Abstract
Objective
The study aims to present an observational study of clinical trials on Oral Potentially Malignant Disorders (OPMDs) and corresponding publications.
Study design and setting
We searched the OPMDs-related clinical studies registered in the ClinicalTrials.gov database before March 1, 2024. Subsequently, we investigated the publication status of primary completed studies using PubMed and Google Scholar.
Results
A total of 185 studies were identified for analysis, including 141 interventional studies and 44 observational studies. The most commonly studied disease type was oral lichen planus (OLP), accounting for 113 studies (61.1 %). Interventional studies on OPMDs were predominantly early-phased, blind, randomized, parallel and single-center. The primary purpose of these studies was treatment (106, 75.2 %). Among the treatments, herbal medicine (21, 19.8 %), photodynamic therapy (17, 16.0 %), and glucocorticoids (14, 13.2 %) were of greatest interest. In addition, 58 (63.0 %) of the primarily completed interventional studies were published, with a median time to publication of 33.6 months. Published interventional studies including OLP patients and factorial designs had shorter time to publication. However, these studies were less frequently published in high-impact journals and most primary results were positive.
Conclusions
Clinical trials on OPMDs predominantly focused on OLP and herbal medicine. The quality of studies is unsatisfactory and publication rate is suboptimal. Improvements are needed in ClinicalTrials.gov registration standards, high-quality study design and more stringent publishing requirements.
Keywords: Clinical studies, OPMDs, Oral potentially malignant disorders, ClinicalTrials.gov, Publication status, Registration
Highlights
What is new?
Key findings.
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The majority of clinical trials on OPMDs primarily focused on OLP, with herbal medicine receiving the most attention as a treatment, followed by photodynamic therapy and glucocorticoid.
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Most current clinical trials were in early phase, single-center studies with small sample size, and many were registered after the study had already begun.
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About 40 % of the primary completed studies had not been published or released, and the time to publication was relatively long, with lower quality of publication.
What this adds to what was known?
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Despite the proliferation of OPMDs clinical trials, there was still a lack of high-quality studies and inadequate release of study results.
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The exploration of treatment methods for OPMDs was diverse, with a considerable focus on herbal medicine and photodynamic therapy, though neither was considered first-line treatments in clinical practice.
What is the implication and what should change?
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Researchers should strengthen registration standards and register before the start of the study. Registration platforms should also enhance registration supervision, and registrations lacking important information should not be approved. To improve research quality, randomized, late-phased and multi-center clinical trials should be included in study design. Transparency of results sharing needs to be ameliorated to a better extent.
1. Introduction
Oral Potentially Malignant Disorders (OPMDs) are a series of chronic lesions and conditions associated with a statistically increased risk of malignant transformation to oral squamous cell carcinoma (OSCC) [1]. According to the 2020 workshop coordinated by the World Health Organization (WHO) Collaborating Centre for Oral Cancer in the UK [1,2], OPMDs include Oral Leukoplakia (OLK), Oral Lichen Planus (OLP), Oral Submucous Fibrosis (OSF), Discoid Lupus Erythematosus (DLE), Oral Erythroplakia (OE), Actinic Cheilitis (AC), Oral Epidermolysis Bullosa (OEB), Dyskeratosis Congenita (DC), Proliferative Verrucous Leukoplakia (PVL), Oral Lichenoid Lesion (OLL), and Palatal Lesions in Reverse Smokers.
Over the past few decades, the prevalence of OPMDs has exponentially increased worldwide, especially in Asian and South American populations with the rates of 10.54 % and 3.93 %, respectively [[3], [4], [5]]. Given the increasing prevalence of OPMDs and high malignant transformation rate (MTR) to OSCC (7.9 %, 99 % CI = 4.9%–11.5 %) [6], early diagnosis and effective treatment are crucial to improving the overall well-being and reducing the MTR. Various studies have reported multidisciplinary care approaches, including surgical excision with or without carbon dioxide laser, chemoprevention with naturally or synthetically fabricated compounds, photodynamic therapy [[7], [8], [9], [10]]. However, no approach has yet gained universal approval as a standard method of prevention and treatment due to the lack of clinical trials and the low overall quality of the evidence [[11], [12], [13], [14]]. Therefore, a thorough understanding of the current landscape and characteristics of clinical trials on OPMDs is essential for identifying neglected areas of research, improving trial design, and providing references for clinicians to further explore the effective treatment methods.
Well-designed randomized controlled clinical trials (RCTs), with appropriate sample sizes and transparency, remain the gold standard to generate the highest level of evidence in determining therapy guidelines and form the solid foundation of evidence-based medicine [15]. In clinical practice, RCTs also inform clinicians about the comparative efficacy and safety of medical interventions and contribute to key clinical practice decision-making [[16], [17], [18]]. The ClinicalTrials.gov database, currently including detailed registries on more than 370,000 international clinical studies, serves as the oldest and largest platform of its kind, continually updating the most comprehensive information about the clinical research worldwide. This database offers an opportunity to explore, inspect and supervise the clinical research landscape [[19], [20], [21]].
Despite constant proliferation of OPMDs clinical studies, there is no systematic, up-to-date evaluation of the clinical trial landscape. Consequently, we still lack a thorough understanding of latest clinical studies regarding OPMDs. This study is the first to investigate OPMDs clinical trials registered on the ClinicalTrials.gov, aiming to: 1) outline the current composition and comprehensive landscape of OPMDs studies; 2) thoroughly evaluate the characteristics and publication status of these studies; 3) suggest future research focuses and identify neglected research areas.
2. Methods
2.1. Searching the ClinicalTrials.gov database and Identifying Eligible studies
This observational study focused on research studies. We searched the ClinicalTrials.gov database on March 01, 2024, using the search terms “Oral Leukoplakia (OLK)”, “Oral Lichen Planus (OLP)”, “Oral Submucous Fibrosis (OSF)”, “Discoid Lupus Erythematosus (DLE)”, “Oral Erythroplakia (OE)”, “Actinic Cheilitis (AC)”, “Epidermolysis Bullosa (EB)”, “Dyskeratosis Congenita (DC)”, “Proliferative Verrucous Leukoplakia (PVL)”, “Oral Lichenoid Lesion (OLL)”, “Palatal Lesions in Reverse Smokers”, “Oral Potentially Malignant Disorders (OPMDs)”. All available results were downloaded as CSV files and imported into a database for systematic and coherent data inclusion, elimination, extraction, classification and management. Duplicate and non-oral relevant studies were excluded.
