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

• ClinicalTrials.gov Identifier: NCT06054438
• Recruitment Status: Recruiting
• First Posted: September 26, 2023
• Last Update Posted: April 11, 2024
• Sponsor: The University of Hong Kong
• Information provided by (Responsible Party): Professor FENG Yibin, The University of Hong Kong

Tracking Information

• First Submitted Date: September 25, 2023
• First Posted Date: September 26, 2023
• Last Update Posted Date: April 11, 2024
• Actual Study Start Date: April 17, 2023
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 10, 2024)

the change in symptom severity from 0 to 12 weeks measured by the modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) [ Time Frame: will be assessed at baseline and 12 weeks. ]

Symptom severity is one of the sub-scale of C19-YRSm. Range 0-78, with higher scores indicating greater impact of symptoms. C19-YRSm is the first validated scale describing post-COVID-19 symptoms and grading the severity of symptoms and functional disability.

Original Primary Outcome Measures (submitted: September 25, 2023)

the self-declared modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) [ Time Frame: will be assessed at baseline, 3 months, and 6 months. ]

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 The scale's subscales include symptom severity, functional ability, other symptoms, and overall health

Current Secondary Outcome Measures (submitted: April 10, 2024)

• the change in Insomnia Severity Index (ISI) from 0 to 12 weeks [ Time Frame: will be assessed at baseline and 12 weeks. ]
  To evaluate insomnia. Maximum values: 28, minimum values:0. Higher scores mean a worse outcome.
• the change in Brief Fatigue Inventory Form (BFI) from 0 to 12 weeks [ Time Frame: will be assessed at baseline and 12 weeks. ]
  To evaluate fatigue. Maximum values: 10, minimum values:0. Higher scores mean a worse outcome.
• the change in St. George's Respiratory Questionnaire (SGRQ) from 0 to 12 weeks [ Time Frame: will be assessed at baseline and 12 weeks. ]
  To evaluate respiratory symptoms. Maximum values: 100, minimum values:0. Higher scores mean a worse outcome.
• the change in Hospital Anxiety and Depression Scale (HADS) from 0 to 12 weeks [ Time Frame: will be assessed at baseline and 12 weeks. ]
  To evaluate anxiety and depression. Maximum values: 21, minimum values:0. Higher scores mean a worse outcome.
• the change in Short Form 12 (SF12) from 0 to 12 weeks [ Time Frame: will be assessed at baseline and 12 weeks. ]
  To evaluate overall quality of life. Maximum values: 100, minimum values:0. Higher scores mean better physical and mental health functioning.

Original Secondary Outcome Measures (submitted: September 25, 2023)

• Insomnia Severity Index (ISI) [ Time Frame: will be assessed at baseline, 3 months, and 6 months. ]
  To evaluate insomnia
• Brief Fatigue Inventory Form (BFI) [ Time Frame: will be assessed at baseline, 3 months, and 6 months. ]
  To evaluate fatigue
• St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: will be assessed at baseline, 3 months, and 6 months. ]
  To evaluate respiratory symptoms
• Hospital Anxiety and Depression Scale (HADS) [ Time Frame: will be assessed at baseline, 3 months, and 6 months. ]
  To evaluate anxiety and depression
• Short Form 12 (SF12) [ Time Frame: will be assessed at baseline, 3 months, and 6 months. ]
  To evaluate overall quality of life
• perform blood test [ Time Frame: will be assessed at baseline, 3 months, and 6 months. ]
  ESR score, serum level of inflammation cytokines

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Examining the Function of Cs4 on Post-COVID-19 Disorders
• Official Title: Examining the Immunomodulatory and Health Improving Function of a Chinese Medicine Nutritional Supplement Cs4 on Immunity-related Disorders in the Post-COVID Era
• Brief Summary: 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 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 treatment while group B will have no Cs4 treatment. In the second-stage clinical trial for 12 weeks, group A will have no Cs4 treatment while group B will have Cs4 treatment. A 12-week follow-up will be conducted after the intervention of Cs4 for group A. The primary outcome will be the change from 0 to 12 weeks in symptom severity measured by 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 change from 0 to 12 weeks 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). Blood tests will be assessed for safety study. primary outcomes and secondary outcomes will be assessed at baseline (week 0) and week 12. 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

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

1. Male or female patients with age from 18 to 75 years old, who have been previously diagnosed with COVID-19 and recovered;
2. The self-declared post-COVID-19 Functional Status scale should be at least over 1;
3. The post-COVID symptoms have lasted at least 28 days after diagnosis;
4. Currently not taking any other orally administered Chinese medicine;
5. Negative COVID-19 antigen or nucleic acid test within 3 days prior to signing the consent form;
6. 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 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Long COVID

Intervention

Other: Chinese medicine nutritional supplement Cs4

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.

