METHODS: Online databases (PubMed, Scopus, Web of Science, ProQuest, and Google Scholar) were searched from date of inception till May 2020. Studies were included if they met the following criteria: 1) observational studies that assessed the relationship between EBV and OLP, 2) the study comprised OLP patients and control subjects, 3) diagnosis of OLP was confirmed histopathologically, and 4) articles were in English. Studies without control groups, experimental studies, case reports, and reviews were excluded. The fixed-effects model was performed for meta-analyses using RevMan 5.3 software.

MATERIALS AND METHODS: PubMed, Scopus, Web of Science, Google Scholar, and ProQuest were searched up to June 7, 2023. All relevant clinical trials were included. RevMan software was used for the statistical analyses.

RESULTS: Elven randomized clinical trials (460 DS patients) were included. Eight studies assessed the efficacy of PDT vs. topical antifungal therapy, while three studies assessed the adjunctive use of PDT (PDT + antifungal therapy) vs. topical antifungal therapy alone. The results revealed comparable efficacy of PDT and conventional antifungal therapy on candida colonization at 15 days (MD: 0.95, 95% CI: -0.28, 2.19, p = 0.13) and at the end of follow-up (MD: -0.17, 95% CI: -1.33, 0.98, p = 0.77). The pooled two studies revealed relatively better efficacy of adjunctive use of PDT with antifungal therapy on candida colonization compared to antifungal therapy alone at 15 days (MD: -6.67, 95% CI: -15.15, 1.82, p = 0.12), and at the end of follow-up (MD: -7.14, 95% CI: -19.78, 5.50, p = 0.27). Additionally, the results revealed comparable efficacy of PDT and topical antifungal therapy on the clinical outcomes.

TRIAL DESIGN: The study is a randomized, placebo-controlled, adaptive clinical trial with parallel group design, superiority framework with an allocation ratio of 1:1 among experimental (HNS) and placebo group. An interim analysis will be done when half of the patients have been recruited to evaluate the need to adapt sample size, efficacy, and futility of the trial.

PARTICIPANTS: All asymptomatic patients with hospital or community based COVID-19 exposure will be screened if they have had 4 days exposure to a confirmed case. Non-pregnant adults with significant exposure level will be enrolled in the study High-risk exposure (<6 feet distance for >10min without face protection) Moderate exposure (<6 feet distance for >10min with face protection) Subjects with acute or chronic infection, COVID-19 vaccinated, and allergy to HNS will be excluded from the study. Recruitment will be done at Shaikh Zayed Post-Graduate Medical Institute, Ali Clinic and Doctors Lounge in Lahore (Pakistan).

INTERVENTION AND COMPARATOR: In this clinical study, patients will receive either raw natural honey (0.5 g) and encapsulated organic Nigella sativa seeds (40 mg) per kg body weight per day or empty capsule with and 30 ml of 5% dextrose water as a placebo for 14 days. Both the natural products will be certified for standardization by Government College University (Botany department). Furthermore, each patient will be given standard care therapy according to version 3.0 of the COVID-19 clinical management guidelines by the Ministry of National Health Services of Pakistan.

MAIN OUTCOMES: Primary outcome will be Incidence of COVID-19 cases within 14 days of randomisation. Secondary endpoints include incidence of COVID-19-related symptoms, hospitalizations, and deaths along with the severity of COVID-19-related symptoms till 14th day of randomization.

RANDOMISATION: Participants will be randomized into experimental and control groups (1:1 allocation ratio) via the lottery method. There will be stratification based on high risk and moderate risk exposure.

BLINDING (MASKING): Quadruple blinding will be ensured for the participants, care providers and outcome accessors. Data analysts will also be blinded to avoid conflict of interest. Site principal investigator will be responsible for ensuring masking.

NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 1000 participants will be enrolled in the study with 1:1 allocation.

TRIAL STATUS: The final protocol version 1.4 was approved by institutional review board of Shaikh Zayed Post-Graduate Medical Complex on February 15, 2021. The trial recruitment was started on March 05, 2021, with a trial completion date of February 15, 2022.

TRIAL REGISTRATION: Clinical trial was registered on February 23, 2021, www.clinicaltrials.gov with registration ID NCT04767087 .