2.2. Study variables
Based on the information from the ClinicalTrials.gov database, the following variables were categorized by two independent investigators: status (ongoing/completed/terminated/withdrawn/unknown status), primary complete (yes/no), register(before study start/after study start), year of study register (1999–2005/2006-2010/2011–2015/2016-2020/2021–2024), sample size (≤50/51–100/>100), results (unavailable/available), age (with children/without children), disease type (AC/DC/DLE/EB/OLK/OLP/OSF/OPMDs), study design (single arm/parallel/factorial/cross-over/cross-sectional/case-control/cohort), countries where the study was carried out (American/European/African/Asian/Multiple), center (single-center/multi-center), funder (NIH/industry/others), purpose of the interventional studies (basic science/diagnostic/prevention/screening/supportive care/treatment/others), primary outcome (negative/positive), phase (early stage/late stage/missing), blind (open label/single-blind/double-blind/triple-blind/quadruple-blind), randomization (yes/no). Whether a study was multi-center was judged by the brief summary, locations, sponsors and collaborators. Trials with an industry listed as the main investor were classified as industry-funded. With similar principles, the others can be divided into the corresponding categories [22]. Primary completion duration was defined as the time interval between study initiation point and the accomplishment of the primary endpoint. The study duration was defined as the time interval between study initiation point and the completion of the entire study.
The therapies of the interventional studies aimed at treatment were categorized as glucocorticoid (GC), biologics (BO), NSAID, antimicrobial (AM), herbal medicine (HM), immunotherapy (IM), photodynamic therapy (PDT), stem cell transplant (SCT), dietary supplement (DS), surgery and other therapies. Biologics included enzymes, monoclonal antibodies, glucosamine sulfate, etc. Antimicrobial therapy consisted of antifungal, antibacterial and antiviral drugs. Herbal medicine included curcuminoids, chamomile, chamaemelum nobile, quercetin, etc. Immunotherapy was composed of immunosuppressants and immunomodulators. Photodynamic therapy involved treatment with various photosensitive compounds and lasers, such as aminolevulinic acid hydrochloride, YAG or YSGG laser.
2.3. Searching for the publication status
Under a standardized strategy, two investigators independently searched for peer-reviewed publications of studies under primary completion on the platform of “publication” field in ClinicalTrials.gov database, PubMed and Google Scholar, using NCT number, headline, sponsor and collaborator. Publications were carefully identified by matching study details, including study description, design, arms and interventions, outcome measures, and eligibility criteria in the ClinicalTrials.gov database with the literature. If multiple publications were retrieved, the original literature demonstrating the primary outcome results was selected. Interim analyses, commentaries, study protocols, reviews and other non-relevant publications were excluded. A third investigator reaffirmed and further searched for the publications not discovered. Disputes were resolved through discussion and verification. For each published article, study design, sample size, primary results (negative or positive), published date, magazine and impact factor (IF < 5/5–9.99/≥10) were collected. Publication status retrieval was updated and finalized by March 12, 2024. The time to publication was defined as the interval time from the study's primary completion date to the publication date or the last search date.
2.4. Statistical analysis
Categorical variables were described as frequencies and percentages and compared between groups using Chi-square tests or Fisher's exact tests. Continuous variables were described as medians and interquartile ranges (IQR) and compared between groups using Mann-Whitney U tests. Missing data were excluded from specific variable analyses. The time to publication was estimated using the Kaplan-Meier method, and the median time to publication was calculated for overall and subgroups. Cox regression analysis was performed to identify factors influencing the time to publication. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were calculated for these factors. Variables with p < 0.05 in univariate analysis were included in the multivariate model. All statistical tests were performed using Stata/MP version 14.0 (Stata Corporation LP, College Station, TX, USA), with a two-sided p < 0.05 considered statistically significant.
3. Results
3.1. Distribution of OPMDs-Relevant studies on ClinicalTrials.gov
As shown in Fig. 1, a total of 427 studies registered in ClinicalTrials.gov Database were identified. After excluding 242 duplicate and non-oral relevant studies, 185 studies were retained for analysis: 141 (76.2 %) interventional and 44 (23.8 %) observational studies. The search term “Discoid Lupus Erythematosus (DLE)” yielded results irrelevant to oral health. Additionally, studies with the terms “Oral Erythroplakia (OE)”, “Proliferative Verrucous Leukoplakia (PVL)”, “Oral Lichenoid Lesion (OLL)” and “Palatal Lesions in Reverse Smokers” were either duplicated with other terms or presented no results, leading to the deletion of these five terms.
Fig. 1.
Study selection flow chart.
Abbreviations: OLK, oral leukoplakia; OLP, oral lichen planus; OSF, oral submucous fibrosis; DLE, discoid lupus erythematosus; OE, Oral Erythroplakia; AC, actinic cheilitis; EB, epidermolysis bullosa; DC, dyskeratosis congenita; PVL, proliferative verrucous leukoplakia; OLL, oral lichenoid lesion; OPMDs, oral potentially malignant disorders.
The distribution of the interventional and observational studies according to the registered year is summarized in Fig. 2. In general, the number of registered studies has gradually increased over the past twenty years, with some fluctuations. Notably, the number of observational studies began to rise after 2017, but it remained significantly lower than the number of interventional studies.
Fig. 2.
Study distributions of register and publication for observational and interventional studies according to the registered or published year.
3.2. General characteristic of interventional and observational studies
The characteristics of included interventional and observational studies are summarized in Table 1. Overall, most studies focused on OLP patients (113, 61.1 %), were registered after study start(127, 68.6 %), had small-sample size (105, 56.8 %), and were single-center (161, 87.0 %).
Table 1.