Study Arms

• Group A- having treatment at first stage

  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 treatment) Group B (patients NO.56-110 will have no Cs4 treatment on the waiting list)

  ⚫ Second-stage clinical trial for 12 weeks (After finishing the first-stage study): Group A (patients NO.1-55 will have no Cs4 treatment) Group B (patients NO.56-110 will have Cs4 treatment)

  Intervention: Other: Chinese medicine nutritional supplement Cs4
• Group B- having treatment at secondstage

  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 treatment) Group B (patients NO.56-110 will have no Cs4 treatment on the waiting list)

  ⚫ Second-stage clinical trial for 12 weeks (After finishing the first-stage study): Group A (patients NO.1-55 will have no Cs4 treatment) Group B (patients NO.56-110 will have Cs4 treatment)

  Intervention: Other: Chinese medicine nutritional supplement Cs4

Publications *

• Whitworth J. COVID-19: a fast evolving pandemic. Trans R Soc Trop Med Hyg. 2020 Apr 8;114(4):241-248. doi: 10.1093/trstmh/traa025. No abstract available.
• Garg M, Maralakunte M, Garg S, Dhooria S, Sehgal I, Bhalla AS, Vijayvergiya R, Grover S, Bhatia V, Jagia P, Bhalla A, Suri V, Goyal M, Agarwal R, Puri GD, Sandhu MS. The Conundrum of 'Long-COVID-19': A Narrative Review. Int J Gen Med. 2021 Jun 14;14:2491-2506. doi: 10.2147/IJGM.S316708. eCollection 2021.
• Chen J, Chan WM, Leung HY, Leong PK, Yan CTM, Ko KM. Anti-Inflammatory Effects of a Cordyceps sinensis Mycelium Culture Extract (Cs-4) on Rodent Models of Allergic Rhinitis and Asthma. Molecules. 2020 Sep 4;25(18):4051. doi: 10.3390/molecules25184051.
• Han F, Dou M, Wang Y, Xu C, Li Y, Ding X, Xue W, Zheng J, Tian P, Ding C. Cordycepin protects renal ischemia/reperfusion injury through regulating inflammation, apoptosis, and oxidative stress. Acta Biochim Biophys Sin (Shanghai). 2020 Feb 3;52(2):125-132. doi: 10.1093/abbs/gmz145.
• Klok FA, Boon GJAM, Barco S, Endres M, Geelhoed JJM, Knauss S, Rezek SA, Spruit MA, Vehreschild J, Siegerink B. The Post-COVID-19 Functional Status scale: a tool to measure functional status over time after COVID-19. Eur Respir J. 2020 Jul 2;56(1):2001494. doi: 10.1183/13993003.01494-2020. Print 2020 Jul.
• Sivan M, Preston N, Parkin A, Makower S, Gee J, Ross D, Tarrant R, Davison J, Halpin S, O'Connor RJ, Horton M. The modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) patient-reported outcome measure for Long Covid or Post-COVID-19 syndrome. J Med Virol. 2022 Sep;94(9):4253-4264. doi: 10.1002/jmv.27878. Epub 2022 Jun 1.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 25, 2023): 110
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 31, 2024
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female patients with age from 18 to 75 years old, who have been previously diagnosed with COVID-19 and recovered;
2. The self-declared post-COVID-19 Functional Status scale should be at least over 1;
3. The post-COVID symptoms have lasted at least 28 days after diagnosis;
4. Currently not taking any other orally administered Chinese medicine;
5. Negative COVID-19 antigen or nucleic acid test within 3 days prior to signing the consent form;
6. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Yuanyuan Chen, MPhil; 85262877807; loracyy@connect.hku.hk

• Listed Location Countries: China

Administrative Information

• NCT Number: NCT06054438
• Other Study ID Numbers: UW23-011; Innovation and Technology Fund ( Other Grant/Funding Number: PRP/069/22FX )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Professor FENG Yibin, The University of Hong Kong
• Original Responsible Party: Same as current
• Current Study Sponsor: The University of Hong Kong
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Yibin Feng, Doctor; The University of Hong Kong

• PRS Account: The University of Hong Kong
• Verification Date: April 2024