Cardiorespiratory Exercise & Chinese Medicine for Rehabilitation of Discharged Coronavirus Disease (COVID-19) Patients

Coronavirus Disease (COVID-19) Clinical Trial

— Covid19Reh  

Official title:

Would Cardiorespiratory Exercise and Chinese Herbal Medicine Facilitate Rehabilitation Among Post-discharge Patients With COVID-19? Clinical Efficacy and Mechanisms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04572360
• Other study ID #: HKCOVID19Rehab
• Status: Recruiting
• Phase: N/A
• Start date: October 1, 2020
• Est. completion date: June 30, 2023

Study information

• Verified date: June 2021
• Source: Hong Kong Baptist University
• Contact: Linda Zhong
• Phone: 852-34116523
• Email: ldzhong0305[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rehabilitation interventions can help to address the consequences of COVID-19, which include medical, physical, cognitive, and psychological related problems. The specific aims of this project are to investigate the effects of a 12-week exercise program on pulmonary fibrosis in recovering COVID-19 patients. A further aim will be to examine how Chinese herbal medicines, gut microbiome, and metabolites regulate immune function and possibly autoimmune deficiency in the rehabilitation process.

Description:

The study will develop a new paradigm for patient rehabilitation needed now and in the future. The specific aims of this project are to investigate the effects of a 12-week program with cardiorespiratory exercise and Chinese herbal medicine on recovering COVID-19 patients and to collect qualitative and quantitative data to examine loneliness, anxiety, depression, quality of life, and mental health. A further aim will be to examine how Chinese herbal medicines, gut microbiome, and the metabolites regulate immune function, intestinal permeability, and possibly autoimmune deficiency (AID) in the pathological recovery/rehabilitation process.

In this multicenter, triple-blinded, randomized, parallel groups, controlled clinical trial, the investigator will recruit adult patients with COVID-19 and have been discharged from the hospital in Hong Kong and the Chinese Mainland.

A total of 172 eligible patients will be randomized 1:1:1:1 into four groups:

cardiorespiratory exercise plus Chinese herbal medicines group, cardiorespiratory exercise group, Chinese herbal medicines group, and waiting list group for 12-week (3 months) with 12-week follow-up period.

A 4-week pilot study will be conducted to test patient recruitment and maintenance, data collection, instrumentation, and observing the adaptability and practicality of the intervention. Amendments will be made if necessary.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 172
• Est. completion date: June 30, 2023
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. aged 18 years and above;

2. a percentage of predicted forced vital capacity (FVC) <90%, and/or a percentage of predicted carbon monoxide diffusing capacity < 90% (King 2014);

3. able to communicate in Cantonese.

Exclusion Criteria:

1. having acute exacerbations in the 12-week preceding recruitment patients;

2. having any contraindications for exercise (e.g., physical disability, uncontrolled mental disorders, unstable heart disease, unable to perform muscle strength tests)

3. Female - Pregnant or plan to become pregnant in the next 1 year

4. Unable to communicate in Cantonese or Mandarin

5. Currently participating in other similar rehabilitation programs or research

Related Conditions & MeSH terms

• Coronavirus Disease (COVID-19)
• Coronavirus Infections

Intervention

Other:
• Cardiorespiratory Exercise
Each exercise session (40-60 minutes) will include warm-up, aerobic training, resistance training, cool-down, as well as inspiratory muscle training
• Modified Bai He Gu Jin Tang
The Chinese herbal formula of Modified Bai He Gu Jin Tang will be prescribed in granules. A dose of 10g a day (5g, b.i.d) will be ingested. Patients will dissolve a sachet of granules (5.0g) in 200ml of hot water, twice a day after breakfast and dinner, seven days a week for three months.

Locations

Country	Name	City	State
Hong Kong	Linda Zhong	Kowloon Tong	Kowloon

Sponsors (7)

Lead Sponsor	Collaborator
Hong Kong Baptist University	Chinese University of Hong Kong, The Hong Kong Polytechnic University, The University of Hong Kong, University of California, San Diego, University of South Wales, Yale University

