Shenhuang granule in the treatment of severe coronavirus disease 2019 (COVID-19): study protocol for an open-label randomized controlled clinical trial

In December 2019, an outbreak of unexplained pneumonia has been diagnosed in Wuhan, Hubei Province, in China, with an epidemiological link to seafood and wet animal wholesale market where there was also sale of live animals [1, 2]. The Chinese scientists isolated an unknown coronavirus from the patient’s respiratory epithelial cells of patients and performed genome sequencing of the virus [3]. Now, this new virus is named “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),” and it causes “coronavirus disease 2019 (COVID-19).” Although COVID-19 is considered to be the origin of zoonotic diseases, human-to human transmission has been occurred [4]. It initially erupted in Wuhan and later spread to all parts of the world, resulting in 2,954,222 confirmed cases, including 202,597 deaths globally as 28 April 2020, which caused a global health emergency [5].

The COVID-19 belongs to the family Coronaviridae and order Nidovirales, and is detected in bats, with similarity in clinical features and genetic sequence to SARS-CoV [3, 6]. Many patients of COVID-19 suffer from fever, fatigue, cough, chest tightness, and dyspnea and some progress to sepsis or septic shock or died of the infection [7]. The diagnosis of new cases includes clinical characteristics, the epidemiological history, and laboratory test according to the “Guidelines for the Diagnosis and Treatment of Novel Coronavirus (COVID-19) Infection by the National Health Commission (Trial Version 7)” [8]. Currently, there is no vaccine or specific antiviral drugs for the infection except meticulous supportive care [9].

TCM, as an important part of complementary and alternative medicine, has been widely applied in preventing and treatment of epidemic disease in China for hundreds of years. Patients with severe COVID-19 often develop into sepsis or septic shock [7]. Severe COVID-19 belongs to the “epidemic febrile disease” in TCM, and the basic pathogenesis is pathogenic toxin and blood stasis. Additionally, severe COVID-19 has some characters of “the acute deficiency syndrome.” As an innovation theory, it refers to the pathological state with a rapid consumption of the vital Qi in the human body, caused by acute and severe pathological factors such as plague, poisoning, hemorrhage, loss of fluid, and all kinds of trauma [10, 11]. Based on TCM characteristic theory “six hollow organs must keep its unobstructed” and “acute deficiency syndrome,” our team put forward “Truncation and Reversion” strategy [12], and the principle on TCM for emergency, “Treating the primary (ben) for emergency cases” [10], timely controlling the course of disease and reverse disease. On the foundation of the above theories, we developed the Shenhuang granule, a formula which is composed of six medicinal herbs, including Panax ginseng (Renshen), Rheum palmatum L. stem (Dahuang), Sargentodoxa cuneate (Hongteng), Taraxacum mongolicum (Pugongying), Aconiti Lateralis Radix Praeparata (Fuzi), and Whitmania pigra Whitman (Shuizhi). Rhubarb is considered a purgative and bactericidal agent to reduce heat and promote blood circulation and resolve dampness [13]. Sargentodoxa cuneate and Taraxacum mongolicum have the same function of clearing heat and detoxifying, activating blood, and removing wind and relieving pain [14, 15]. Our previous studies have demonstrated that Jinhong Decoction, composed of Rheum palmatum L. stem, Sargentodoxa cuneata, and Taraxacum mongolicum, can inhibit the levels of TNF-α, IL-6, IL-8, and other inflammatory cytokines, protect against excessive inflammatory response, and maintain organism’s balance between inflammation and anti-inflammatory in severe infectious diseases [16, 17]. Ginseng has the functions to strongly tonify the Qi, nourishing lungs and spleen, promoting the secretion of saliva and quenching thirst, strengthening the heart, and calming the mind [18]. Several studies recently report that ginseng can directly kill bacteria and regulate bacterial adhesion, inflammation, cytotoxicity, and hemagglutination [19]. Wang et al. [20] report that ginseng extracts can inhibit different strains of influenza viruses. Aconiti Lateralis Radix Praeparata is considered an effective stimulant for the spleen and kidneys [21]. Recent studies report that aconite had antibacterial activity, especially against S. aureus and E. coli, as well as immunoregulation efficacy [22, 23]. Whitmania pigra Whitman has functions of breaking stagnant and eliminating blood stasis. Yao et al. [24] believe that Whitmania pigra Whitman extract effectively reduces deep vein thrombosis by inhibiting inflammation via modulating silent information regulator 1 (SIRT1)/nuclear factor-κB (NF-κB) signaling pathway. Therefore, according to the theory of TCM and modern Western medical research, Shenhuang granule should have beneficial and curative effects on severe COVID-19 [11, 12, 25].

