Introduction: RT-induced SO contributes to initiation of mucosal injury; eg, oral mucositis (OM) and esophagitis. GC4419 specifically mimics SOD’s dismutation of SO to hydrogen peroxide (H2O2), interdicting OM initiation. GC4419 reduced RT-severe OM (SOM) in a hamster cheek pouch model, and protected mucosa and other normal tissues from radiation-induced injury in other animal models. In a published phase 1b/2a open-label trial (Anderson et al, IJROBP, 1 Feb 2018), GC4419 attenuated SOM in patients (Pts) receiving intensity-modulated RT (IMRT) plus concurrent cisplatin (CDDP) for locally advanced head & neck cancer (HNC). Objectives: Determine whether GC4419 reduces duration, incidence, & severity of SOM. Methods: Pts with locally advanced oral cavity or oropharyngeal cancer; definitive or postoperative intensity-modulated (IM)RT (approximately 70 Gy [>50 Gy to > 2 oral sites]) plus CDDP (weekly or q3wk) were randomized (stratification: tumor HPV status, CDDP schedule) to 30 or 90 mg of GC4419, or placebo (PBO), 60-minute IV infusion, M–F, ending <60 minutes before IMRT delivered in 35 fractions over 7 weeks. WHO grade OM was assessed by trained evaluators biw during IMRT & qwk for up to 8 wks after IMRT. Primary endpoint: duration of SOM. Efficacy was tested for each active dose vs PBO (ITT population) by a sequential, conditional approach (2-sided alpha, 0.05). Results: 223 pts (44 sites): 90 mg (n=76), 30 mg (n=73), or PBO (n=74). Baseline patient and tumor characteristics and treatment delivery were balanced. Efficacy: At 90 mg GC4419 vs PBO, duration of SOM was significantly reduced (median, 1.5 vs 19 d; P=.024). SOM incidence (43% vs 65%; P=.009), and grade 4 incidence (16% vs 30%; P=.045) also improved. There were intermediate improvements with 30 mg. Safety was comparable across arms; no significant GC4419-specific toxicity; other known toxicities of IMRT/CDDP were not increased. Conclusions: GC4419 demonstrated a significant, clinically meaningful reduction of SOM duration, and dose-dependent improvements in other SOM parameters, with acceptable safety. A confirmatory phase 3 trial (NCT03689712) is in progress. Clinical trials to reduce RT-related esophagitis are also planned.