Inclusion criteria.

The inclusion criteria are as follows:

• Individuals aged > 19 years who have been diagnosed with COVID-19 for a minimum duration of 12 weeks or exhibit persistent fatigue that was not present before COVID-19 diagnosis for > 4 weeks.
• Individuals scoring > 4 points on the Fatigue Severity Scale (FSS).
• Individuals experiencing fatigue not attributable to another medical condition.
• Participants demonstrating no overall cognitive function issues who willingly provide written consent for study participation.

Exclusion criteria.

• Individuals with diagnosed diseases that may lead to fatigue, such as cancer, insomnia, chronic hepatitis, liver cirrhosis, chronic renal failure, active tuberculosis, latent tuberculosis, asthma, multiple sclerosis, and other similar conditions, but not limited to those specifically mentioned.
• Individuals experiencing medical issues affecting drug intake or absorption (dysphagia, clinically significant digestive disorders, galactose intolerance, Lapp lactase deficiency, or glucose–galactose malabsorption).
• Individuals with uncontrolled diabetes (HbA1c ≥  6.5%).
• Individuals with uncontrolled hypertension (systolic blood pressure ≥  160 mmHg or diastolic blood pressure ≥  100 mmHg).
• Individuals with current or past allergies to the investigational drug (Kyungok-go).
• Individuals diagnosed with liver or kidney disease or exhibiting abnormal liver and kidney function blood test results (AST, ALT, BUN, or creatinine exceeding twice the upper limit of normal).
• Pregnant, potentially pregnant, or lactating women.
• Individuals who do not consent to using contraception.
• Individuals who participated in another clinical study within 30 days before joining this study.
• Individuals experiencing symptoms of appetite loss, aversion, or vomiting.
• Individuals who consumed herbal or traditional medicines, over-the-counter drugs, nonprescription medications, vitamin supplements, health functional foods, or any substances that could affect fatigue within the month prior to the clinical trial.
• Individuals who have taken medications that can affect fatigue within 30 days before participating in the clinical trial (corticosteroids within 1 month of the final dose, immunosuppressants within 3 months of the final dose, antipsychotic drugs within 1 month of the final dose, hormone preparations within 1 month of the final dose).
• Individuals who have undergone organ or bone marrow transplantation.
• Individuals who have undergone procedures (such as surgery) within the past 3 months that may impact fatigue.
• High-risk alcohol consumers (>7 drinks per occasion for men or > 5 drinks per occasion for women, where one drink is equivalent to 4 cans of beer, 4 bowls of makgeolli, 4 glasses of wine, 1 bottle of soju, or 4 glasses of whiskey for men and three cans of beer, three bowls of makgeolli, three glasses of wine, 3/4 bottle of soju, or 3 glasses of whiskey for women).
• Long-term smokers (>1 pack daily for > 10 years).
• Individuals with clinically significant psychiatric symptoms, medical conditions, or laboratory findings that will make study participation challenging, as judged by the researcher.

Withdrawal and discontinuation criteria.

• Severe acute reaction (allergy, hypersensitivity, and others) to the intervention.
• Confirmation of a major violation of the inclusion/exclusion criteria during the trial.
• Inability to take the intervention or make observations due to unexpected diseases or accidents.
• Inability to take the intervention or make observations due to severe adverse events or adverse drug reactions.
• Pregnancy diagnosis.
• Withdrawal of informed consent by the participant or their representative.
• Significant deviations from the clinical trial protocol.
• Emergence of new conditions during the clinical trial period that may impact fatigue (e.g., SARS-CoV-2 reinfection).
• Trial continuation deemed inappropriate by the researchers.

Primary outcome.

The primary outcome will involve evaluating and comparing FSS scores between the two groups following intervention administration over a period of up to 12 weeks. The FSS questionnaire, which assesses fatigue in the past week, will be directly administered to the subject under the direction of the research director or person in charge [21]. It consists of nine questions. Each question is evaluated on a scale of 1–7, and the more severe the symptoms, the higher the score. The FSS score is then calculated as the average of the scores of nine items. Based on the treatment guidelines for long COVID and clinical research results, a score greater than 4 points indicates that the person has significant fatigue symptoms [22]. Fatigue during the past week before (Visit 1) and after herbal medicine administration (Visit 4) will be assessed, and comparative analyses will be conducted to compare the two study groups.

