Abstract
Background/Aim: Plantar warts are cutaneous lesions on the plantar aspect of the foot caused by the infection of keratinocytes with the human papillomavirus (HPV). The severity and magnitude of warts can vary, but they cause pain and discomfort for all age groups. The treatment for plantar warts remains a continuing challenge. The purpose of this research was to compare the efficacy and safety of naturally derived Nowarta110 topical formula versus a matching placebo in treating plantar warts. Patients and Methods: The study is a randomized, double-blind, parallel assignment control interventional phase I/II clinical trial. This study included 54 patients with plantar warts. Patients were randomized to two groups: the placebo group, which included 26 patients treated with a matching placebo and the Nowarta110 group, which included 28 patients who received topical Nowarta110. The diagnosis of plantar warts was made by clinical examination. The treatment’s efficacy and safety were assessed every week and after 6 weeks from the initiation of the intervention. Results: In the Nowata110 group, 18 patients (64.3%) were completely cleared of their warts, and 10 patients (35.7%) partially responded to the therapy with a 20% to 80% decrease in warts dimensions. In the placebo group, only 2 patients (7.7%) were completely cleared of their warts, and 3 patients (11.5%) partially responded to the intervention with a 10% to 35% decrease in warts dimensions. The difference was highly significant between the two groups. There was 1 event with minor pain as a side effect in the Nowarta110 group and 9 events of non-serious local side effects in the placebo group, which included 2 patients who dropped out. Conclusion: Topical Nowarta110 is a safe, well-tolerated, and highly effective therapeutic modality in treating refractory and recurrent plantar warts. The breakthrough findings of the study encourage further extensive clinical trials to fully explore the prospect of Nowarta110 in managing all types of warts and HPV-related diseases.
Plantar warts are lesions on the foot skin caused by human papillomavirus (HPV) infection of keratinocyte (1). Plantar warts often occur in the pressure exerted by the body weight between the sole, heel, and front foot area. The typical symptom is pain or swelling under the foot (2). The severity and magnitude of warts can vary, but they cause pain and discomfort for all age groups. Most plantar warts are histologically benign, with only rare instances of malignant transformation, such as verrucous carcinoma (3-5).
Plantar warts have an estimated annual incidence of 14% (6) and are commonly found in children and adolescents (7). Immunocompromised patients are at an increased risk of acquiring plantar warts (8), which can cause pain, embarrassment, and, in rare cases, cancer. Several destructive therapeutic options are available to treat plantar warts, including a high topical concentration of salicylic acid, cryotherapy, topical or intralesional 5-fluorouracil, bleomycin, cantharidin, excision, electrocautery, laser therapy, and combination of these approaches. However, these modalities remove the visibly infected lesions only, leaving the nonvisible infected tissue untouched, and they are commonly associated with significant adverse effects, such as pain, itching, infection, bleeding, and scarring (9-11). Moreover, they require multiple sessions and individual treatment of each wart, thus they are considered unsuitable for patients with multiple warts, particularly in the case of distant locations. Additionally, the currently available treatment methods are aimed at plantar warts, not underlying HPV viral infections. As a result, the risk of transmission cannot be fully controlled (2). As a viral disease, plantar warts continue to affect the patients’ quality of life seriously, and there are currently no noninvasive, safe, and perfect treatment methods. The current study compares the efficacy and safety of naturally derived Nowarta110 topical versus a matching placebo in treating plantar warts.
Patients and Methods
Recruitment and randomization of participants. The study recruited participants from a single certified podiatry clinic and primary care, and eligible participants provided written informed consent. This randomized, double-blinded, parallel assignment, control interventional clinical trial involved 54 patients diagnosed with plantar warts. Patients were randomly assigned to one of two groups: the placebo group, which included 26 patients treated with a matching placebo, or the Nowarta110 group, which included 28 patients treated with topical Nowarta110. The diagnosis of plantar warts was made through clinical examination.
Materials. Nowarta110 is a new compound composed of colloidal silver, fig extract, and appropriate pharmaceutical excipients that have demonstrated therapeutic efficacy against HPV-induced genital warts. An FDA-certified laboratory conducted preclinical and toxicological studies on experimental animals, evaluating three methods of administering Nowarta110. The objectives included physiological and histopathological examinations, which were statistically compared to the control group. After a 90-day study, it was concluded that Nowarta110 had no toxic effects when administered orally, topically, or intra-vaginally in experimental animals. These findings led to an FDA-approved phase I/II clinical trial of Nowarta110 for plantar wart patients.
