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Frontiers of Medicine

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Front. Med.    2021, Vol. 15 Issue (5) : 704-717    https://doi.org/10.1007/s11684-021-0853-6
RESEARCH ARTICLE
Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial
Li Ni1, Zheng Wen1, Xiaowen Hu2, Wei Tang3, Haisheng Wang4, Ling Zhou1, Lujin Wu1, Hong Wang1, Chang Xu1, Xizhen Xu1, Zhichao Xiao1, Zongzhe Li1, Chene Li1, Yujian Liu1, Jialin Duan1, Chen Chen1, Dan Li1, Runhua Zhang1, Jinliang Li5, Yongxiang Yi6, Wei Huang1,7, Yanyan Chen8, Jianping Zhao9, Jianping Zuo3(), Jianping Weng2(), Hualiang Jiang3,10(), Dao Wen Wang1()
1. Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2. The First Affiliated Hospital of University of Science and Technology of China, Hefei 230026, China
3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4. Harbin Pharmaceutical Group Co., Ltd., Harbin 150070, China
5. The Sixth Hospital of Harbin, Harbin 150036, China
6. The Second Hospital of Nanjing and the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210003, China
7. Department of Cardiology, Chinese People’s Liberation Army Central War Command General Hospital, Wuhan 430010, China
8. Department of Information Management, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
9. Division of Respiratory, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
10. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
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Abstract

We conducted a randomized, open-label, parallel-controlled, multicenter trial on the use of Shuanghuanglian (SHL), a traditional Chinese patent medicine, in treating cases of COVID-19. A total of 176 patients received SHL by three doses (56 in low dose, 61 in middle dose, and 59 in high dose) in addition to standard care. The control group was composed of 59 patients who received standard therapy alone. Treatment with SHL was not associated with a difference from standard care in the time to disease recovery. Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group (93.4% vs. 73.9%, P=0.006). Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia, which was evaluated by density reduction of inflammatory focus from baseline, at day 7 (mean difference (95% CI), −46.39 (−86.83 to −5.94) HU; P=0.025) and day 14 (mean difference (95% CI), −74.21 (−133.35 to −15.08) HU; P=0.014). No serious adverse events occurred in the SHL groups. This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.
Keywords COVID-19      SARS-CoV-2      Shuanghuanglian oral liquid      clinical trial     
Corresponding Author(s): Jianping Zuo,Jianping Weng,Hualiang Jiang,Dao Wen Wang   
Just Accepted Date: 18 March 2021   Online First Date: 27 April 2021    Issue Date: 01 November 2021
 Cite this article:   
Li Ni,Zheng Wen,Xiaowen Hu, et al. Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial[J]. Front. Med., 2021, 15(5): 704-717.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0853-6