We design this study as a multicenter, randomized, and controlled clinical trial based on the “Truncation and Reversion” strategy of TCM innovation theory and “acute deficiency syndrome.” The aim of this clinical trial is to confirm the effectiveness and safety of Shenhuang granule in blocking the deterioration of severe COVID-19 and provide reliable evidence for clinical research.

COVID-19 mainly causes respiratory tract infections, high infectivity and fatality rate, and serious harm on public health [2]. Common clinical presentations are fever, fatigue, and dry cough and some are accompanied by diarrhea [3]. Several severe patients presented with dyspnea, and some rapidly developed sepsis or septic shock [3]. It is an urgent issue to develop effective drugs against the virus. From the perspective of TCM, pathogenic toxin, blood stasis, and Qi deficiency are considered the main causes of severe COVID-19. According to the innovation theory of “Truncation and Reversion” strategy and “acute deficiency syndrome,” our team developed the Shenhuang granule, a Chinese medicine compound for the symptomatic treatment of severe COVID-19. Shenhuang granule contains Panax ginseng, Rheum palmatum L. stem, Sargentodoxa cuneata, Taraxacum mongolicum, Aconiti Lateralis Radix Praeparata, and Whitmania pigra Whitman. The TCM compounds have antipyretic and purgative effects, promoting blood circulation and removing blood stasis, as well as tonifying the Qi, lung, and spleen. Preliminary clinical trial results indicated that Jinhong Decoction is composed of Rheum palmatum L. stem, Sargentodoxa cuneata, and Taraxacum mongolicum, which can significantly reduce mortality, mechanical ventilation time, and the use of antibiotic, with no adverse reactions such as liver and kidney dysfunction in patients with infection diseases [28, 29]. Therefore, the results of this clinical trial can provide valuable evidence on Shenhuang granule in the treatment of severe COVID-2019. However, the safety of the six medicinal herbs to be administered to patients should always be a concern. A number of preclinical and clinical studies have testified that the dosages of these herbs are far less than toxic dose and are used frequently in clinical treatment with good result, especially in treating severe and critical symptoms [30‐34]. In addition, all the above herbs are qualified with the national standards.

This trial is designed as a multicenter, open-label randomized and controlled clinical study from the perspective of evidence-based medicine and is considered to be the most definitive research method of treatment evaluation of Shenhuang granule. In this trial, we select the 14-day clinical improvement as the primary outcome. The 14-day clinical improvement directly reflects the condition of severe COVID-19 patients and the efficacy of TCM treatment. The secondary outcomes of this trial include the mortality and rate of receiving invasive ventilator in the severe category, the improvement of oxygen saturation, and Acute Physiology and Chronic Health Evaluation (APACHE-II) score. The selected indicators in this study are used to reflect the condition of patients and to evaluate the effectiveness and safety of Shenhuang granule.

We hope this study could further explain the scientific connotation of the treatment of severe COVID-19 based on TCM innovation theory “Truncation and Reversion” strategy and “acute deficiency syndrome,” and open up new ideas and methods for clinical exploration of prevention strategy, TCM, and integrated medicine diagnosis and therapy of COVID-19. Nevertheless, the design of the trial also has potential limitations. The impact of some of the end points, such as a long-term mortality, has not yet been analyzed.