Background: Approximately 70% of patients receiving intensity-modulated radiotherapy (IMRT) plus cisplatin for locally advanced head and neck cancer (HNC) develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring enteral nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by converting superoxide to H2O2. It showed promising reduction of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). In a subsequent randomized, double-blind placebo-controlled trial in 223 patients receiving IMRT/cisplatin for HNC (ASCO 2018), 90 mg of GC4419 administered M-F prior to IMRT demonstrated statistically significant reduction in SOM duration (p=0.024, median 1.5 days @ 90 mg vs. 19 days placebo) and meaningful reductions @ 90 mg in SOM incidence (43% vs. 65%) and severity (incidence of Grade 4, 16% vs. 30%). The safety results were acceptable and consistent with the known toxicities of IMRT/cisplatin. Methods: 335 patients at multiple centers in the U.S. and Canada with locally-advanced, nonmetastatic head and neck cancer (oral cavity/oropharyngeal) receiving 70 Gy IMRT (>50 Gy to > 2 oral sites) plus cisplatin (40 mg/m2 qwk x 6-7, or 100 mg/m2 q3wk x 3) are being randomized (double-blinded) 3:2 to 90 mg of GC4419 or placebo, M-F before each RT fraction. Enrollment is stratified by cisplatin schedule and treatment setting (definitive vs. post-op). OM by the WHO scale will be assessed twice weekly during RT & weekly for 2 weeks post RT. The primary efficacy endpoint is incidence of SOM through the end of IMRT. Secondary efficacy endpoints include severity (incidence of Grade 4 OM through the end of IMRT), & days of SOM (days from first to last SOM for all patients, with patients never developing SOM having 0 days of SOM by definition). Days of SOM for the subset developing SOM will be analyzed descriptively. Patients will be followed for one year post IMRT for tumor progression/recurrence and for two years for survival. Clinical trial information: NCT03689712.