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I5/704
Fig.1  Randomization and treatment assignment.
Characteristic Standard care Low-dose SHL Middle-dose SHL High-dose SHL Total
(N = 59) (N = 56) (N = 61) (N = 59) (N = 235)
Age, median (IQR), year 51.00 (38.50, 65.00) 54.00 (42.00, 62.25) 56.00 (44.00, 65.00) 53.00 (41.50, 63.00) 54.00 (42.00, 64.00)
Male sex, no. (%) 25 (42.4) 23 (41.1) 33 (54.1) 27 (45.8) 108 (46.0)
Classification, no. (%)
Mild cases 2 (3.4) 0 1 (1.6) 0 3 (1.3)
Moderate cases 46 (78.0) 43 (76.8) 51 (83.6) 49 (83.1) 189 (80.4)
Severe cases 11 (18.6) 13 (23.2) 9 (14.8) 10 (16.9) 43 (18.3)
Days from illness onset to randomization, median (IQR) 22.00 (14.00, 31.50) 21.50 (16.00, 35.75) 23.00 (18.00, 34.00) 18.00 (14.00, 31.50) 22.00 (15.00, 33.00)
Body temperature (℃), median (IQR) 36.60 (36.30, 36.85) 36.50 (36.20, 36.80) 36.60 (36.30, 36.80) 36.60 (36.40, 36.85) 36.60 (36.30, 36.80)
Heart rate (beat/min), median (IQR) 80.00 (76.00, 89.50) 82.00 (78.75, 90.50) 84.00 (78.00, 94.00) 84.00 (72.00, 94.00) 83.00 (76.00, 92.00)
Respiratory rate (breath/min), median (IQR) 20.00 (20.00, 21.00) 20.00 (19.00, 21.00) 20.00 (19.00, 21.00) 20.00 (19.50, 20.00) 20.00 (19.50, 21.00)
Systolic blood pressure (mmHg), median (IQR) 128.00 (117.00, 146.00) 122.00 (113.75, 133.25) 127.00 (118.00, 139.00) 128.00 (120.00, 140.50) 125.00 (117.50, 141.00)
Fever, no. (%) 7 (11.9) 6 (10.7) 12 (19.7) 10 (16.9) 35 (14.9)
Cough, no. (%) 27 (45.8) 26 (46.4) 25 (41.0) 30 (50.8) 108 (46.0)
Fatigue, no. (%) 12 (20.3) 12 (21.4) 10 (16.4) 14 (23.7) 48 (20.4)
Diarrhea, no. (%) 2 (3.4) 5 (8.9) 5 (8.2) 6 (10.2) 18 (7.7)
White-cell count (× 109/L), median (IQR) 6.23 (4.94, 7.52) 5.77 (4.96, 6.96) 6.34 (5.01, 8.44) 5.41 (4.64, 6.90) 5.95 (4.89, 7.69)
4× 109/L −10 × 109/L, no. (%) 6 (10.2) 8 (14.5) 1 (1.6) 7 (12.1) 22 (9.4)
<4 × 109/L, no. (%) 48 (81.4) 41 (74.5) 53 (86.9) 49 (84.5) 191 (82.0)
>10 × 109/L, no. (%) 5 (8.5) 6 (10.9) 7 (11.5) 2 (3.4) 20 (8.6)
Lymphocyte count (× 109/L), median (IQR) 1.65 (1.21, 2.09) 1.41 (0.98, 1.89) 1.57 (1.16, 1.95) 1.47 (1.19, 1.73) 1.50 (1.14, 1.92)
<1.0 × 109/L, no. (%) 9 (15.3) 16 (29.1) 10 (16.4) 8 (13.8) 43 (18.5)
≥1.0 × 109/L, no. (%) 50 (84.7) 39 (70.9) 51 (83.6) 50 (86.2) 190 (81.5)
Platelet count (× 109/L), median (IQR) 225.00 (179.50, 293.50) 220.00 (194.50, 278.50) 231.00 (192.00, 280.00) 233.50 (195.50, 286.00) 228.00 (192.00, 287.00)
<100 × 109/L, no. (%) 0 1 (1.8) 0 1 (1.7) 2 (0.9)
≥100 × 109/L, no. (%) 59 (100.0) 54 (98.2) 61 (100.0) 57 (98.3) 231 (99.1)
Alanine aminotransferase (U/L), median (IQR) 24.00 (15.50, 44.50) 22.00 (14.00, 36.00) 26.00 (16.50, 42.50) 21.00 (14.00, 39.00) 23.00 (15.00, 40.00)
<40 U/L 42 (71.2) 42 (77.8) 42 (71.2) 46 (80.7) 172 (75.1)
≥40 U/L 17 (28.8) 12 (22.2) 17 (28.8) 11 (19.3) 57 (24.9)
Aspartate aminotransferase (U/L), median (IQR) 22.00 (17.00, 30.50) 19.00 (15.25, 27.75) 20.00 (17.00, 28.00) 21.00 (18.00, 30.00) 21.00 (17.00, 29.00)