The vials used for the placebo control group, which had the same color as the Nowarta110 solution, were created using an extract of black tea. A certified pharmaceutical laboratory manufactured the placebo product and conducted tests to ensure that it met the required quality standards for therapeutic use.
Intervention. The intervention assignment was stratified by the size of the plantar wart (lesions size measured in square millimeters). The size of the plantar wart stratified random assignment. If the lesion size was less than 1 cm2, 3 drops were applied once weekly for 5 weeks. If the lesion size was between 1 cm2~ 2 cm2, 6 drops were applied once weekly for 5 weeks. If the lesion size was larger than 2 cm2, 10 drops were applied once weekly for 5 weeks. The treatment assessment occurred weekly, starting from the beginning of the intervention with the placebo and Nowarta110, and continued for a total of 6 weeks.
Main outcome measures. The primary endpoint was the complete eradication of all plantar warts after 6 weeks. Secondary endpoints included a partial reduction in the size of plantar warts after 6 weeks and the occurrence of any adverse events among the treated patients during a 6-week follow-up period.
Control error method and data processing. The patients were closely monitored and treated at the clinic, with full guidance on the research protocol requirements and adherence throughout the study. Biomedical statistical methods were employed to process the data, using the SPSS 20.0 software for Windows. The statistical analysis involved comparing each study outcome using a paired t-test, and ratios were evaluated using the chi-square test (χ2) for a significance level of p<0.05.
Eligibility criteria. Patients had to meet the following criteria to be eligible for inclusion in this study. They must have had refractory or recurrent plantar warts and be aged 18 years or older. Additionally, they should not have received wart treatment in the last 12 weeks and must have been healthy males or non-pregnant, non-lactating females aged 18 years or older. A female of childbearing potential must have used an acceptable form of birth control during the study. Finally, patients had to provide written informed consent or (HIPAA consent/authorization).
Exclusion criteria. Patients who met any of the following criteria were excluded from this study. They had a concurrent medical disorder or disease that would make implementing or interpreting the protocol or results difficult or unsafe. Female subjects who were breastfeeding or planning to become pregnant were not eligible to participate. Patients with a history of allergy to silver or fruits were also excluded. Subjects with a clinically significant unstable medical disorder, life-threatening disease, or current malignancies were not eligible. Those with a history of alcohol or other drug abuse within 2 years before randomization or who had been treated with an investigational drug or investigational device within 30 days of study enrollment were also excluded. Additionally, any other wart therapy as a concomitant medication was prohibited during the study.
Clinical trial registration. ClinicalTrials.gov identifier (NCT number): NCT02338336.
Results
Patients baseline characteristics are shown in Table I. No significant demographic differences existed in the placebo and Nowarta110 groups of the recruited patients. The detailed protocol for intervention in the current clinical trial is presented in Table II. The efficacy and safety of the treatment were evaluated weekly, as well as after 6 weeks from the start of the intervention. The findings are displayed in Table III. In the group that received Nowarta110, 18 patients (64.3%) achieved complete clearance of their warts, whereas 10 patients (35.7%) experienced a partial response with reduced wart dimensions ranging from 20% to 80%. Conversely, in the placebo group, only 2 patients (7.7%) were completely cleared of their warts, and 3 patients (11.5%) partially responded with a reduction of wart dimensions ranging from 10% to 35%. The difference between the two groups was highly significant, with a p-value of less than 0.001.
Patients’ demographic characteristics.
Intervention protocol.
Primary outcome of the clinical trials.
During the intervention, there was one reported event of minor pain as a side effect in the Nowarta110 group at week 4. However, the patient was able to complete the full course of therapy. Conversely, the placebo group experienced 9 non-serious local side effects, leading to 2 patients dropping out. All adverse events in both groups were deemed minor and transient. According to the data presented in Table IV, Nowarta110 was well-tolerated and safe for all treated patients during the 6-week follow-up period.
Adverse events of the clinical trial.
Discussion
Research has shown that 65% of cutaneous warts will naturally regress within two years, particularly in young children (12). However, in individuals older than 12 years, the rate of spontaneous regression significantly decreases (13). Effective cellular immune responses are responsible for wart regression (14), with humoral immunity generating antiviral antibodies in B cells that can prevent future reinfection by specific HPV type (15). It is estimated that HPV infects 40% of the population, with 7% to 12% of those infected developing warts (16-18). Clinical diagnosis is usually sufficient for plantar warts, but in cases of diagnostic uncertainty or treatment resistance, a biopsy with histopathologic evaluation may be necessary (19).