Study characteristics between interventional and observational studies.
| Overall (n = 185) | Observational studies (n = 44) | Interventional studies (n = 141) | |
|---|---|---|---|
| Study status | |||
| Ongoing | 38 (20.5) | 13 (29.5) | 25 (17.7) |
| Completed | 99 (53.5) | 22 (50.0) | 77 (54.6) |
| Terminated | 10 (5.4) | 1 (2.3) | 9 (6.4) |
| Withdrawn | 5 (2.7) | 0 | 5 (3.5) |
| Unknown status | 33 (17.8) | 8 (18.2) | 25 (17.7) |
| Duration of study completed (mo.) | 17.0 (10.0, 35.5) | 12.0 (5.8, 35.4) | 19.5 (11.7, 37.9) |
| Primary completed | |||
| No | 68 (36.8) | 19 (43.2) | 49 (34.8) |
| Yes | 117 (63.2) | 25 (56.8) | 92 (65.2) |
| Duration of primary completed (mo.) | 17.0 (10.0, 35.5) | 12.0 (5.8, 35.4) | 19.5 (11.7, 37.9) |
| Register | |||
| Before study start | 58 (31.4) | 15 (34.1) | 43 (30.5) |
| After study start | 127 (68.6) | 29 (65.9) | 98 (69.5) |
| Year of study registered | |||
| 1999–2005 | 16 (8.6) | 2 (4.5) | 14 (9.9) |
| 2006–2010 | 23 (12.4) | 2 (4.5) | 21 (14.9) |
| 2011–2015 | 27 (14.6) | 2 (4.5) | 25 (17.7) |
| 2016–2020 | 73 (39.5) | 23 (52.3) | 50 (35.5) |
| 2021–2024 | 46 (24.9) | 15 (34.1) | 31 (22.0) |
| Age | |||
| Without child | 146 (78.9) | 33 (75.0) | 113 (80.1) |
| With child | 39 (21.1) | 11 (25.0) | 28 (19.9) |
| Sex | |||
| Only female | 1 (0.5) | 1 (2.3) | 0 |
| All | 184 (99.5) | 43 (97.7) | 141 (100.0) |
| Sample size | |||
| ≤50 | 105 (56.8) | 10 (22.7) | 95 (67.4) |
| 51-100 | 51 (27.6) | 19 (43.2) | 32 (22.7) |
| >100 | 27 (14.6) | 15 (34.1) | 12 (8.5) |
| missing | 2 | 2 | |
| Disease types | |||
| OLP | 113 (61.1) | 28 (63.6) | 85 (60.3) |
| OLK | 31 (16.8) | 4 (9.1) | 27 (19.1) |
| AC | 9 (4.9) | 0 | 9 (6.4) |
| OSF | 8 (4.3) | 3 (6.8) | 5 (3.5) |
| DC | 4 (2.2) | 1 (2.3) | 3 (2.1) |
| EB | 2 (1.1) | 0 | 2 (1.4) |
| Mixed | 18 (9.7) | 8 (18.2) | 10 (7.1) |
| Study design | |||
| Single arm | 35 (18.9) | – | 35 (24.8) |
| Parallel | 97 (52.4) | – | 97 (68.8) |
| Factorial | 3 (1.6) | – | 3 (2.1) |
| Cross-over | 6 (3.2) | – | 6 (4.3) |
| Cross-Sectional | 8 (4.3) | 8 (18.2) | – |
| Case-Control | 19 (10.3) | 19 (43.2) | – |
| Cohort | 17 (9.2) | 17 (38.6) | – |
| Region | |||
| American | 54 (29.2) | 7 (15.9) | 47 (33.3) |
| European | 44 (23.8) | 11 (25.0) | 33 (23.4) |
| African | 46 (24.9) | 16 (36.4) | 30 (21.3) |
| Asian | 37 (20.0) | 10 (22.7) | 27 (19.1) |
| Multiple | 4 (2.2) | 0 | 4 (2.8) |
| Center | |||
| Single-center | 161 (87.0) | 38 (86.4) | 123 (87.2) |
| Multi-center | 24 (13.0) | 6 (13.6) | 18 (12.8) |
| Funder | |||
| NIH | 13 (7.0) | 3 (6.8) | 10 (7.1) |
| Industry | 8 (4.3) | 3 (6.8) | 5 (3.5) |
| Others | 164 (88.6) | 38 (86.4) | 126 (89.4) |
Except where indicated otherwise, values are the number (%).
Abbreviations: mo., months; OLP, oral lichen planus; OLK, oral leukoplakia; AC, actinic cheilitis; OSF, oral submucous fibrosis; DC, dyskeratosis congenita; EB, epidermolysis bullosa.
For study design, interventional studies were mostly parallel design (97, 68.8 %), early-phase (70, 68.6 %), randomized (100, 70.9 %), blind (92, 65.2 %), single-center (123, 87.2 %) and aimed for treatment (106, 75.2 %) (Table 1). Among observational studies, 19 (43.2 %) were case-control studies, 17 (38.6 %) were cohort studies and 8 (18.2 %) were cross-sectional studies (Table 1).
Fifteen studies were terminated or withdrawn (Table 1), with the most common reason being slow accrual of enrollment (8, 53.3 %). Four terminated studies were also published.
3.3. Distribution and Comparison of disease types
In terms of disease type distribution by registered year (Supplementary Figure 1), studies focusing on OLP have received considerable attention since 2005. Between 2004 and 2007, researchers showed interest in OLK. However, over time, a noticeable rise in the prevalence of OSF was observed from 2015 to 2018. Since 2009, the studies on AC have emerged, but their number remained low. Mixed studies emerged in 2012 and subsequently experienced a general upward trend, despite occasional fluctuations.
Study characteristics were compared between the different disease types among 141 interventional studies (Table 2). Nearly all study characteristics showed significant differences between different disease types (p < 0.05). Studies on DC or EB patients included children, while studies on other diseases mostly did not. Most studies on OLP were parallel design, while most studies on OLK or DC were single-arm design. The proportion of randomized studies was highest in OLP studies (84.7 %), while most OLK and DC studies did not use randomization. The majority of OLP studies employed blinding (80 %), while over half of studies on other diseases were open-label. OLP studies had a higher proportion from Africa and Europe, while OLK, AC, DC, or EB studies had a higher proportion from America, and studies on OSF were all from Asia. Although the number of centers and funding sources varied among studies on different diseases, most studies were still single-center (66.7%–100 %) and non-NIH/industry funded (66.7%–100 %).
Table 2.