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Six-Minute Walk Test (6MWT) in Cardiorespiratory Fitness Test	To assess the functional exercise capacity that reflects daily physical activities and to measure the distance the participant is able to walk over six minutes on a hard, flat surface.; Items measured during 6MWT are: Distance Walked (m); Number of Rests	6 months
Primary	Blood Pressure	Blood pressure (Systolic/Diastolic) in mmHg will be measured before & after 6MWT	6 months
Primary	Heart Rate	Heart rate in beats per minute will be measured before & after 6MWT	6 months
Primary	Peripheral oxygen saturation (SpO2)	SpO2 in % will be measured before & after 6MWT	6 months
Primary	Borg Dyspnea Scale	The Borg Category Ratio 10 (CR10) Scale® (Borg Dyspnea Scale), will be used to rate the patients' dyspnea and overall fatigue level. At the beginning and end the end of the 6 MWT. The scale will also be used during Cardiopulmonary Exercise Test (CPET).; Scale: 0=Rest; 0.5=Really Really Easy; 1=Really Easy; 2=Easy; 3=Moderate; 4=Sort of Hard; 5,6=Hard; 7,8,9=Really Hard; 10=Maximal	6 months
Primary	Body composition - Segmental Muscle Mass	Bio-impedance analysis approach will be used to assess patient's segmental muscle mass in percentage (%).	6 months
Primary	Body composition - Body Mass Index (BMI)	A stadiometer will be used to measure stature (in metres) and weight is measured in kg to calculate body mass index (BMI) .; Body Mass Index (BMI): weight (in kilograms) divided by the square of your height (in metres)	6 months
Primary	Body composition - Anatomical Circumferences	Anatomical circumferences - waist (cm) & Hip (cm) will be measured using a steel measuring tape, to calculate the Waist-to-Hip Ratio.	6 months
Primary	FVC (L) in Lung function Test using Spirometry	Forced vital capacity test (FVC) will be measured and used to calculate FEV1/FVC ratio to assess the functional severity and capacity of the patient's lung.	6 months
Primary	FEV1 (L) in Lung function Test using Spirometry	Forced expiratory volume (FEV1) will be measured and used to calculate FEV1 /FVC ratio to assess the functional severity and capacity of the patient's lung.	6 months
Primary	MVV (L/min) in Lung function Test using Spirometry	Maximal Voluntary Ventilation (MVV) measures peak performance of the lungs and respiratory muscles to assess overall pulmonary ventilation.	6 months
Primary	Fractional exhaled Nitric Oxide (FeNO)	Fractional exhaled Nitric Oxide (FeNO), the results will be in parts per billion (ppb) of nitric oxide in patient's breath, will be used to assess inflammatory response to exercise and medicinal intervention.	6 months
Primary	Diffusing capacity of the lungs for carbon monoxide (DLCO)	Diffusing capacity of the lungs for carbon monoxide (DLCO), measured in millilitre/minute/Kilopascal (ml/min/kPa), will be used to evaluate gas diffusion in the lungs.	6 months
Primary	Cardiopulmonary Exercise Test (CPET) - Work Rate(WR)	CPET provides information concerning the level of exercise that the patient can perform without undue stress. The test results will guide the research team regarding exercise prescription for physical rehabilitation methodologies, and provides quantitative evidence of the benefits of a rehabilitation program as well as information on the mechanism(s) involved.; Work Rate(WR), an incremental ergometry exercise test, will be used to assess the cellular, cardiovascular, and ventilatory systems' responses under precise conditions of metabolic stress	6 months
Primary	Cardiopulmonary Exercise Test (CPET) - Breath by Breath Measurements of Minute ventilation (VE)	Breath by breath measurements of minute ventilation (VE) in L/min will be measured and used to calculate ventilatory efficiency - VE/VCO2 and VE/VO2, ventilatory equivalents for carbon dioxide and oxygen.	6 months
Primary	Cardiopulmonary Exercise Test (CPET) - CO2 output (VCO2)	CO2 output (VCO2) in L/min, will be measured and used to calculate ventilatory efficiency - VE/VCO2, ventilatory equivalents for carbon dioxide.	6 months
Primary	Cardiopulmonary Exercise Test (CPET) - O2 uptake (VO2)	O2 uptake (VO2) in L/min, will be measured and used to calculate ventilatory efficiency - VE/VO2, ventilatory equivalents for oxygen.	6 months
Primary	Change in Chinese Medicine (CM) Diagnostic Pattern & Clinical Characteristics using CM Syndrome Differentiation Assessment	The changes in participants' health as characterized by CM diagnostic pattern & clinical characteristics using CM Syndrome Differentiation according to the Guidelines for Chinese Medicine New Drug Clinical Study (China Medical Science Press, 2002) will be assessed.	Change from baseline the CM Diagnostic Pattern & Clinical Characteristics at 6 months
Primary	Change in Body Constitution Scores using Body Constitution Questionnaires Assessment	The changes in participants' health as characterized by body constitution scores using the Body Constitution Questionnaires for the nine specific types of body constitutions will be assessed on each visit during the treatment and follow up period.	Change from baseline the Body Constitution at 6 months
Secondary	Blood Biochemistry Tests - Serum Levels of Insulin (pmol/l)	Venous blood will be drawn & after coagulation at room temperature for 30 minutes, the samples will be centrifuged at 3000 rpm for 20 minutes. Serum as supernatant will be extracted & stored at -80°C until assay. Serum levels of insulin will be assessed by a commercially available Enzyme-linked immunosorbent Assay (ELISA) kit (Merck).	6 months