<40 U/L 50 (84.7) 47 (87.0) 53 (89.8) 50 (87.7) 200 (87.3)
≥40 U/L 9 (15.3) 7 (13.0) 6 (10.2) 7 (12.3) 29 (12.7)
Serum creatinine (µmol/L), median (IQR) 60.50 (54.00, 73.75) 61.00 (53.25, 73.75) 65.50 (57.75, 79.25) 67.00 (60.00, 77.00) 64.00 (56.00, 77.00)
<133 µmol/L 57 (98.3) 54 (100.0) 60 (100.0) 57 (100.0) 228 (99.6)
≥133 µmol/L 1 (1.7) 0 0 0 1 (0.4)
Lactate dehydrogenase (U/L), median (IQR) 201.00 (169.00, 240.50) 198.00 (160.25, 232.75) 200.00 (153.50, 242.00) 203.00 (181.25, 233.25) 200.00 (163.00, 237.00)
<245 U/L 45 (76.3) 43 (79.6) 45 (75.0) 47 (81.0) 180 (77.9)
≥245 U/L 14 (23.7) 11 (20.4) 15 (25.0) 11 (19.0) 51 (22.1)
Total bilirubin (µmol/L), median (IQR) 9.50 (6.50, 14.05) 9.40 (6.42, 13.17) 9.90 (7.50, 15.10) 9.45 (6.53, 11.80) 9.55 (6.60, 13.10)
<21 µmol/L 56 (94.9) 50 (92.6) 57 (93.4) 55 (94.8) 218 (94.0)
≥21 µmol/L 3 (5.1) 4 (7.4) 4 (6.6) 3 (5.2) 14 (6.0)
Prothrombin time (s), median (IQR) 13.30 (12.97, 13.90) 13.60 (13.20, 14.10) 13.60 (12.80, 14.22) 13.70 (13.20, 14.10) 13.60 (13.00, 14.10)
<16 s 56 (100.0) 50 (94.3) 59 (98.3) 54 (96.4) 219 (97.3)
≥16 s 0 3 (5.7) 1 (1.7) 2 (3.6) 6 (2.7)
Tab.1  Demographic and clinical characteristics of patients at baselinea
Standard care Low-dose SHL Middle-dose SHL High-dose SHL Total
(N = 59) (N = 56) (N = 61) (N = 59) (N = 235)
Coexisting conditions, no. (%)
Hypertension 14 (23.7) 10 (17.9) 20 (32.8) 15 (25.4) 59 (25.1)
Diabetes 8 (13.6) 7 (12.5) 13 (21.3) 9 (15.3) 37 (15.7)
Coronary heart disease 2 (3.4) 3 (5.4) 1 (1.6) 4 (6.8) 10 (4.3)
Respiratory disease 2 (3.4) 0 5 (8.2) 2 (3.4) 9 (3.8)
Treatment, no. (%)
Angiotensin II receptor blocker 0 3 (5.4) 5 (8.2) 1 (1.7) 9 (3.8)
b-blocker 4 (6.8) 4 (7.1) 8 (13.1) 4 (6.8) 20 (8.5)
Calcium channel blockers 10 (16.9) 8 (14.3) 16 (26.2) 14 (23.7) 48 (20.4)
Diuretic 1 (1.7) 2 (3.6) 1 (1.6) 1 (1.7) 5 (2.1)
Antiplatelet drugs 2 (3.4) 3 (5.4) 6 (9.8) 2 (3.4) 13 (5.5)
Chinese herb 0 0 0 1 (1.7) 1 (0.4)
Lianhuaqingwen capsule 22 (37.3) 17 (30.4) 14 (23.0) 13 (22.0) 66 (28.1)
Other Chinese patent medicine 18 (30.5) 9 (16.1) 15 (24.6) 12 (20.3) 54 (23.0)
Lopinavir–ritonavir 2 (3.4) 4 (7.1) 3 (4.9) 1 (1.7) 10 (4.3)
Oseltamivir 12 (20.3) 8 (14.3) 21 (34.4) 16 (27.1) 57 (24.3)
Arbidol 3 (5.1) 6 (10.7) 0 3 (5.1) 12 (5.1)
Other antiviral drugs 31 (52.5) 25 (44.6) 22 (36.1) 26 (44.1) 104 (44.3)
Hydroxychloroquine 4 (6.8) 3 (5.4) 2 (3.3) 3 (5.1) 12 (5.1)
Glucocorticoid therapy 14 (23.7) 6 (10.7) 9 (14.8) 8 (13.6) 37 (15.7)
Intravenous immunoglobulin 4 (6.8) 5 (8.9) 6 (9.8) 3 (5.1) 18 (7.7)
Antibiotics 24 (40.7) 27 (48.2) 30 (49.2) 16 (27.1) 97 (41.3)
Interferon 6 (10.2) 6 (10.7) 5 (8.2) 6 (10.2) 23 (9.8)
Tab.2  Coexisting conditions and combined medicationa
Fig.2  Kaplan–Meier curve for time to disease recovery. (A) Time to disease recovery in different doses of the SHL treatment groups and control group. (B) Time to disease recovery in combined dose of the SHL treatment groups and control group.