Secondary outcomes.

The selection of secondary outcome measures was based on the complex and multifaceted nature of fatigue in long COVID [23]. Post-COVID fatigue is closely interconnected with various physical, cognitive, and psychological manifestations that can affect and exacerbate fatigue symptoms [24]. Specifically, the inclusion of cognitive function assessments is justified by the established relationship between cognitive dysfunction and fatigue in long COVID. Also, research has demonstrated that depression and sleep problems are not only common comorbidities but can also amplify fatigue symptoms in long COVID patients [25]. These comprehensive secondary outcome measures will not only help validate the primary findings but also provide valuable insights into the various mechanisms through which Kyungok-go may affect fatigue and related symptoms in long COVID patients.

Medication adherence.

Medication adherence will be meticulously tracked by assessing the number of returned and taken medications during each visit. In instances where the count of returned and taken drugs deviates from the number of prescribed drugs, the reasons for this disparity will be methodically documented in the case report form. The medication adherence rate will be calculated as a percentage using the following formula:

*The number of prescribed medications in the duration refers to the medication intended for consumption from the time of initial administration until the return of any untaken drugs.

Medication adherence (%) will be calculated and documented at Visits 2, 3, and 4 (or the endpoint of medication). Descriptive statistics, including the mean, standard deviation, median, and minimum and maximum values of the final medication adherence assessment (Visit 4 or the endpoint of medication), will be presented for each intervention group and then analyzed and compared to identify any significant differences between the two groups.

Fatigue severity scale.

FSS scores will be compared between the two groups at Visits 2 and 3.

Chalder fatigue scale.

The Korean version of the Chalder Fatigue Scale questionnaire [26] will be administered at Visits 1, 2, 3, and 4, and the results will be recorded. While FSS focuses on the severity and impact of fatigue on daily activities, ChFS provides detailed insights into the physical (questions 1-7) and mental (questions 8-11) components of fatigue, which are particularly relevant for long COVID patients who often report both physical exhaustion and cognitive fatigue [23]. Each item is evaluated on a scale of 0–4, with 0 indicating no symptoms and 4 indicating the maximum level of symptoms. The total score ranges from 0 to 33, reflecting both physical and psychological fatigue.

EQ-5D-5L.

The EQ-5D-5L, a standardized measurement of health-related quality of life, measures the quality of life across five dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression [27]. Each dimension has five levels: 1, no problems; 2, slight problems; 3, moderate problems; 4, severe problems; and 5, unable to (for mobility, self-care, and usual activities), extreme (pain/depression), or extremely (anxious/depressed). The EQ-D-5L will be administered at Visits 1 and 4, and comparisons will be made between the two groups for each visit.

Korean version of the pittsburgh sleep quality index.

The Korean version of the Pittsburgh Sleep Quality Index, a self-reported questionnaire, evaluates seven components associated with sleep quality, including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction [28]. The global score is determined by summing the scores within the range of 0–21. Global scores will be appraised at Visits 1 and 4, and comparisons will be made between the two groups for each visit.

Korean-montreal cognitive assessment.

The Korean-Montreal Cognitive Assessment, a cognitive function assessment tool, comprehensively evaluates various aspects such as visuospatial/executive functions, naming, attention, language, abstraction, orientation, and delayed recall [29]. The maximum score is 30 points, and the normal range is > 23 points. The total scores will be computed during Visits 1 and 4. Comparative analyses will be performed between the two groups for each visit.

Beck depression inventory.

The Beck Depression Inventory will be used as an assessment tool for depression and its severity post-COVID-19 or recovery. It comprises 21 items classified into cognitive, emotional, motivational, and physical symptoms of depression, and each item is rated on a scale of 0–3. The cumulative score ranges from 0–63, with higher scores signifying more severe depression symptoms [30]. Beck Depression Inventory assessments will be conducted during Visits 1 and 4, and comparative analyses will be performed between the two study groups for each visit.