Study characteristics for interventional studies overall and by disease types.
| Overall (n = 141) | OLP (n = 85) | OLK (n = 27) | AC (n = 9) | OSF (n = 5) | DC (n = 3) | EB (n = 2) | Mixed (n = 10) | p-value | |
|---|---|---|---|---|---|---|---|---|---|
| Year of study registered | 0.012 | ||||||||
| 1999–2005 | 14 (9.9) | 6 (7.1) | 8 (29.6) | 0 | 0 | 0 | 0 | 0 | |
| 2006–2010 | 21 (14.9) | 10 (11.8) | 8 (29.6) | 2 (22.2) | 0 | 1 (33.3) | 0 | 0 | |
| 2011–2015 | 25 (17.7) | 17 (20.0) | 2 (7.4) | 2 (22.2) | 0 | 2 (66.7) | 1 (50.0) | 1 (10.0) | |
| 2016–2020 | 50 (35.5) | 31 (36.5) | 5 (18.5) | 4 (44.4) | 4 (80.0) | 0 | 0 | 6 (60.0) | |
| 2021–2024 | 31 (22.0) | 21 (24.7) | 4 (14.8) | 1 (11.1) | 1 (20.0) | 0 | 1 (50.0) | 3 (30.0) | |
| Age | <0.001 | ||||||||
| Without child | 113 (80.1) | 69 (81.2) | 24 (88.9) | 9 (100.0) | 3 (60.0) | 0 | 0 | 8 (80.0) | |
| With child | 28 (19.9) | 16 (18.8) | 3 (11.1) | 0 | 2 (40.0) | 3 (100.0) | 2 (100.0) | 2 (20.0) | |
| Sample size | 0.088 | ||||||||
| ≤50 | 95 (68.4) | 61 (71.8) | 16 (64.0) | 8 (88.9) | 4 (80.0) | 3 (100.0) | 1 (50.0) | 2 (20.0) | |
| 51–100 | 32 (23.0) | 16 (18.8) | 8 (32.0) | 1 (11.1) | 1 (20.0) | 0 | 1 (50.0) | 5 (50.0) | |
| >100 | 12 (8.6) | 8 (9.4) | 1 (4.0) | 0 | 0 | 0 | 0 | 3 (30.0) | |
| missing | 2 | 2 | |||||||
| Study design | <0.001 | ||||||||
| Single arm | 35 (24.8) | 10 (11.8) | 13 (48.2) | 4 (44.4) | 2 (40.0) | 2 (66.7) | 1 (50.0) | 3 (30.0) | |
| Parallel | 97 (68.8) | 72 (84.7) | 11 (40.7) | 4 (44.4) | 3 (60.0) | 1 (33.3) | 0 | 6 (60.0) | |
| Factorial | 3 (2.1) | 0 | 1 (3.7) | 1 (11.1) | 0 | 0 | 0 | 1 (10.0) | |
| Cross-over | 6 (4.3) | 3 (3.5) | 2 (7.4) | 0 | 0 | 0 | 1 (50.0) | 0 | |
| Phase | 0.024 | ||||||||
| Early stage | 70 (68.6) | 38 (65.5) | 21 (91.3) | 4 (50.0) | 1 (25.0) | 1 (50.0) | 2 (100.0) | 3 (60.0) | |
| Late stage | 32 (31.4) | 20 (34.5) | 2 (8.7) | 4 (50.0) | 3 (75.0) | 1 (50.0) | 0 | 2 (40.0) | |
| missing | 39 | 27 | 4 | 1 | 1 | 1 | 5 | ||
| Randomization | <0.001 | ||||||||
| No | 41 (29.1) | 13 (15.3) | 15 (55.6) | 4 (44.4) | 2 (40.0) | 3 (100.0) | 1 (50.0) | 3 (30.0) | |
| Yes | 100 (70.9) | 72 (84.7) | 12 (44.4) | 5 (55.6) | 3 (60.0) | 0 | 1 (50.0) | 7 (70.0) | |
| Blind | 0.022 | ||||||||
| Open label | 49 (34.8) | 17 (20.0) | 16 (59.3) | 5 (55.6) | 3 (60.0) | 3 (100.0) | 1 (50.0) | 4 (40.0) | |
| Single | 34 (24.1) | 23 (27.1) | 2 (7.4) | 1 (11.1) | 2 (40.0) | 0 | 1 (50.0) | 5 (50.0) | |
| Double | 32 (22.7) | 24 (28.2) | 7 (25.9) | 1 (11.1) | 0 | 0 | 0 | 0 | |
| Triple | 13 (9.2) | 11 (12.9) | 1 (3.7) | 0 | 0 | 0 | 0 | 1 (10.0) | |
| Quadruple | 13 (9.2) | 10 (11.8) | 1 (3.7) | 2 (22.2) | 0 | 0 | 0 | 0 | |
| Purpose | <0.001 | ||||||||
| Treatment | 106 (75.2) | 72 (84.7) | 15 (55.6) | 8 (88.9) | 5 (100.0) | 3 (100.0) | 1 (50.0) | 2 (20.0) | |
| Prevention | 19 (13.5) | 3 (3.5) | 11 (40.7) | 0 | 0 | 0 | 0 | 5 (50.0) | |
| Diagnostic | 5 (3.6) | 3 (3.5) | 0 | 0 | 0 | 0 | 0 | 2 (20.0) | |
| Supportive care | 5 (3.6) | 3 (3.5) | 0 | 1 (11.1) | 0 | 0 | 1 (50.0) | 0 | |
| Basic science | 3 (2.1) | 2 (2.4) | 0 | 0 | 0 | 0 | 0 | 1 (10.0) | |
| Screening | 1 (0.7) | 1 (1.2) | 0 | 0 | 0 | 0 | 0 | 0 | |
| Other | 2 (1.4) | 1 (1.2) | 1 (3.7) | 0 | 0 | 0 | 0 | 0 | |
| Treatment | <0.001 | ||||||||
| HM | 21 (19.8) | 17 (23.6) | 0 | 0 | 2 (40.0) | 0 | 0 | 2 (100.0) | |
| PDT | 17 (16.0) | 6 (8.3) | 6 (40.0) | 5 (62.5) | 0 | 0 | 0 | 0 | |
| GC | 14 (13.2) | 13 (18.1) | 0 | 0 | 1 (20.0) | 0 | 0 | 0 | |
| IM | 12 (11.3) | 11 (15.3) | 0 | 1 (12.5) | 0 | 0 | 0 | 0 | |
| DS | 10 (9.4) | 8 (11.1) | 1 (6.7) | 0 | 1 (20.0) | 0 | 0 | 0 | |
| NSAID | 7 (6.6) | 3 (4.2) | 4 (26.7) | 0 | 0 | 0 | 0 | 0 | |
| BO | 5 (4.7) | 3 (4.2) | 1 (6.7) | 0 | 0 | 0 | 1 (100.0) | 0 | |
| AM | 5 (4.7) | 4 (5.6) | 1 (6.7) | 0 | 0 | 0 | 0 | 0 | |
| SCT | 3 (2.8) | 0 | 0 | 0 | 0 | 3 (100.0) | 0 | 0 | |
