Phase 2a Randomized, Double-Blinded, Placebo-Controlled Trial of a Topical Nitric Oxide Releasing Solution (NORS) for the Treatment of Plantar Warts (HPV-Warts-01)

Abstract

Background: 
Verrucae plantaris (plantar warts) are common cutaneous lesions of the plantar aspect of the foot that are caused by the human papillomavirus (HPV) infection of keratinocytes. When plantar warts cause pain, they may alter patient’s normal posture or gait, occasionally without them realizing it. Nitric oxide has known antimicrobial, antiviral, and immunomodulatory properties. NORS (nitric oxide releasing solution) was evaluated for safety and efficacy in participants with multiple plantar warts. Standard approaches such as salicylic acid and surgical removal can be uncomfortable for patients, slow to act, and still have wart recurrence. Nitric oxide is an endogenous signaling molecule with multimodal effects, including disruption of viral replication, interference with host cell entry, and enhancement of local immune activity. A nitric oxide releasing solution (NORS) in the form of a soak provides a noninvasive treatment strategy that may overcome the limitations of current therapies. This phase 2a study evaluated the safety and efficacy of NORS in participants with multiple plantar warts. 

Methods: 
This multicenter, randomized, double-blinded, placebo-controlled phase 2a trial (HPV-Warts-01; NCT05877313) enrolled 20 participants with ≥3 plantar warts. Participants were randomized 1:1:1 to NORS 1X (41.1 PPM*min), NORS 3X (121.9 PPM*min), or placebo (sterile water). Treatment consisted of a self-administered foot bath (500 mL for 15 minutes) three times weekly for three weeks. The primary endpoint was complete wart clearance at Day 35, measured by photographic assessment. Secondary endpoints included reduction in wart area size, pain reduction reported by participants, and safety. 

Results: 
Twenty participants (70% male; mean age 49 years) with 116 warts were randomized: NORS 1X (n=6, 33 warts), NORS 3X (n=8, 50 warts), and placebo (n=6, 33 warts). Six HPV genotypes were detected; HPV2, HPV27, and HPV57 predominated. Complete wart clearance was observed in 6% of warts in the 1X arm, 8% in the 3X arm, and 0% in placebo. At least 70% reduction in wart area occurred in 21% (NORS 1X), 16% (NORS 3X), and 12% (placebo). Pain scores improved only in the NORS 3X arm (mean change –0.8). Treatment was generally well tolerated; most adverse events (AEs) were mild, including skin discoloration, dryness, and blistering. No severe or serious AEs occurred. 

Conclusions: 
NORS demonstrated a favorable safety profile and a trend toward wart clearance and pain reduction. More frequent or prolonged dosing may be necessary. Future studies will evaluate optimized dosing schedules in younger populations with less chronic disease burden. Whereas conventional therapies can frequently cause pain, tissue damage, or scarring, NORS offered a painless and noninvasive soak that participants could self-administer, underscoring its potential as a safer and more comfortable alternative to conventional wart therapies.

Sponsored: SaNOtize Research and Development Corporation