Treatment of Early-Stage Covid-19 With a Herbal Compound, Xagrotin
Phase: PHASE1
Conditions: Covid19
Sponsor: Biomad AS

1 
 
 
Treatment of Early-Stage Covid-19 With a Herbal Compound, 
Xagrotin  
NCT05017493 
ClinicalTrials.gov Submission Date 30- NOVEMBER -2021 
Unique Protocol Identification Number: 02-032021-SULXAG/NO 
Protocol Version 1.4.2:   24- NOVEMBER-2021 
Study Type: Interventional 
Record Verification Date: March, 2021 
Board Approval Number:  118/KRGJUL/CH/ADM/ 09  
Board Name:  Institutional Ethical Committee 
Board Affiliation: Directorate of health of Sulaimani, Iraq -KRG 
 
Study start Date: 
July 1, 2020 
[Actual] 
Primary Completion Date: 
December 7, 2020 
[Actual] 
Study Completion Date: 
February 8, 2021 
[Actual] 
 
Sponsor: 
Biomad AS 
Responsible Party: 
Sponsor 
Collaborators: 
Directorate of health of Sulaimani, Iraq -KRG 
 
 
 

2 
 
Introduction: 
In designing and manufacturing new drugs, two new and strong trends have emerged. 
Biotechnology has developed a new group of biological drugs, and offers a completely 
new approach to drug design. And there is a growing trend towards the use of herbal 
products in the treatment of diseases (Robert,2000). The use of medicinal plants for 
the treatment of diseases has been around for centuries, and is still considered a major 
treatment in many developed and developing countries (Sindambiwe,1999). Currently, 
most modern drugs are chemical. But at the same time, about 30% of pharmaceutical 
products are of plant origin (Robert,2000). New research has shown that some herbs 
are used in traditional medicine. They have antiviral effects. The extract of some plants 
has been described as an antiviral agent (Vanden,1986). In particular, the antiviral 
effects of several types of flavonoids (Hayashi,1992 & 1997), Anthraquinones and their 
derivatives have been studied (Andersen, 1991 & Sydiskis, 1991). Hypericin and 
Pseudohypericin Which have a significant effect on retroviruses. From plant species 
Hypericum are taken (Meruelo,1988). It has also been shown that entroquinones that 
inhibit polyphenolic or sulfonate bridges inhibit the reverse transcriptase enzyme 
(Schinazi, 1990). Treatment of viral infections with existing drugs for reasons such as 
drug resistance due to mutations in viruses. Some latent infections and recurrent 
infections sometimes fail. Therefore, there is a growing need to find new antiviral 
compounds (Field,1994). Research on medicinal plants and their compounds is a useful 
strategy in this regard (Vlietinck, 1991). In the present study, the effects of inhibiting 
the antiviral activity of a herbal drug consisting of several plant species on the clinical 
status of 35 positive corona patients were investigated. 
Related studies 
The coronavirus disease 2019 (COVID-19) pandemic has caused a worldwide outbreak 
of respiratory illness. This review aims to evaluate the effectiveness and adverse events 
of herbal medicines for the treatment of COVID-19. METHODS: Twelve databases were 
searched through 12 May 2020. Randomized controlled trials (RCTs) and quasi-RCTs 