Secondary	Blood Biochemistry Tests - Prothrombin Time (seconds)	The Prothrombin time test will be used to measure blood coagulation. Venous blood will be collected by venepuncture in a tube with sodium citrate. Plasma will be isolated after centrifugation at 1000rpm for 30 min, 4°C. Thromboplastin will be added into the plasma and kept at 37°C for two minutes. Calcium chloride will be added to the mixture, and the plasma is allowed to coagulate. The time needed for the coagulation will be recorded as the Prothrombin Time.	6 months
Secondary	Quality of Life - Personal Wellbeing Index - Chinese Version (Adult)	Quality of life (QoL) will be measured using the Personal Well-being Index-Chinese Version (PWI-C). It is a subjective QoL measure with questionnaires that have been translated and validated.; Questions included are: How satisfied are you with…?"; your standard of living ?; your health ?; what you are achieving in life ?; your personal relationships ?; how safe you feel ?; feeling part of your community ?; your future security ?; Answers are measured using scale from zero to 10 (0...1…2...3...4…5...6...7...8...9…10).; Zero means feel no satisfaction at all; 10 means feel completely satisfied.	6 months
Secondary	Other mental health-related measures - Depression Anxiety Stress Scale (DASS-21)	Anxiety and stress will be measured using the Chinese version of the Depression Anxiety Stress Scale (DASS-21). The scale will discriminate between the negative emotional syndromes of depression, anxiety, and stress in Chinese populations. Only the subscales of anxiety and stress will be used.; The anxiety scale assesses autonomic arousal, skeletal muscle effects, situational anxiety, and subjective experience of anxious affect. The stress scale is sensitive to levels of chronic nonspecific arousal. It assesses difficulty relaxing, nervous arousal, and being easily upset/agitated, irritable/over-reactive & impatient.; The rating scale is as follows: 0=Did not apply to me at all; Applied to me to some degree, or some of the time; Applied to me to a considerable degree or a good part of time; Applied to me very much or most of the time; Scores are calculated by summing the scores for the relevant items. Higher scores indicate greater degrees of anxiety and stress.	6 months
Secondary	Other mental health-related measures - Revised UCLA Loneliness Scale (R-UCLA)	Loneliness will be measured using the Revised UCLA Loneliness Scale (R-UCLA). It consists of 20 items and participants are to indicate how often they feel the way described by placing a check in the space provided, using the following scale: Never; Rarely; Sometimes; Often; Score scale for item 1,5,6,9,10,15,16,19,20 are reversed, and score for each item then summed together. Higher scores indicate greater degrees of loneliness.	6 months
Secondary	Other mental health-related measures - General Health Questionnaire (GHQ)	General mental health will be measured using the General Health Questionnaire (GHQ), which is commonly used to screen minor psychiatric symptoms (Hu 2007).; It consists of 12 items, beginning by asking "Have you recently…", each assessing the severity of a mental problem over the past few weeks using a 4-point scale of: (always) 0...1…2…3 (never).; The score was used to generate a total score ranging from 0 to 36, with higher scores indicating worse conditions.	6 months
Secondary	Gut microbiome Test	Patient is to self-sample morning first feces & immediately freeze it in a home freezer (-20?) & transport to facilities in a provided freezer pack stored at -80?. Total DNA of 200 mg fecal samples will be extracted & purified. The DNA concentration & size distribution will be estimated by a Nano drop instrument & agarose gel electrophoresis respectively. The DNA one paired-end (PE) library will be prepared using a DNA high-throughput (HT) Sample Prep Kit, & whole-genome shotgun sequencing of samples will be carried out by the Illumina platform. The high quality sequences will be mapped with the published gene catalog of reference genes in the human gut microbiome (Li 2014). Taxonomic assignment of the predicted genes and Kyoto Encyclopedia of Genes & Genomes (KEGG) analysis will be performed as described (Feng 2015). Relative abundances of phyla, genera, species, & Kegg Orthology (KOs) will be calculated from the relative abundances of the respective genes.	6 months
Secondary	Metabolomics-related Measurement of Depression - Metabolomics Analysis	Metabolomics analysis of selected neurotransmitters as potential markers of depression: Ultra-performance liquid chromatography triple quadrupole mass spectrometry will be used to quantitatively measure the metabolites selected (neurotransmitters) as potential markers of depression. Briefly, an aliquot of 40 µl of urine or plasma will be spiked with 10 µL of internal standard (L-4-chlorophenylalanine in water, 30 µg/mL), and extracted with 200 µL of acetonitrile and methanol (9:1, v/v). The mixture will be vortexed and centrifuged. After centrifugation, the supernatant will be transferred to the sampling vials and subject to analysis. The raw data generated will be processed using the Target Lynx Applications Manager Version 4.1 (Waters Corp., Milford, MA) for targeted metabolite annotation and to obtain calibration equations and the concentration of each metabolite in the samples Metabolomics analysis	6 months