Standard care SHL Combined dose groups P value
Low-dose SHL Middle-dose SHL High-dose SHL For trend across doses vs. standard care For combined dose groups vs. standard care
Conversion rate of virusa N = 23 N = 30 N = 31 N = 30 N = 91 0.043 0.006
17 (73.9) 28 (93.3) 30 (96.8) 27 (90.0) 85 (93.4)
Clinical improvementb N = 32 N = 29 N = 28 N = 33 N = 90
Primary symptoms improvement, day 4.00 (2.00, 7.00) 2.00 (2.00, 7.00) 4.00 (2.00, 5.50) 4.00 (2.00, 7.00) 4.00 (2.00, 7.00) 0.914 0.782
Clinical improvement rate, day 7 24 (75.0) 25 (86.2) 24 (85.7) 26 (78.8) 75 (83.3) 0.62 0.301
Hazard ratio (95% CI) – 1.31 (0.75–2.29) 1.28 (0.72–2.25) 1.06 (0.61–1.84) 1.20 (0.76–1.90)
P – 0.765 0.783 0.948 0.835
Clinical improvement rate, day 14 30 (93.8) 29 (100.0) 25 (89.3) 31 (93.9) 85 (94.4) 0.381 0.885
Hazard ratio (95% CI) – 1.34 (0.80–2.24) 1.09 (0.64–1.86) 1.02 (0.62–1.68) 1.13 (0.74–1.72)
P – 0.749 0.92 0.98 0.213
Tab.3  Secondary outcomes
Fig.3  Effects of SHL treatment on the symptoms scores as compared with standard care. Shown are the median symptoms scores. Control, standard care; Low dose, low dose of SHL; Mid dose, middle dose of SHL; High dose, high dose of SHL.
Fig.4  Reduction in density of infection focus on CT imaging from baseline. (A, B) The reduction in density of infection focus on CT imaging from baseline in combined dose of the SHL treatment groups and control group on day 7 (A) and day 14 (B). (C, D) The reduction in density of infection focus on CT imaging from baseline in different doses of the SHL treatment groups and control group on day 7 (C) and day 14 (D). Shown are the mean (standard error of mean, SEM) changes from baseline. Control, standard care; Low dose, low dose of SHL; Mid dose, middle dose of SHL; High dose, high dose of SHL; HU, Hounsfield unit.
Standard care
(N = 59)		 SHL P value
Low-dose SHL Middle-dose SHL High-dose SHL Combined dose groups For trend across doses vs. standard care For combined dose groups vs. standard care
(N = 56) (N = 61) (N = 59) (N = 176)
Rash 0 0 1 (1.6) 2 (3.4) 3 (1.7) 0.303 0.313
Skin allergies 0 1 (1.8) 0 0 1 (0.6) 0.36 0.562
Gastrointestinal discomfort 0 0 3 (4.9) 2 (3.4) 5 (2.8) 0.156 0.191
Nausea 0 1 (1.8) 0 1 (1.7) 2 (1.1) 0.55 0.411
Vomiting 0 0 0 2 (3.4) 2 (1.1) 0.111 0.411
Diarrhea 0 1 (1.8) 0 1 (1.7) 2 (1.1) 0.55 0.411
Abdominal distension and pain 0 0 0 1 (1.7) 1 (0.6) 0.392 0.562
Poor appetite 0 0 1 (1.6) 0 1 (0.6) 0.413 0.562
Hypokalemia 0 0 1 (1.6) 0 1 (0.6) 0.413 0.562
Constipation 1 (1.7) 0 0 0 0 0.392 0.083
Urinary tract infection 0 1 (1.8) 0 0 1 (0.6) 0.36 0.562
Increased aspartate aminotransferase 0 2 (3.6) 0 1 (1.7) 3 (1.7) 0.264 0.313
Increased alanine aminotransferase 1 (1.7) 3 (5.4) 0 1 (1.7) 4 (2.3) 0.237 0.79
Increased g-glutamyl transpeptidase 0 3 (5.4) 0 1 (1.7) 4 (2.3) 0.088 0.243
Hyperlipidemia 0 0 2 (3.3) 0 2 (1.1) 0.124 0.411
Tab.4  Summary of adverse events
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