Digit span test in the Korean-Wechsler adult intelligence scale.

The Korean-Wechsler Adult Intelligence Scale, a widely used intelligence test tool in clinical practice [31], will be employed to evaluate changes in cognitive impairment associated with cognitive dysfunction. A subset of the Korean-Wechsler Adult Intelligence Scale, the digit span test, is a well-validated and convenient measure for assessing verbal short-term memory and working memory capacity. This test comprises two components: digits forward (DF) and digits backward (DB). In the DF component, subjects repeat a series of spoken digits (typically 3–9 digits) in their original order. In the DB component, subjects repeat a series of digits (2–8 digits) in reverse order. The test assesses whether the subject provides consecutive incorrect responses. The DF score indicates the number of digits in the largest number correctly repeated, and the DB score indicates the number of digits in the largest number correctly repeated in reverse order. The higher the DF and DB scores, the better the subject’s short-term memory. The difference between the DF and DB score is also calculated, and if it exceeds 5, this signifies abnormal working memory. The digit span test will be administered during Visits 1 and 4, with subsequent comparisons conducted between the two groups for each visit.

Computerized neurocognitive function test (CNT).

A CNT is a tool to evaluate neurocognitive functions, such as language ability, memory, attention, planning, thinking ability, and motor ability. This study will use CNT40, which was developed in South Korea and is in clinical use, to evaluate cognitive decline in patients with long COVID. It comprises five components to evaluate attention and higher cognitive functions. [32]. A language sustainability test, conditional language continuous test, visual continuous test, and conditional visual continuous test will be administered. CNT will be conducted at Visits 1 and 4, and comparisons will be made between the two groups for each visit.

Short physical performance battery.

The Short Physical Performance Battery evaluates the physical function of older adults or those who are weak after illness. It consists of a static balance test, Gait speed test, and stand-up test [33] and will be conducted to evaluate physical function decline and functional recovery in patients with long COVID. An AndanteFit (Dyphi Inc., Daejeon, Korea) multisensor-based kiosk, which comprises devices for the performance of gait speed, stand-up, and static balance tests, will be used for accurate measurements. The Short Physical Performance Battery will be conducted at Visits 1 and 4, and comparisons will be made between the two groups for each visit.

Feasibility evaluation.

The subject recruitment rate will be determined by calculating the ratio of the overall number of recruited subjects during the study duration to the intended number of study participants (100 subjects: n =  50 in the Kyungok-go and placebo groups, respectively). The study enrollment rate will be derived by dividing the total number of study subjects by the total number of participants who undergo screening. Detailed documentation of the reason for any dropouts will be systematically recorded. The dropout rate will be calculated and compared for all study subjects, as well as individually for each group.

Final treatment success rate.

Fatigue symptoms will be assessed on a visual analog scale (0–100 mm) before (Visit 1) and after (Visit 4) intervention administration for 12 weeks. Treatment success will be defined as a difference of more than 15 points, and the frequency and ratio of subjects successfully treated in both groups will be presented [34].

Subgroup analysis.

A subgroup analysis will be conducted according to the early warning score (EWS) to explore the differences in the effects based on the severity of COVID-19. The EWS evaluation will involve assessing oxygen saturation, supplemental oxygen usage, heart rate, systolic blood pressure, respiratory rate, body temperature, and level of consciousness [35]. The study participants will be classified into a mild group (EWS < 5) or a severe group (EWS ≥ 5) [36]. This analysis will focus on the primary outcome variable (FSS scores after 12 weeks of intervention).

Safety evaluation.

Safety will be assessed with a comprehensive evaluation of various parameters, including adverse events, vital signs, laboratory test results, and electrocardiograms per protocol. Clinically significant abnormal observed values and changes from baseline will be investigated. Adverse events will include any harmful and unintended symptoms, abnormal laboratory test results, or diseases that occur in subjects in the Kyungok-go group, even if there is no direct causal relationship. Study subjects or their representatives will voluntarily and promptly report any adverse effects.