| Surgery | 2 (1.9) | 1 (1.4) | 0 | 0 | 1 (20.0) | 0 | 0 | 0 | |
| Others | 10 (9.4) | 6 (8.3) | 2 (13.3) | 2 (25.0) | 0 | 0 | 0 | 0 | |
| Region | <0.001 | ||||||||
| American | 47 (33.3) | 15 (17.7) | 20 (74.1) | 7 (77.8) | 0 | 2 (66.7) | 2 (100.0) | 1 (10.0) | |
| European | 33 (23.4) | 25 (29.4) | 3 (11.1) | 1 (11.1) | 0 | 0 | 0 | 4 (40.0) | |
| African | 30 (21.3) | 27 (31.8) | 0 | 0 | 0 | 0 | 0 | 3 (30.0) | |
| Asian | 27 (19.2) | 17 (20.0) | 2 (7.4) | 1 (11.1) | 5 (100.0) | 0 | 0 | 2 (20.0) | |
| Multiple | 4 (2.8) | 1 (1.2) | 2 (7.4) | 0 | 0 | 1 (33.3) | 0 | 0 | |
| Center | 0.017 | ||||||||
| Single-center | 123 (87.2) | 78 (91.8) | 18 (66.7) | 8 (88.9) | 5 (100.0) | 2 (66.7) | 2 (100.0) | 10 (100.0) | |
| Multi-center | 18 (12.8) | 7 (8.2) | 9 (33.3) | 1 (11.1) | 0 | 1 (33.3) | 0 | 0 | |
| Funder | 0.033 | ||||||||
| NIH | 10 (7.1) | 3 (3.5) | 7 (25.9) | 0 | 0 | 0 | 0 | 0 | |
| Industry | 5 (3.6) | 2 (2.4) | 2 (7.4) | 0 | 0 | 0 | 0 | 1 (10.0) | |
| Others | 126 (89.4) | 80 (94.1) | 18 (66.7) | 9 (100.0) | 5 (100.0) | 3 (100.0) | 2 (100.0) | 9 (90.0) |
Except where indicated otherwise, values are the number (%).
Abbreviations: OLP, oral lichen planus; OLK, oral leukoplakia; AC, actinic cheilitis; OSF, oral submucous fibrosis; DC, dyskeratosis congenita; EB, epidermolysis bullosa; HM, herbal medicine; PDT, photodynamic therapy; GC, glucocorticoid; IM, immunotherapy; DS, dietary supplement; BO, biologics; AM, antimicrobial; SCT, stem cell transplantation.
Although the purposes of studies on different disease types varied, the majority of studies still aimed for treatment (50%–100 %), except for mixed-type disease studies (20 %). Subsequently, we extracted data from 106 interventional studies with the purpose of treatment for deeper analysis. In terms of treatment, the public showed higher interest in herbal medicine (21, 19.81 %), photodynamic therapy (17, 16.04 %), glucocorticoid (14, 13.21 %), immunotherapy (12, 11.32 %), dietary supplement (10, 9.43 %). Herbal medicine was primarily used in the treatment of OLP and OSF. Notably, OLP studies employed the most diverse types of treatment, including photodynamic therapy, glucocorticoids, immunotherapy, dietary supplements, NSAID, biologics, antimicrobials, surgery and other treatments.
3.4. Publication status of primary completed studies
Among 92 primary completed interventional studies, 58 (63.0 %) were published, containing 50 (86.2 %) positive primary outcomes and 16 (27.6 %) with impact factors (IFs) over 5. Additionally, 56.0 % (14/25) of completed observational studies were published, containing 12 (85.7 %) with positive primary outcomes, but only 2 (14.3 %) with IFs over 5 (Table 3). According to Fig. 2, the number of publications, to our delight, has been increasing in the past decade, providing the public with greater access to contemporary clinical trials on OPMDs.
Table 3.
Study characteristic comparisons by publication status among primary completed intervational studies.
| Overall (n = 92) | No publication (n = 34) | Publication (n = 58) | p-value | |
|---|---|---|---|---|
| PrimaryDuration | 19.5 (11.7, 37.9) | 19.0 (12.0, 45.8) | 19.5 (11.4, 32.0) | 0.596 |
| Register | 0.603 | |||
| Before study start | 20 (21.7) | 6 (17.7) | 14 (24.1) | |
| After study start | 72 (78.3) | 28 (82.3) | 44 (75.9) | |
| Year of study registered | 0.004 | |||
| 1999–2005 | 13 (14.1) | 9 (26.5) | 4 (6.9) | |
| 2006–2010 | 16 (17.4) | 6 (17.7) | 10 (17.2) | |
| 2011–2015 | 19 (20.7) | 6 (17.7) | 13 (22.4) | |
| 2016–2020 | 31 (33.7) | 5 (14.7) | 26 (44.8) | |
| 2021–2024 | 13 (14.1) | 8 (23.5) | 5 (8.6) | |
| Age | 0.605 | |||
| Without child | 73 (79.3) | 26 (76.5) | 47 (81.0) | |
| With child | 19 (20.7) | 8 (23.5) | 11 (19.0) | |
| Sample size | 0.435 | |||
| ≤50 | 63 (70.0) | 20 (62.5) | 43 (74.1) | |
| 51–100 | 22 (24.4) | 10 (31.3) | 12 (20.7) | |
