Efficacy and Safety of High-dose Vitamin C Combined With Chinese Medicine Against Coronavirus Pneumonia (COVID-19)

Study Overview
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Brief Summary
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In December 2019, coronavirus pneumonia (COVID-19) was detected in many cases in Wuhan, China. With the rapid spread of the coronavirus, cases of COVID-19 were also reported in other cities of China and other countries. COVID-19 can cause amplification of the pulmonary inflammatory responses, including the production of a large amount of free radicals and the release of inflammatory factors, in a short time after infection, leading to lung tissue damage and dysfunction, even resulting in life-threatening respiratory distress syndrome and respiratory failure. At present, there are no effective drugs targeting COVID-19. Previous studies have shown that Buzhong Yiqi Decoction has anti-bacterial, anti-viral, and anti-allergy effects. High-dose vitamin C also has anti-oxidative and anti-toxin effects, possibly exhibiting good effects in the treatment of viral infection and critical respiratory diseases. The study objectives include (1) investigate whether Buzhong Yiqi Decoction can improve the clinical symptoms of patients with mild and severe COVID-19 and accelerate recovery and to further investigate the clinical efficacy of high-dose vitamin C combined with traditional Chinese medicine in the treatment of mild and severe COVID-19; (2) to assess the safety of high-dose vitamin C combined with Chinese medicine in the treatment of mild and severe COVID-19.

Detailed Description
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Preparation prior to treatment Record of age, sex, race, height, body mass, body mass index, body temperature, blood pressure, pulse, and respiratory rate; Record of previous medical history, current medical history, treatment history, concomitant disease/treatment history; Record of laboratory tests: routine blood test, routine stool and urine tests, fecal occult blood test, C-reactive protein measurement, biochemical assay, PCR testing for respiratory virus, tumor marker test, and ABO typing Cytokine detection: Serum levels of interleukin-6, interleukin-10, and tumor necrosis factor-alpha (TNF-α) Auxiliary examination: Chest CT for assessment of lung infection Chinese medicine treatments Chinese medicine treatments include oral administration of concentrated Chinese herbal decoction, fumigation/inhalation of Chinese medicine and vitamin C, and bolus administration of vitamin C. Traditional Chinese and western medicine prescription details Traditional Chinese medicine treatment details Prescription 1: Buzhong Yiqi plus and minus formula (recommended for patients who had no fever and those who are in the convalescent period): This formula is composed of Radix Astragali 30 g, Radix Ginseng 15 g, Radix Glycyrrhizae 15 g, Rhizoma Atractylodis Macrocephalae 10 g, Pericarpium Citri Reticulatae 6 g, Radix Angelicae Sinensis 10 g, Fructus Jujubae 6, Rhizoma Zingiberis Recens 9 pieces, Radix Bupleuri 12 g, Rhizoma Cimicifugae 6 g. Preparation method: The aforementioned herbs are decocted with water. After removal of macromolecules, 50 g concentrate is left, and then packaged, 25 g/dose. Suggested usage: 1 dose once, twice a day, taking with warm water. Prescription 2: Huhuang Detoxicity Paste (recommended for patients who have no fever): This formula is composed of Rhizoma Coptidis 20 g, Radix Et Rhizoma Rhei 10 g, Rhizoma Atractylodis 10 g, Radix Asteris 10 g, Herba Houttuyniae 10 g, Herba Taraxaci 10 g, Rhizoma Polygoni Cuspidati 10 g, Radix Astragali 20 g. Preparation method: The aforementioned herbs are boiled with water. The extract was subjected to high-speed centrifugation. After removal of impurities, 50 g concentrate is left, and then packaged, 25 g/dose. Suggested usage: One dose once, twice a day, taking with warm water. Prescription 3: Baimu Qingre Jiedu Paste This formula is composed of Radix Puerariae 15 g, Radix Angelicae Dahuricae 12 g, Flos Magnoliae 9 g, Radix Isatidis 30 g, Fructus Forsythiae 15 g, Bulbus Fritillariae Thunbergii 12 g Preparation method: The aforementioned herbs are boiled with water. The extract was subjected to high-speed centrifugation. After removal of impurities, 50 g concentrate is left, and then packaged, 25 g/dose. Suggested usage: One dose once, twice a day, taking with warm water. Prescription 4: Fumigation/inhalation of Chinese herbs and vitamin C The formula consists of Rhizoma Coptidis 20 g, Radix Et Rhizoma Rhei 10 g, Rhizoma Atractylodis Macrocephalae 10 g, Radix Astragali 10 g, Radix Asteris 10 g, Herba Houttuyniae 10 g, Herba Taraxaci 10 g, Rhizoma Polygoni Cuspidati 10 g, Radix Astragali 20 g. Preparation method: The aforementioned herbs are boiled with water. The extract was subjected to high-speed centrifugation. After removal of impurities, 50 g concentrate is left, and then packaged, 25 g/dose. Fumigation/inhalation method: 3L of water is added to the intelligent rice cooker (specification 5L), and then the aforementioned semifluid paste is also placed in the cooker. After boiling, 10 g vitamin C is added. The oxygen tube is inserted into the bottom of the traditional Chinese medicine solution (oxygen flow is about 3-4 L/min). The steam is sucked with the mouth and nose alternately, 30-40 minutes once, 3-7 times a day. Patients take vitamin E capsule and folic acid every day. Bolus administration of vitamin C 100 mL of 5% glucose containing vitamin C (10 g/60 kg body mass) is intravenously administered twice a day. Western medicine treatment details Atomized inhalation of 5 million U α-interferon and 2 mL sterilized water, twice a day; 0.2 g arbidol, three times a day, treatment course no more than 10 days; intravenous administration of ribavirin 500 mg, once every 12 hours, treatment course no more than 10 days; intravenous administration of 10 g immunoglobulin C, once a day, 3-5 days. Anti-bacterial infection treatment is given to the patients who have yellow sputum and increased levels of procalcitonin and other bacterial infection specific indicators. Notes for case and course record The medical record of integrated Chinese and western medicine treatment for each case should be carefully filled. A summary of the medical record is made every three days. The name and dosage of the traditional Chinese medicine and western medicine used, the route of administration, curative effect, and side effects are recorded. The record form of the curative effect should be filled every day.