The existing therapeutic approaches for plantar warts rely on destructive methods. Unfortunately, these treatments are often accompanied by pain, require significant time commitments, and have a high likelihood of adverse effects and recurrence (20). Moreover, despite undergoing treatment, many individuals experience continuous growth of warts and face significant resistance to various treatments (21). Unfortunately, the current therapies do not target the root cause of plantar warts, which is the HPVvirus (3). According to the current study, treatment of plantar warts with Nowarta110 topical application once a week for five weeks is effective. This therapeutic approach is a significant breakthrough, as Nowarta110 is well-tolerated and has minimal adverse side effects, except for one minor case of local pain that did not result in treatment discontinuation.
Topical salicylic acid and cryotherapy with liquid nitrogen are the two most commonly used treatments for plantar warts (17, 22). However, the expected cure rates for these first- or second-choice treatments, such as salicylic acid (13.6%) and cryotherapy (45.61%) were not achieved (23). In a recent randomized, double-blind control clinical study, 242 plantar warts patients were randomly divided into two groups, with 124 receiving salicylic acid topical treatment and 118 receiving cryotherapy (24). Cryotherapy involved up to four treatments delivered by a healthcare professional, spaced two to three weeks apart. In the salicylic acid group, patients were self-treated with Verrugon, applying it daily for up to eight weeks. The study found no significant difference between the salicylic acid and cryotherapy groups in terms of the proportions of participants with complete clearance of all plantar warts at 12 weeks, which was only 14% in both groups.
The treatment with salicylic acid requires daily applications for several months and is commonly used as the initial therapy. However, it may not be suitable for certain patients, such as those with diabetic peripheral neuropathy or peripheral vascular disease, who should be cautious about using this agent for at-home plantar wart therapy (25, 26). In contrast, cryotherapy is associated with more severe adverse effects than salicylic acids, such as mobility-limiting pain (27). This therapy is repeated every two to three weeks for up to three months, and due to the pain associated with it, it is not recommended for young children.
Based on the aforementioned scientific evidence, it has been observed that Nowarta110 topical treatment once a week for five weeks provides a much more effective and safe profile compared to topical salicylic acid and cryotherapy. Since Nowarta110 topical treatment is well-tolerated with minimal side effects and is easy to use, we propose that more frequent applications than once a week and longer treatment duration than five weeks may result in a higher rate of complete clearance of plantar warts. Plantar warts are often resistant to treatment when present for more than six months (28), and thus, initiating therapy before wart recalcitrance may be more beneficial (25).
Our current study has demonstrated excellent clinical efficacy and safety characteristics of Nowarta110, which strongly suggest that it could be a preferred therapy for the treatment of early wart development. Furthermore, due to its antiviral activity, Nowarta110 could help prevent the resistance and spreading of the disease to other parts of the body. Hence, Nowarta110 has the potential to be a therapy of choice in the management of plantar warts.
Considering all the above factors, conducting further clinical research on Nowarta110 for the treatment and prophylaxis of plantar warts is important. Furthermore, it is crucial to explore the therapeutic efficacy of Nowarta110 as a topical and systemic antiviral preparation for potentially managing patients with all types of HPV-related diseases. Therefore, it is imperative to investigate the full potential of Nowarta110 in addressing various HPV-related diseases, which could pave the way for developing more effective treatment options for patients.
Conclusion
Topical Nowarta110 is a safe, well-tolerated, and highly effective therapeutic treatment for refractory and recurrent plantar warts. The breakthrough findings of the study encourage further extensive clinical trials to fully explore the prospect of Nowarta110 in managing all types of warts and HPV-related diseases.
Footnotes
Authors’ Contributions
Mahkameh Yousefpour: Investigation; Methodology; Data curation; Formal analysis, Iraj Zamanian: Investigation; Methodology; Data curation; Formal analysis, Ferre Akbarpour: Methodology; Data curation; Formal analysis, William H. Fang: Writing - review & editing, Bo Han: Conceptualization; Data curation; Formal analysis. Methodology, Ba X. Hoang: Conceptualization; Data curation; Formal analysis. Methodology: Writing - original draft.
Conflicts of Interest
The Authors declare no conflicts of interest in writing and publishing this manuscript.
Funding
The study was funded by Nowarta Biopharma, Huntington Beach, CA, USA.
- Received March 7, 2023.
- Revision received March 16, 2023.
- Accepted March 20, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
