Examining the Function of Cs4 on Post-COVID-19 Disorders

Study Overview
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Brief Summary
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Cordyceps is a medicinal Chinese medicine. The benefits of cordyceps-related therapeutic action have been studied due to its anti-inflammation and immunomodulation features. Thus, Cordyceps may have efficacy against inflammation-related health problems in the post-COVID era. the Cs4 is a Chinese medicine nutritional supplement fermented by Cordyceps. This Project conducts a two-stage waitlist-controlled trial to examine the therapeutic effect of the Cs4 on long-COVID patients. 110 Patients will be recruited and divided into two groups. Each group contains 55 patients. In the first-stage clinical trial for 12 weeks, group A will have no treatment while group B will have Cs4 treatment. In the second-stage clinical trial for 12 weeks, group A will have Cs4 treatment while group B will have no treatment. A 12-week follow-up will be conducted after the intervention of Cs4. The primary outcome will be the self-declared modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm). In our study, we intend to analyse the efficacy of Cs4 on the improvement of long Covid symptoms by using a comprehensive measurement to cover most symptoms, and be condition-specific. The secondary outcomes will include the self-declared validated Post-COVID-19 Functional Status (PCFS) Scale, five health condition surveys and blood tests assessed at baseline, end of the intervention and the end of follow-up. Health condition surveys include the score of Insomnia Severity Index (ISI), Brief Fatigue Inventory Form, St. George's Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Scale (HADS), and the Short Form 12 (SF12). A certain number of items are measured by scoring on each of these scales. There will be a total score for each scale. The anticipated outcome of the study is to provide evidence of Cs4 in the improvement of long COVID symptoms. This project can serve to the development of a nutritional supplement for the management of post-COVID-related health problems.

Detailed Description
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Research Methodologies Participants Setting This is a waitlist-controlled trial to examine the therapeutic effect of Cs4 on long-COVID patients, which are divided into two groups. The study will be conducted in the Specialist Clinical Centre for Teaching and Research (Sassoon Road), School of Chinese Medicine, The University of Hong Kong (HKU). Inclusion Criteria Male or female patients with age from 18 to 75 years old, who have been previously diagnosed with COVID-19 and recovered; The self-declared post-COVID-19 Functional Status scale should be at least over 1; The post-COVID symptoms have lasted at least 28 days after diagnosis; Currently not taking any other orally administered Chinese medicine; Negative COVID-19 antigen or nucleic acid test within 3 days prior to signing the consent form; Voluntary participation in this clinical study. Exclusion Criteria 1. Inability to read and/or write Chinese or English; 2. Inability to communicate (e.g. with cognitive impairment) 3. Allergy to Cordyceps sinensis; 4. Pregnant or lactating women; 5. Impaired hepatic or renal function. Methods Participants will be recruited through advertisements on local newspapers, and the webpage of the School of Chinese Medicine, HKU. Clinical history and comprehensive examination will be performed during the first interview by registered Chinese Medicine practitioners or registered nurses who will be informed about the aims, procedure and nature of the study, and possible side effects of Cs4 and written consent will be obtained from each subject who agrees to get into the study. The participant will be also informed that they have the freedom to withdraw at any time during the study. Study design This will be a waitlist-controlled trial in which participants will alternately receive the intervention of Cs4 for 12 weeks, followed by a 12-week follow-up. 110 long-COVID patients will be randomly divided into two groups (Group A and Group B). Randomisation will be carried out according to the computer- based Excel random number generator. An integer number between 1 and 110 will be assigned to each individual at random. Group A consists of individuals assigned integer numbers between 1 and 55. Group B consists of individuals assigned integer numbers between 56 and 110. Intervention Cs4 will be provided by Chinese Pharm, produced by GMP standard manufacturing. The intervention will be given according to the product instruction. Each capsule is 0.4g. According to the product sheet, adults should take 3-4 capsules daily as a way to nourish and strengthen the lungs and kidneys. In our study, the participants are people with long-COVID symptoms. Therefore, in order to achieve maximum efficacy, we will follow the directions and let participants take the maximum amount allowed by the product which is 4 capsules daily. Participants will take one capsule (each 400mg) 4 times a day, for a total of 1.6g. Treatment will last 12 weeks.

