Abstract
Oral mucositis (OM) is a frequent and clinically important toxicity of conditioning therapy for hematopoietic cell transplantation (HCT). This trial evaluated whether prophylactic N-acetylcysteine (NAC) mouthwash reduces the incidence and severity of OM in HCT recipients. In this single-center, double-blind, randomized, placebo-controlled trial, adults undergoing autologous or allogeneic HCT were assigned 1:1 to NAC mouthwash (600 mg every 6 h; 2400 mg/day) or matching placebo from the first day of conditioning until day +14 after transplantation or neutrophil engraftment, whichever occurred first. OM was assessed daily using the World Health Organization (WHO) Oral Toxicity Scale. The primary outcomes were the incidence of any OM and severe OM (WHO grades 3-4). Safety and exploratory predictors of OM were also evaluated. A total of 106 patients were randomized (NAC, n = 54; placebo, n = 52) and included in the intention-to-treat efficacy analysis. Any-grade OM occurred in 33/54 patients (61.1%) receiving NAC and 38/52 patients (73.1%) receiving placebo (P = 0.190). Severe OM was significantly less frequent with NAC than with placebo (3/54 [5.6%] vs. 13/52 [25.0%]; P = 0.006), and the overall distribution of WHO grades favored NAC (P = 0.046). NAC was well tolerated; gastrointestinal adverse events were mild and infrequent. In multivariable analysis, allogeneic HCT, myeloablative conditioning, suboptimal adherence, and placebo assignment were associated with higher odds of OM. NAC mouthwash did not significantly reduce the overall incidence of OM but significantly reduced severe OM in adults undergoing HCT. Given its low cost, availability, and favorable tolerability, NAC mouthwash may be a practical supportive-care strategy for reducing clinically consequential mucosal toxicity. Multicenter trials with standardized formulations and patient-reported outcomes are warranted. ClinicalTrials.gov identifier NCT07325383 (registered on November 16, 2025); Iranian Registry of Clinical Trials (IRCT20140818018842N42).