| >100 | 5 (5.6) | 2 (6.2) | 3 (5.2) | |
| missing | 2 | 2 | ||
| Disease types | 0.001 | |||
| OLP | 61 (66.3) | 16 (47.1) | 45 (77.6) | |
| OLK | 17 (18.5) | 12 (35.3) | 5 (8.6) | |
| AC | 4 (4.3) | 3 (8.8) | 1 (1.7) | |
| OSF | 4 (4.3) | 0 | 4 (6.9) | |
| DC | 1 (1.1) | 0 | 1 (1.7) | |
| EB | 1 (1.1) | 0 | 1 (1.7) | |
| Mixed | 4 (4.3) | 3 (8.8) | 1 (1.7) | |
| Study design | 0.214 | |||
| Single arm | 17 (18.5) | 9 (26.5) | 8 (13.8) | |
| Parallel | 70 (76.1) | 23 (67.6) | 47 (81.0) | |
| Factorial | 2 (2.2) | 0 | 2 (3.5) | |
| Cross-over | 3 (3.3) | 2 (5.9) | 1 (1.7) | |
| Phase | 1.000 | |||
| Early stage | 45 (67.2) | 16 (69.6) | 29 (65.9) | |
| Late stage | 22 (32.8) | 7 (30.4) | 15 (34.1) | |
| missing | 25 | 11 | 14 | |
| Purpose | 0.264 | |||
| Treatment | 76 (82.6) | 26 (76.5) | 50 (86.2) | |
| Others | 16 (17.4) | 8 (23.5) | 8 (13.8) | |
| Treatment | 0.007 | |||
| HM | 16 (21.1) | 3 (11.5) | 13 (26.0) | |
| PDT | 15 (19.7) | 8 (30.8) | 7 (14.0) | |
| IM | 9 (11.8) | 1 (3.8) | 8 (16.0) | |
| GC | 8 (10.5) | 2 (7.7) | 6 (12.0) | |
| DS | 7 (9.2) | 5 (19.2) | 2 (4.0) | |
| NSAID | 6 (7.9) | 4 (15.4) | 2 (4.0) | |
| BO | 4 (5.3) | 1 (3.8) | 3 (6.0) | |
| AM | 3 (3.9) | 2 (7.7) | 1 (2.0) | |
| SCT/surgery/others | 8 (10.5) | 0 | 8 (16.0) | |
| Randomization | 0.801 | |||
| No | 22 (23.9) | 9 (26.5) | 13 (22.4) | |
| Yes | 70 (76.1) | 25 (73.5) | 45 (77.6) | |
| Blind | 0.486 | |||
| Open Label | 28 (30.4) | 12 (35.3) | 16 (27.6) | |
| Blind | 64 (69.6) | 22 (64.7) | 42 (72.4) | |
| Region | 0.048 | |||
| American | 28 (30.4) | 16 (47.1) | 12 (20.7) | |
| European | 23 (25.0) | 6 (17.7) | 17 (29.3) | |
| African | 22 (23.9) | 8 (23.5) | 14 (24.1) | |
| Asian | 17 (18.5) | 3 (8.8) | 14 (24.1) | |
| Multiple | 2 (2.2) | 1 (2.9) | 1 (1.7) | |
| Center (n,%) | 1.000 | |||
| Single-center | 83 (90.2) | 31 (91.2) | 52 (89.7) | |
| Multi-center | 9 (9.8) | 3 (8.8) | 6 (10.3) | |
| Funder (n,%) | 0.019 | |||
| NIH | 8 (8.7) | 6 (17.6) | 2 (3.5) | |
| Industry | 3 (3.3) | 2 (5.9) | 1 (1.7) | |
| Others | 81 (88.0) | 26 (76.5) | 55 (94.8) | |
| Primary outcome | ||||
| Negative | 8 (13.8) | |||
| Positive | 50 (86.2) | |||
| IFgroup | ||||
| <5 | 22 (37.9) | |||
| 5–9.99 | 11 (19.0) | |||
| ≥10 | 5 (8.6) | |||
| missing | 20 | |||
Abbreviations: OLP, oral lichen planus; OLK, oral leukoplakia; AC, actinic cheilitis; OSF, oral submucous fibrosis; DC, dyskeratosis congenita; EB, epidermolysis bullosa; HM, herbal medicine; PDT, photodynamic therapy; GC, glucocorticoid; IM, immunotherapy; DS, dietary supplement; BO, biologics; AM, antimicrobial; SCT, stem cell transplantation.
The median times to publication of interventional and observational studies were 33.6 months (95 % CI = 24.4–46.9) and 19.7 months (95 % CI = 10.9-NA), respectively. The 1, 2, and 3-year cumulative publication rates were 17.8 %, 36.7 % and 54.8 % for interventional studies, 35.4 %, 54.9 % and 66.2 % for observational studies (Fig. 3).
Fig. 3.
Cumulative publication rate curve of primary completed studies.
Comparing to unpublished interventional studies, published interventional studies were more often registered between 2016 and 2020 and conducted in European and Asian, were less often funded by NIH, included more OLP patients, had less PDT (Table 3). Univariable and multivariable Cox regressions analyses for publication among primary completed interventional studies are shown in Table 4. Studies registered after 2016, involving OLP patients, using factorial design, conducted outside of America or funded by others had less time to publication (less than 30 months). However, in multivariate Cox analysis, only study design and disease type were found to be significant factors.
Table 4.
Univariable and multivariable Cox regressions for publication among primary completed interventional studies (n = 92).
