immune response History of nasal or sinus surgery Receipt of immunotherapy within 3 years prior to enrollment or planned immunotherapy during the study period Any other condition that, in the investigator's judgement, would preclude safe participation or compromise the integrity of the trial A total of 501 participants were enrolled and randomized. Seventeen participants per group did not complete the study, resulting in 450 participants included in the modified intention-to-treat analysis (150 per group). RANDOMIZATION AND BLINDING Eligible participants were randomized in a 1:1:1 ratio to one of three groups using a computer-generated allocation sequence produced via REDCap (Research Electronic Data Capture), stratified by site and implemented with permuted blocks of variable size to ensure balanced allocation across centres. Block sizes were not disclosed to investigators prior to unblinding. Allocation concealment was ensured through sequentially numbered containers assigned automatically at the time of recruitment via REDCap. The randomization sequence was generated by an independent statistician not involved in patient recruitment or clinical assessment. The study was conducted as a double-blind trial. Participants were unaware of their treatment allocation throughout the study. Clinical assessments at all follow-up visits were performed by a trained otolaryngology resident physician at each participating centre, blinded to treatment assignment. The senior investigators responsible for overseeing patient management were likewise blinded to individual allocation. All investigational products were identical in appearance, odour, and taste to ensure allocation concealment. Only the independent statistician and the pharmacist responsible for treatment dispensing had access to the allocation sequence prior to unblinding. Unblinding occurred after database lock and completion of the primary statistical analysis. Whilst blinding was maintained throughout the T1 assessment, the integrity of participant blinding at T2 may have been compromised by the subjective experience of treatment effects. INTERVENTIONS All participants received a standardized background therapy consisting of intranasal mometasone furoate spray (one puff per nostril twice daily for 3 weeks) and oral deflazacort (30 mg once daily in the morning for 6 days). On this common background, participants were allocated to one of three groups according to the randomization sequence. Group 1 - Intervention group: Nutraceutical combination (omega-3 fatty acids, Spirulina, magnesium, and vitamin B6; one tablet daily at bedtime; Otoair Flogo, Shedirpharma s.r.l., Piano di Sorrento, Naples, Italy) for 3 weeks, in addition to the background therapy. Group 2 - Active control group: Oral bilastine (20 mg once daily at bedtime) for 3 weeks, in addition to the background therapy. Bilastine was selected as a second-generation H1 antihistamine commonly prescribed in clinical practice for OME, particularly in patients with concomitant allergic conditions, representing current clinical practice in many centres. Group 3 - Placebo group: Identical placebo tablet (maltodextrins and stabilizers) on the same schedule as the active treatment arms, in addition to the background therapy. Placebo tablets were identical to the active treatment in appearance, odour, and packaging to ensure allocation concealment. Treatment adherence was assessed by tablet count and defined as intake of ≥80% of the prescribed doses. OUTCOME MEASURES Co-primary outcomes (assessed at T1, week 3): Tympanometric resolution: defined as normalization of the tympanometric curve from type B to type A, assessed by standard tympanometry. Audiometric improvement: defined as a reduction in pure-tone average (PTA) of more than 15 dB hearing level (HL) at the affected frequencies, assessed by pure-tone audiometry. Both co-primary outcomes were assessed as independent endpoints. Secondary outcomes: Visual Analogue Scale (VAS): a 10-point unidimensional scale used to quantify subjective symptom severity, with scores ranging from 0 (no symptoms) to 10 (worst possible symptoms). The minimum clinically important difference (MCID) is defined as an improvement of ≥1.5 points from baseline. Eustachian Tube Dysfunction Questionnaire (ETDQ-7): a validated 7-item questionnaire quantifying symptoms related to Eustachian tube obstruction, with higher scores indicating greater symptom burden. The pre-specified MCID threshold is ≥3.5 points. Hearing Handicap Inventory for Adults (HHIA): a validated 25-item self-report questionnaire assessing the psychosocial impact of hearing impairment across emotional and social/situational subscales, yielding a total score ranging from 0 to 100, where higher scores indicate greater perceived handicap. The pre-specified MCID threshold is ≥4 points. Eustachian tube patency: assessed by the Valsalva maneuver, categorized as positive (patent) or negative (obstructed). Recurrence rate at T2 (60-day post-treatment follow-up visit): defined as re-emergence of a type B tympanogram in patients who had achieved type A tympanometric resolution at T1. Treatment adherence: assessed by tablet count and defined as intake of ≥80% of the prescribed doses. Use of concomitant medications (antibiotics or systemic corticosteroids) during the study period. Need for surgical intervention (tympanostomy tube placement) by the end of the follow-up period. Safety outcomes: Incidence and nature of adverse events throughout the study duration, classified according to the Medical Dictionary for Regulatory Activities (MedDRA) by affected organ system, and reported as the proportion of participants experiencing at least one adverse event. Safety outcomes were monitored continuously throughout the study. Assessment timepoints: T0: baseline (enrollment) T1: end of treatment (week 3) T2: 60-day post-treatment follow-up At each timepoint, clinical assessments (nasal endoscopy and Valsalva maneuver) and instrumental assessments (tympanometry and pure-tone audiometry) were performed by a physician blinded to treatment allocation. The T0 evaluation was performed by a first otolaryngologist, while T1 and T2 assessments were carried out by a second otolaryngologist blinded to treatment assignment throughout the study. SAMPLE SIZE CALCULATION Sample size was calculated using G\*Power (version 3.1). Based on audiometric data from comparable interventions in inflammatory middle ear disease, a mean difference in pure-tone average of 5 dB between active treatment and placebo groups was assumed, with a pooled standard deviation of 13 dB (effect size d = 0.38). Using a two-sided significance level of α = 0.05 and a statistical power of 90%, a minimum of 150 participants per group was required. Accounting for an anticipated dropout rate of 10%, a total of 501 participants were enrolled, with 167 allocated to each group. STATISTICAL ANALYSIS The primary analysis was conducted on a modified intention-to-treat basis, including all participants who received at least one dose of the assigned treatment and completed at least one post-baseline assessment (n = 450, 150 per group). Missing data from participants who discontinued the study were handled using the last observation carried forward (LOCF) method. Baseline characteristics were compared across groups using the Chi-square test for categorical variables and one-way ANOVA for continuous variables. Within-group changes from T0 to T1 were assessed using paired Student's t-test. Between-group differences at T1 were compared using one-way ANOVA with post-hoc pairwise comparisons corrected by the Holm-Bonferroni method. Binary outcomes (tympanometric resolution, Valsalva positivity, audiometric threshold achievement) were compared using the Chi-square test, with odds ratios (OR) and 95% confidence intervals (CI) calculated for all pairwise comparisons. Effect sizes were reported as Cohen's d for t-tests and eta-squared (η²) for ANOVA. Recurrence rates at T2 were compared using the Chi-square test. Statistical significance was set at p \< 0.05. All statistical analyses were performed using GraphPad Prism version 10.4.2 (GraphPad Software, San Diego, CA, USA).