Official Title
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Examining the Immunomodulatory and Health Improving Function of a Chinese Medicine Nutritional Supplement Cs4 on Immunity-related Disorders in the Post-COVID Era

Conditions
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Long COVID

Intervention / Treatment
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* Other: Chinese medicine nutritional supplement Cs4


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients with age from 18 to 75 years old, who have been previously diagnosed with COVID-19 and recovered; The self-declared post-COVID-19 Functional Status scale should be at least over 1; The post-COVID symptoms have lasted at least 28 days after diagnosis; Currently not taking any other orally administered Chinese medicine; Negative COVID-19 antigen or nucleic acid test within 3 days prior to signing the consent form; Voluntary participation in this clinical study. Exclusion Criteria: Inability to read and/or write Chinese or English; Inability to communicate (e.g. with cognitive impairment) 3. Allergy to Cordyceps sinensis; 4. Pregnant or lactating women; 5. Impaired hepatic or renal function.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group A- having treatment at second stage<br>110 long-COVID patients will be divided into 2 groups (55 individuals per group). ⚫ Group A: 55 long-COVID patients (NO. 1- NO.55) Group B: 55 long-COVID patients (NO. 56- NO.110) Group distribution and treatment in a two-stage waitlist design: ⚫ First-stage clinical trial for 12 weeks: Group A (patients NO.1-55 will have no treatment on the waiting list) Group B (patients NO.56-110 will have Cs4 treatment) ⚫ Second-stage clinical trial for 12 weeks (After finishing the first-stage study): Group A (patients NO.1-55 will have Cs4 treatment) Group B (patients NO.56-110 will have no treatment) | Other: Chinese medicine nutritional supplement Cs4<br>* Cs4 will be provided by Chinese Pharm, produced by GMP standard manufacturing. The intervention will be given according to the product instruction. Each capsule is 0.4g. According to the product sheet, adults should take 3-4 capsules daily as a way to nourish and strengthen the lungs and kidneys. In our study, the participants are people with long-COVID symptoms. Therefore, in order to achieve maximum efficacy, we will follow the directions and let participants take the maximum amount allowed by the product which is 4 capsules daily. Participants will take one capsule (each 400mg) 4 times a day, for a total of 1.6g. Treatment will last 12 weeks.<br>|
| Other: Group B- having treatment at first stage<br>110 long-COVID patients will be divided into 2 groups (55 individuals per group). ⚫ Group A: 55 long-COVID patients (NO. 1- NO.55) Group B: 55 long-COVID patients (NO. 56- NO.110) Group distribution and treatment in a two-stage waitlist design: ⚫ First-stage clinical trial for 12 weeks: Group A (patients NO.1-55 will have no treatment on the waiting list) Group B (patients NO.56-110 will have Cs4 treatment) ⚫ Second-stage clinical trial for 12 weeks (After finishing the first-stage study): Group A (patients NO.1-55 will have Cs4 treatment) Group B (patients NO.56-110 will have no treatment) | Other: Chinese medicine nutritional supplement Cs4<br>* Cs4 will be provided by Chinese Pharm, produced by GMP standard manufacturing. The intervention will be given according to the product instruction. Each capsule is 0.4g. According to the product sheet, adults should take 3-4 capsules daily as a way to nourish and strengthen the lungs and kidneys. In our study, the participants are people with long-COVID symptoms. Therefore, in order to achieve maximum efficacy, we will follow the directions and let participants take the maximum amount allowed by the product which is 4 capsules daily. Participants will take one capsule (each 400mg) 4 times a day, for a total of 1.6g. Treatment will last 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the self-declared modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) | an ordinal patient-reported outcome measure. The scale has been recommended in NHS England Clinical Guidance for PCS services and NICE rapid guidelines. C19-YRSm is the first validated scale describing post-COVID-19 symptoms and grading the severity of symptoms and functional disability. This 17-item C19-YRSm was developed with subscales (scores): symptom severity (0-30), functional disability (0-15), other symptoms (0-25), and overall health (0-10). Higher scores mean a worse outcome. | will be assessed at baseline, 3 months, and 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insomnia Severity Index (ISI) | To evaluate insomnia. Maximum values: 28, minimum values:0. Higher scores mean a worse outcome. | will be assessed at baseline, 3 months, and 6 months. | 
| Brief Fatigue Inventory Form (BFI) | To evaluate fatigue. Maximum values: 10, minimum values:0. Higher scores mean a worse outcome. | will be assessed at baseline, 3 months, and 6 months. | 
| St. George's Respiratory Questionnaire (SGRQ) | To evaluate respiratory symptoms. Maximum values: 100, minimum values:0. Higher scores mean a worse outcome. | will be assessed at baseline, 3 months, and 6 months. | 
| Hospital Anxiety and Depression Scale (HADS) | To evaluate anxiety and depression. Maximum values: 21, minimum values:0. Higher scores mean a worse outcome. | will be assessed at baseline, 3 months, and 6 months. | 
| Short Form 12 (SF12) | To evaluate overall quality of life. Maximum values: 100, minimum values:0. Higher scores mean better physical and mental health functioning. | will be assessed at baseline, 3 months, and 6 months. | 
| perform blood test | ESR score, serum level of inflammation cytokines | will be assessed at baseline, 3 months, and 6 months. |