| Median TTPa (mo.) | Univariable |
Multivariable |
|||
|---|---|---|---|---|---|
| HR (95 % CI) | p-value | HR (95 % CI) | p-value | ||
| Duration of primary completed (mo.) | 33.6 | 0.99 (0.98, 1.00) | 0.211 | ||
| Register | |||||
| After study start | 35.0 | 1.00 | 0.118 | ||
| Before study start | 21.6 | 1.62 (0.89, 2.97) | |||
| Year of study registered | |||||
| 1999–2005 | NA | 1.00 | 1.00 | ||
| 2006–2010 | 34.0 | 2.82 (0.88, 9.02) | 0.080 | 1.79 (0.47, 6.72) | 0.394 |
| 2011–2015 | 42.1 | 2.98 (0.97, 9.18) | 0.057 | 1.35 (0.36, 5.08) | 0.660 |
| 2016–2020 | 17.1 | 6.29 (2.16, 18.33) | 0.001 | 3.38 (0.96, 11.91) | 0.058 |
| 2021–2024 | 24.0 | 4.74 (1.23, 18.27) | 0.024 | 2.44 (0.52, 11.42) | 0.257 |
| Sample size | |||||
| ≤50 | 28.1 | 1.00 | |||
| 51-100 | 88.0 | 0.61 (0.32, 1.16) | 0.135 | ||
| >100 | 47.0 | 0.69 (0.22, 2.24) | 0.542 | ||
| Age | |||||
| Without child | 33.6 | 1.00 | |||
| With child | 33.2 | 0.90 (0.47, 1.74) | 0.759 | ||
| Disease type | |||||
| Others | NA | 1.00 | 1.00 | ||
| OLP | 28.1 | 2.46 (1.32, 4.60) | 0.005 | 2.45 (1.16, 5.17) | 0.019 |
| Study Design | |||||
| Single arm | NA | 1.00 | 1.00 | ||
| Parallel | 31.2 | 2.41 (1.01, 4.53) | 0.048 | 0.84 (0.33, 2.10) | 0.703 |
| Factorial | 1.0 | 17.49 (3.45, 88.77) | 0.001 | 20.46 (3.28, 127.69) | 0.001 |
| Cross-over | NA | 0.82 (0.10, 6.55) | 0.851 | 0.30 (0.03, 2.70) | 0.286 |
| Phase | |||||
| Early stage | 33.6 | 1.00 | |||
| Late stage | 33.0 | 1.16 (0.62, 2.16) | 0.644 | ||
| Purpose | |||||
| Others | 47.0 | 1.00 | |||
| Treatment | 31.2 | 1.83 (0.86, 3.86) | 0.114 | ||
| Treatment | |||||
| HM | 33.6 | 1.00 | |||
| PDT | NA | 0.56 (0.22, 1.42) | 0.224 | ||
| IM | 24.2 | 1.61 (0.61, 4.27) | 0.339 | ||
| GC | 15.9 | 1.21 (0.50, 2.93) | 0.674 | ||
| DS | 33.2 | 0.64 (0.14, 2.85) | 0.560 | ||
| NSAID | NA | 0.32 (0.07, 1.42) | 0.134 | ||
| BO | 13.8 | 1.39 (0.39, 4.89) | 0.610 | ||
| AM | NA | 0.22 (0.03, 1.71) | 0.148 | ||
| SCT/surgery/others | 12.0 | 1.66 (0.69, 4.01) | 0.261 | ||
| Randomization | |||||
| No | 46.9 | 1.00 | |||
| Yes | 31.2 | 1.39 (0.75, 2.59) | 0.294 | ||
| Blind | |||||
| Open Label | 46.9 | 1.00 | |||
| Blind | 31.2 | 1.31 (0.74, 2.34) | 0.359 | ||
| Region | |||||
| American | NA | 1.00 | |||
| European | 28.1 | 2.25 (1.07, 4.74) | 0.032 | 1.16 (0.48, 2.79) | 0.746 |
| African | 21.6 | 2.25 (1.17, 5.57) | 0.019 | 0.96 (0.37, 2.51) | 0.931 |
| Asian | 29.1 | 2.65 (1.22, 5.77) | 0.014 | 1.07 (0.43, 2.67) | 0.879 |
| Multiple | 28.8 | 1.23 (0.16, 9.48) | 0.845 | 1.01 (0.09, 11.66) | 0.995 |
| Center | |||||
| Single-center | 33.0 | 1.00 | |||
| Multi-center | 46.9 | 0.94 (0.40, 2.19) | 0.882 | ||
| Funder | |||||
| NIH | NA | 1.00 | |||
| Industry | NA | 1.50 (0.14, 16.53) | 0.741 | 1.14 (0.07, 18.79) | 0.927 |
| Others | 29.1 | 5.36 (1.30, 22.07) | 0.020 | 2.62 (0.49, 14.03) | 0.260 |
Abbreviations: TTP, time to publication; mo., months; NA, not available, OLP, oral lichen planus; HM, herbal medicine; PDT, photodynamic therapy; GC, glucocorticoid; IM, immunotherapy; DS, dietary supplement; BO, biologics; AM, antimicrobial; SCT, stem cell transplantation.
The median times to publication were estimated by Kaplan-Meier method.
4. Discussion
To our knowledge, this study represents the most systematic evaluation and overview of clinical studies on OPMDs, providing high-level evidence based on the data extracted from the ClinicalTrials.gov database. We identified 185 relevant studies for a detailed analysis, comparing observational studies and interventional studies, and examining factors that might influence publication. During our review, five search terms—“Discoid Lupus Erythematosus (DLE)”, “Oral Erythroplakia (OE)”, “Proliferative Verrucous Leukoplakia (PVL)”, “Oral Lichenoid Lesion (OLL)”, and “Palatal Lesions in Reverse Smokers”—were excluded. Initially, 36 studies on DLE were identified; however, none were oral-relevant upon closer examination. DLE is predominantly considered as a skin disease, with diagnostic criteria and treatment guidelines defined by dermatology experts [23]. Mucosal discoid lupus erythematosus occurs in 3 %–25 % of DLE patients [24], usually involved in systemic dermatologic treatment, with few treatments specifically targeting oral lesions. Therefore, future studies focusing on oral lesions in DLE are recommended. For OE, all relevant studies overlapped with studies in OLP, OLK, OPMDs and AC, likely because OE is traditionally described as the red counterpart of oral leukoplakia [25].
Numerous studies have analyzed the landscape of clinical trials for various diseases using medical trial registration databases. Existing studies, including those involving OPMDs patients, primarily emphasize clinical outcomes based on databases like ClinicalTrials.gov, [26,27]. These studies have assessed the results to ascertain whether specific treatment methods or diagnostic approaches provide significant guidance for clinical practice. In contrast, we are the first to specifically focus on clinical studies related to OPMDs, examining the overall research landscape, its characteristics, and the publication of results.
Most OSF studies were conducted in Asian countries, except for one, due to the high prevalence of OSF among Asians who chew betel quid products [28]. AC is associated with solar radiation, resulting in a higher incidence in tropical countries and among outdoor workers [29]. However, the number of registered studies on AC remains low, possibly because histopathological confirmation is rather laborious, making biopsy not usually recommended for AC diagnosis [3]. While the prevalence of AC is highest in Asia (10.54 %) [3], most clinical trials were carried out in US/Canada and Brazil, likely due to the stringent registration and transparency requirements of the ClinicalTrials.gov database, managed by US federal organizations such as the FDA and NIH. This focus may introduce a location bias in our study. Solely based on ClinicalTrials.gov database, our study may have a location bias.
Our research revealed that many clinical trials are in early phases and single-center with small sample sizes (Table 1), highlighting limitations and orientation needing improvement. Early-phase clinical trials (phase I and II), are typically small and single-center, economizing resources but providing limited evidence compared to well-designed, randomized, multi-center, phase III trials. Proper sample size planning is crucial to avoiding resources waste or compromising results [30,31]. Additionally, although there has been an upward trend in registrations in recent years, many trials are registered post-study start, which contradicts the 2004 advocacy by the International Committee of Medical Journal Editors (ICMJE) [32,33]. We also found information inconsistencies between ClinicalTrials.gov database and published literature, underscoring the need for improved transparency and supervision of clinical trials.
