Effectiveness and Safety of a Supplement Containing a Pharmacologically Active Basidiomycete Mushroom for Chronic Fatigue and Post-COVID-19 Fatigue Syndrome: Protocol for a Randomized Controlled Trial.

Chronic fatigue syndrome (myalgic encephalomyelitis) is diagnostically complex due to symptom overlap with other disorders and absence of definitive biomarkers, contributing to limited therapeutic options.

• The condition is characterized by persistent, unexplained exhaustion unalleviated by rest.
• Its pathophysiology is described as distinct from underlying medical conditions.
• The lack of definitive biomarkers contributes to diagnostic complexity.

The trial is designed as a randomized, waitlist-controlled study enrolling 130 participants in Hong Kong equally allocated to intervention or waitlist control groups.

• Allocation ratio is 1:1 between CP003 intervention group and waitlist control group.
• The trial is registered at ClinicalTrials.gov (NCT06739720).
• As of December 2025, all participants had been enrolled but data entry had not yet commenced.
• The study was funded in March 2024 (ITF/PRP/029/24FX).

The intervention consists of a 6-week intake of CP003, a lingzhi-containing supplement, followed by a 6-week follow-up phase.

• The intervention period spans 6 weeks.
• A 6-week follow-up phase is included to assess sustained effects.
• Lingzhi is described as a pharmacologically active basidiomycete mushroom used in traditional Chinese medicine for two millennia.

The primary outcome is reduction of physical and mental fatigue in patients with chronic fatigue syndrome or post-COVID-19 fatigue.

• The trial has a dual focus: evaluating efficacy and safety of lingzhi and elucidating clinical associations with inflammatory, immune, and oxidative stress biomarkers.
• Secondary objectives include assessing effects on sleep quality, anxiety, depression, and general health status.
• Biomarker associations are explored to uncover potential therapeutic mechanisms.

The statistical analysis plan uses an intention-to-treat approach with inverse probability weighting for missing data and generalized linear regression.

• Analysis will be conducted at 6 and 12 weeks.
• Models will be adjusted for covariates and interaction terms.
• Results will be reported as mean differences with 95% CIs, with P<.05 considered significant.
• Subgroup and sensitivity analyses will be performed in R.
• Trial data will be managed using REDCap (Research Electronic Data Capture).

Results from the trial are expected to be submitted for publication in mid-2026, with safety outcomes also to be assessed and reported.

• Data analysis will commence after completion of the 12-week follow-up for all participants.
• Safety outcomes will be assessed and reported alongside efficacy findings.
• The findings are anticipated to provide experimental data to inform future clinical applications and research on traditional Chinese medicine-based interventions for fatigue-related disorders.