Official Title
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Efficacy and Safety of High-dose Vitamin C Combined With Traditional Chinese Medicine in the Treatment of Moderate and Severe Coronavirus Pneumonia (COVID-19)

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Alpha-interferon alpha, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste, fumigation/inhalation of vitamin C
* Drug: Alpha-interferon, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste and 5% glucose
* Drug: Alpha-interferon, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste and high-dose vitamin C treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with mild and severe COVID-19 confirmed according to the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) that was issued by the National Health Commission & State Administration of Traditional Chinese Medicine; Patients with suspected COVID-19 who meet one of the following pathogenic or serological evidence are also confirmed infected with the virus: a) COVID-19 nucleic acid test positive, as confirmed by real-time fluorescence RT-PCR detection; b) viral gene sequencing is highly homologous with the known COVID-19; c) serum test positive for both COVID-19 specific IgM and IgG antibodies; d) serum IgG antibody turns positive from negative or IgG antibody level in the recovering phase rises four times or higher than in the acute phase Patients with moderate COVID-19 have fever and respiratory symptoms and present with the imaging features of coronavirus disease Subjects will be considered developing severe COVID-19 if one of the following conditions occur: a) dyspnea, respiratory ≥ 30 beats/minute, blood oxygen saturation ≤ 93%, partial pressure of arterial oxygen (PaO2)/ fraction of inspired oxygen ratio (FiO2) ≤ 300, and /or lung infiltrates > 50% within 24 to 48 hours Age > 18 years, of either sex Provision of written informed consent Exclusion Criteria: Patients with critical COVID-19 presenting with shock, acute respiratory distress syndrome, multiple organ failure Patients with mild COVID-19 Pregnant or lactating woman Upon the investigator's judgment, patients had the diseases that possibly influence patient participation in this study or study outcomes (such as malignant disease, autoimmune disease, severe malnutrition, liver and kidney disease, blood disease, nervous system disease, endocrine diseases) or currently suffer from the diseases that seriously affect the immune system (such as human immunodeficiency virus infection) or blood system, or splenectomy/organ transplantation. Upon the request of the investigators or sponsors, patients with other acute malignant or chronic disease or mental disorder are not suitable for participation in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Parallel Assignment
Interventional Model Description: participants are assigned to one of two or more groups in parallel for the duration of the study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: moderate COVID-19 group<br>patients with moderate COVID-19 receiving western medicine treatment | Drug: Alpha-interferon alpha, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste, fumigation/inhalation of vitamin C<br>* Atomized inhalation of 5 million U α-interferon and 2 mL sterilized water, twice a day; 0.2 g arbidol, three times a day, treatment course no more than 10 days; intravenous administration of ribavirin 500 mg, once every 12 hours, treatment course no more than 10 days; intravenous administration of 10 g immunoglobulin C, once a day, 3-5 days. Anti-bacterial infection treatment is given to the patients who have yellow sputum and increased levels of procalcitonin and other bacterial infection specific indicators.<br>* Other names: Western medicine treatment;|
| Experimental: severe COVID-19 group<br>patients with severe COVID-19 receiving western medicine treatment | Drug: Alpha-interferon alpha, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste, fumigation/inhalation of vitamin C<br>* Atomized inhalation of 5 million U α-interferon and 2 mL sterilized water, twice a day; 0.2 g arbidol, three times a day, treatment course no more than 10 days; intravenous administration of ribavirin 500 mg, once every 12 hours, treatment course no more than 10 days; intravenous administration of 10 g immunoglobulin C, once a day, 3-5 days. Anti-bacterial infection treatment is given to the patients who have yellow sputum and increased levels of procalcitonin and other bacterial infection specific indicators.<br>* Other names: Western medicine treatment;|
| Experimental: moderate COVID-19 with traditional Chinese medicine group<br>patients with moderate COVID-19 receiving western medicine treatment + traditional Chinese medicine + intravenous administration of 5% glucose | Drug: Alpha-interferon, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste and 5% glucose<br>* Buzhong Yiqi plus and minus formula: 1 dose once, twice a day, taking with warm water. Huhuang Detoxicity Paste: One dose once, twice a day, taking with warm water; Baimu Qingre Jiedu Paste: One dose once, twice a day, taking with warm water; Fumigation/inhalation of Chinese herbs and vitamin C: 30-40 minutes once, 3-7 times a day. Patients take vitamin E capsule and folic acid every day. plus invention 1<br>* Other names: Traditional Chinese medicine treatment plus Western medicine treatment;|
