A randomized controlled trial protocol of herbal formulas for modifying susceptible body constitution to enhance COVID-19 resistance in Hong Kong residents.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), triggers symptoms including fever, persistent cough, and respiratory distress. By the week ending May 10, 2025, the Centre for Health Protection of Hong Kong reported a COVID-19 sample positivity rate of 13.66%, with XDV and NB.1.8.1 as the dominant circulating strains. Despite widespread vaccination and hybrid immunity in Hong Kong, breakthrough and reinfections remain common in vulnerable populations. Despite the long history of traditional Chinese medicine (TCM) and its proven effectiveness in epidemic control, its preventive measures against COVID-19, which have been widely adopted in mainland China, have yet to be integrated into Hong Kong's healthcare system. This study proposes a constitution-targeted preventive approach using TCM herbal formulas for Hong Kong residents at high risk of COVID-19 infection. METHODS: We plan to implement a randomized, forward-looking, quadruple-blind study. Participants with Qi-Yang deficiency or Qi-Yin deficiency will be stratified and allocated to one of four groups, and receive oral herbal granules/placebo at a dosage of 5 grams, twice daily, for a consecutive four-week intervention with TCM formulas customized to their specific TCM body constitution. The primary outcomes will be evaluated using TCM-based self-assessment tools, symptom questionnaires, and a fatigue scale. Secondary outcomes will consist of a detailed questionnaire survey to identify demographic and health factors related to increased vulnerability to COVID-19. The trial adopts a quadruple-blind design (participant, care provider, investigator, outcomes assessor) with allocation concealment implemented via sequentially numbered, opaque, sealed envelopes (SNOSE); the randomization sequence is generated by an independent statistician using random.org and stored in a password-protected central web-based system, with only the unblinded pharmacist having access to the allocation list for drug dispensing. Data management will prioritize confidentiality and data integrity, with statistical analyses conducted using R or SPSS software. Safety outcomes will be analyzed using descriptive statistics (incidence rate, severity grade) and the Chi-squared test/Fisher's exact test for comparing adverse event rates between groups, while continuous safety indicators will be analyzed using the independent samples t-test. DISCUSSION: TCM offers a significant holistic paradigm for immune modulation and epidemic prevention. People with Qi-Yang deficiency and Qi-Yin deficiency are at a higher risk of SARS-CoV-2 infection due to impaired innate and adaptive immune function. We hypothesize that customized herbal formula interventions for Qi-Yang and Qi-Yin deficiency constitutions will significantly improve TCM constitution scores and reduce fatigue in Hong Kong residents, and potentially lower COVID-19 infection risk by modulating inflammatory and immune biomarkers, providing a localized TCM preventive strategy for COVID-19 in Hong Kong. The core TCM strategy for preventing COVID-19 is to "invigorate Qi and Yang, as well as to invigorate Qi and Yin" to enhance the body's resistance to pathogenic factors. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04668222, Registered on 28 April 2021.