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Purpose Approximately 30%higher-grade premalignant oral intraepithelial neoplasia (OIN) lesions will progress to oral cancer. While surgery is the OIN treatment mainstay, many OIN lesions recur which is highly problematic for both surgeons and patients. This clinical trial assessed the chemopreventive efficacy of a natural-product based bioadhesive gel on OIN lesions. Experimental Design This placebo-controlled multicenter study investigated the effects of topical application of bioadhesive gels that contained either 10% w/w freeze dried black raspberries (BRB) or an identical formulation devoid of BRB placebo to biopsy-confirmed OIN lesions (0.5 gm × q.i.d., 12 weeks). Baseline evaluative parameters (size, histologic grade, LOH events) were comparable in the randomly assigned BRB (n=22) and placebo (n=18) gel cohorts. Evaluative parameters were: histologic grade, clinical size and loss of heterozygosity (LOH). Results Topical application of the BRB gel to OIN lesions resulted in statistically significant reductions in lesional sizes, histologic grades and LOH events. In contrast, placebo gel lesions demonstrated a significant increase in lesional size and no significant effects on histologic grade or LOH events. Collectively, these data strongly support BRB’s chemopreventive impact. A cohort of very BRB-responsive patients-as demonstrated by high therapeutic efficacy-was identified. Corresponding protein profiling studies, which demonstrated higher pretreatment levels of BRB metabolic and keratinocyte differentiation enzymes in BRB-responsive lesions, reinforce the importance of local metabolism and differentiation competency. Conclusions Results from this trial substantiate the LOH reductions identified in the pilot BRB gel study and extend therapeutic effects to significant improvements in histologic grade and lesional size.