| Experimental: moderate COVID-19 with combination therapy group<br>patients with moderate COVID-19 receiving western medicine treatment + traditional Chinese medicine + intravenous administration of 5% glucose containing high-dose vitamin C | Drug: Alpha-interferon, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste and 5% glucose<br>* Buzhong Yiqi plus and minus formula: 1 dose once, twice a day, taking with warm water. Huhuang Detoxicity Paste: One dose once, twice a day, taking with warm water; Baimu Qingre Jiedu Paste: One dose once, twice a day, taking with warm water; Fumigation/inhalation of Chinese herbs and vitamin C: 30-40 minutes once, 3-7 times a day. Patients take vitamin E capsule and folic acid every day. plus invention 1<br>* Other names: Traditional Chinese medicine treatment plus Western medicine treatment;|
| Experimental: severe COVID-19 with traditional Chinese medicine group<br>patients with severe COVID-19 receiving western medicine treatment + traditional Chinese medicine + intravenous administration of 5% glucose | Drug: Alpha-interferon, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste and high-dose vitamin C treatment<br>* invention 1 plus invention 2 plus 100 mL of 5% glucose containing vitamin C (10 g/60 kg body mass) is intravenously administered twice a day.<br>* Other names: Traditional Chinese medicine treatment plus Western medicine treatment plus Bolus administration of vitamin C;|
| Experimental: severe COVID-19 with combination therapy group<br>patients with severe COVID-19 receiving western medicine treatment + traditional Chinese medicine + intravenous administration of 5% glucose containing high-dose vitamin C | Drug: Alpha-interferon, abidol, ribavirin, Buzhong Yiqi plus and minus formula, Huhuang Detoxicity Paste, Baimu Qingre Jiedu Paste and high-dose vitamin C treatment<br>* invention 1 plus invention 2 plus 100 mL of 5% glucose containing vitamin C (10 g/60 kg body mass) is intravenously administered twice a day.<br>* Other names: Traditional Chinese medicine treatment plus Western medicine treatment plus Bolus administration of vitamin C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recovery time | The discharge criteria of Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) are applied: a) body temperature is back to normal for more than three days; b) respiratory symptoms improve obviously; c) pulmonary imaging shows obvious resolution of inflammation; d) nuclei acid tests negative twice consecutively on respiratory tract samples such as sputum and nasopharyngeal swabs (sampling interval being at least 24 hours) | From date of randomization until the date of discharge, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of disappearance of fever symptoms | Time of disappearance of fever in degrees centigrade | From date of randomization until the date of discharge, assessed up to 6 months | 
| The rate of conversion from COVID-19 positive to COVID-19 negative | The rate of conversion from COVID-19 positive to COVID-19 negative | From date of randomization until the date of discharge, assessed up to 6 months. | 
| Time of disappearance of cough | Time of disappearance of cough in times per day | From date of randomization until the date of discharge, assessed up to 6 months | 
| Respiratory rate | Respiratory rate in times/minute with blood gas analysis | 1-14 days after treatment | 
| Blood oxygen saturation | Blood oxygen saturation in percent with blood gas analysis | 1-14 days after treatment | 
| PaO2 | PaO2 in kPa with blood gas analysis | 1-14 days after treatment | 
| PaCO2 | PaCO2 in kPa with blood gas analysis | 1-14 days after treatment | 
| The time of obvious improvement as shown on chest CT scans relative to admission | The time in days of patients of obvious improvement as shown on chest CT scans relative to admission | From date of randomization until the date of discharge, assessed up to 6 months | 
| The rate of obvious improvement as shown on chest CT scans relative to admission | The rate in percentages of patients of obvious improvement as shown on chest CT scans relative to admission | From date of randomization until the date of discharge, assessed up to 6 months | 
| Levels of C-reactive protein | Levels of C-reactive protein measurement in mg/L | 1-14 days after treatment | 
| Erythrocyte sedimentation rate | Erythrocyte sedimentation rate in mm/h | 1-14 days after treatment | 
| Levels of Procalcitonin | Levels of Procalcitonin in ng/mL | 1-14 days after treatment | 
| Levels of interleukin-6 | Serum Levels of interleukin-6 in ng/L | 1-14 days after treatment | 
| Levels of interleukin-10 | Levels of interleukin-10 in ng/L | 1-14 days after treatment | 
| Levels of tumor necrosis factor-alpha | Levels of tumor necrosis factor-alpha in ng/mL | 1-14 days after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, vitamin C, traditional Chinese medicine