There is a notable divergence in therapy distribution across diseases. PDT was the predominant therapy for AC, consistent with its favorable therapeutic profile despite higher recurrence rates [34,35]. The significant use of herbal medicine in OLP studies might be correlated with the high prevalence of OLP in Africa and the region's long history of herbs application [36].
Anti-inflammatory therapies have been proved to reduce carcinogenesis for its characteristic of reducing angiogenesis, proliferation, metastasis and increasing the response to the immune system [[37], [38], [39]]. Given its key role in precancerous lesion's development and progression, anti-inflammatory therapy has been put into wide application on OPMDs patients over the past decades and showed excellent therapeutic potential [40,41]. In our comprehensive analysis, more than 30 % of the interventional studies concentrated on anti-inflammatory therapy including glucocorticoid, immunotherapy and NSAID for OPMDs, especially for OLP. Notably, studies combining corticosteroids with supplements like zinc (NCT04278599), vitamin E (NCT04126720), and glutamine (NCT04442633) showed promising outcomes in OLP patients, suggesting a potential for improved treatments [[42], [43], [44], [45], [46]]. However, not all combinations are effective, as seen with the use of miconazole with corticosteroid [47], indicating a need for further research. As far as we have known, the common mechanism of the three supplements is their anti-oxidant and anti-inflammatory properties. In recent years, the increase of oxidative stress is related to the pathogenesis of erosive oral lichen planus. If it can be proven to be effective with more clinical trials and higher-level evidence in the future, antioxidants can be used as a safer alternative of long-term use of NSAIDs or other medicine for therapy with adverse reactions [46,48].
Another efficacious substitution of glucocorticoids is herbal medicine. Though herbal medicine is not considered to be a first-line treatment method for clinical application [49], it has attracted growing attention, with a significant increase in research quantity. In consideration of their anti-inflammatory, anti-oxidant, and anti-carcinogenesis properties, it's rational to consider that herbal medicine is effective in other autoimmune conditions where glucocorticosteroids are applied [50]. Compared with the side‐effects of glucocorticosteroids – candidiasis, diabetes mellitus, adrenal insufficiency, herbal medicine is safer and also possesses the merit of availability and low cost [51,52]. These results indicate another promising alternative and more clinical trials evaluating herbal medicine in other autoimmune diseases are supposed to be considered in the future [50].
Timely dissemination of clinical trial results is crucial for public benefit [53], yet many findings remain unpublished years after study completion [[54], [55], [56], [57]]. Our study found that only 63.0 % of primary completed interventional studies were eventually published, with an increasing trend over the past few decades. Resources limitation, time restrictions, changed interests, inadequate advocation for negative findings dissemination were potential reasons of the postponement or non-publication [53]. Positive primary outcomes were more likely to be published, while negative results often faced delays or suppression [58]. Hence, it is essential to mandate the release of all study results, regardless of outcome, to accelerate knowledge dissemination [59].
Inevitably, our study has certain limitations. In spite of the ClinicalTrials.gov database serving as the oldest and largest platform that allows clinical trials from all over the world to register and meets the ICMJE registration requirements, there are some other registry platforms as well [60]. Therefore, our research included the potential selection bias. In addition, the information on ClinicalTrials.gov database is absent in some columns, not invariably up-to-date and inconsistent with the detailed descriptions in published literature, all of which may weaken our evidence. Moreover, we are unable to completely eliminate the probability of errors due to certain data not being obtained or misclassified during the whole procedure. Despite these limitations, our comprehensive analysis provides valuable insights into research quality and publication trends in OPMDs, emphasizing the need for improved trial design, registration, and result dissemination.
5. Conclusion
Overall, OLP-related studies account for the largest proportion of disease types, with herbal medicine being the most frequently studied treatment, followed by photodynamic therapy and glucocorticoids. There is a need for more high-quality, randomized, late-phase clinical trials and timely publication of results. Improvements in ClinicalTrials.gov registration standards, study design quality and publishing requirements are essential for the future advancements.
CRediT authorship contribution statement
Lijian Zhao: Writing – review & editing, Writing – original draft, Methodology, Data curation, Conceptualization. Yuqing Qu: Writing – original draft, Methodology, Conceptualization. Yanshu Zhang: Writing – original draft, Conceptualization. Zhaolei Zou: Formal analysis. Jingyi Lu: Data curation. Zhi Wang: Writing – review & editing, Supervision. Bin Li: Writing – review & editing, Supervision, Methodology, Formal analysis, Data curation. Juan Fang: Writing – review & editing, Supervision, Funding acquisition, Conceptualization.
Ethics committee approval
Not required.
Data availability statement
All raw data were sourced from the ClinicalTrials.gov database, with the corresponding NCT numbers provided in the supplementary materials. Also, the data supporting the findings of this study are available from the corresponding author upon request.
Funding statement
This article was supported by National Natural Science Foundations of China (No. 82101017); Guangdong Basic and Applied Basic Research Foundation (2022A1515010771); Innovative Entrepreneurship Training Program for College Students (202310765, 20240531).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
We would like to thank all researchers of the included studies.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e39408.
Contributor Information
Lijian Zhao, Email: zhaolj25@mail2.sysu.edu.cn.
Bin Li, Email: libin48@mail.sysu.edu.cn.
Juan Fang, Email: fangj6@mail2.sysu.edu.cn.
Appendix A. Supplementary data
The following are the Supplementary data to this article.
Disease types distribution by registered year.
Abbreviations: AC, actinic cheilosis; DC, Dyskeratosis congenita; EB, epidermolysis bullosa; OLK, oral leukoplakia; OLP, oral lichen planus; OSF, oral submucous fibrosis.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Disease types distribution by registered year.
Abbreviations: AC, actinic cheilosis; DC, Dyskeratosis congenita; EB, epidermolysis bullosa; OLK, oral leukoplakia; OLP, oral lichen planus; OSF, oral submucous fibrosis.
Data Availability Statement
All raw data were sourced from the ClinicalTrials.gov database, with the corresponding NCT numbers provided in the supplementary materials. Also, the data supporting the findings of this study are available from the corresponding author upon request.