3 
 
assessing the effects of herbal medicines for the treatment of COVID-19 were eligible. 
The study selection and data extraction were performed by two independent 
reviewers. The Cochrane risk of bias tool was used for the assessment of the risk of bias 
in all included RCTs. Mean differences (MDs), risk ratios (RRs) and odds ratios (ORs) with 
95% confidence intervals (CIs) were calculated, and the effect sizes of the studies were 
pooled. RESULTS: Seven RCTs with a total of 855 patients were included. All included 
trials compared the combined therapy of herbal medicine with Western medicine to 
Western medicine alone. The combined therapy significantly improved the total 
effective rate (RR 1.23, 95% CI 1.13 to 1.34, p < 0.001), cough symptom disappearance 
rate (RR 1.45, 95% CI 1.12 to 1.89, p = 0.005), and sputum production symptom 
disappearance rate (RR 1.73, 95% CI 1.19 to 2.50, p = 0.004). Beneficial effects of the 
combined therapy were also seen in TCM syndrome score of cough (MD -1.18, 95% CI 
-1.34 to -1.03, p < 0.001), fever (MD -0.62, 95% CI -0.79 to -0.45, p < 0.001), dry and 
sore throat (MD -0.83, 95% CI -1.45 to -0.20, p = 0.009), and fatigue (MD -0.60, 95% CI 
-1.04 to -0.17, p = 0.007). The overall risk of bias of the included studies was unclear. 
No serious adverse events were reported. CONCLUSION: Significant effects of the 
combined therapy of herbal medicine with Western medicine were found, and revealed 
the potential role of herbal medicine in treating COVID-19. More high-quality RCTs are 
needed to further validate the effectiveness and adverse events of herbal medicine in 
the treatment of COVID-19.  ) Ang, L., et al, 2020).  
Coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2) is evolving across the world and new treatments 
are urgently needed as with vaccines to prevent the illness and stem the contagion. The 
virus affects not only the lungs but also other tissues, thus lending support to the idea 
that COVID-19 is a systemic disease. The current vaccine and treatment development 
strategies ought to consider such systems medicine perspectives rather than a 
narrower focus on the lung infection only. COVID-19 is associated with elevated levels 
of the inflammatory cytokines such as interleukin-6 (IL-6), IL-10, and interferon-gamma 
(IFN-gamma). Elevated levels of cytokines and the cytokine storm have been linked to 

4 
 
fatal disease. This suggests new therapeutic strategies through blocking the cytokine 
storm. IL-6 is one of the major cytokines associated with the cytokine storm. IL-6 is also 
known to display pleiotropic/diverse pathophysiological effects. We suggest the 
blockage of IL-6 signaling and its downstream mediators such as Janus kinases (JAKs), 
and signal transducer and activators of transcription (STATs) offer potential hope for 
the treatment of severe cases of COVID-19. Thus, repurposing of already approved IL-
6-JAK-STAT signaling inhibitors as well as other anti-inflammatory drugs, including 
dexamethasone, is under development for severe COVID-19 cases. We conclude this 
expert review by highlighting the potential role of precision herbal medicines, for 
example, the Cannabis sativa, provided that omics technologies can be utilized to build 
a robust scientific evidence base on their clinical safety and efficacy. Precision herbal 
medicine buttressed by omics systems science would also help identify new molecular 
targets for drug discovery against COVID-19. (Dzobo, K., et al, 2021).  
Coronavirus disease 2019 (COVID-19) is a novel, human-infecting beta-coronavirus 
enveloped, positive-sense single-stranded RNA viruses, similar to the severe acute 
respiratory syndrome (SARS) infection that emerged in November 2002. In traditional 
Chinese medicine (TCM), the epidemic disease concepts of "febrile epidemics" (wenyi) 
or "warm diseases" (wenbing) are based on geographic and cultural aspects, and 
Chinese herbal medicine (CHM) played an important role in the treatment of epidemic 
diseases. CHM was widely used to treat patients suffered with SARS almost two decades 
ago during outbreak of SARS, with proven safety and potential benefits. TCM has also 
been widely used to treat cancer patients for a long history and much of them associate 
with immunomodulatory activity and are used to treat coronavirus-related diseases. 
We propose the use of CHM treatment principles for clinical practice, based on four 
main stages of COVID-19 infection: early, intermediate, severe, and convalescence. We 
suggest corresponding decoctions that exhibit antiviral activity and anti-inflammatory 
effects in the early stage of infection; preventing the disease from progressing from an 
intermediate to severe stage of infection; restoring normal lung function and improving 
consciousness in the severe stage; and ameliorating pulmonary and vascular injury in 

5 
 
the convalescent stage. We summarize the pharmaceutical mechanisms of CHM for 
treating coronavirus via antiviral, anti-inflammatory and immunomodulatory effects. 
(Huang, S. T., et al, 2020).  
Background: There is currently no effective treatment against coronavirus disease 2019 
(COVID-19). The optimal selection of interventions targeting the virus is unknown. 
Therefore, evidence from randomized controlled trials (RCTs) to support specific 
treatment against COVID-19 is urgently needed. The use of Chinese herbal medicines 
(CHMs) might have a role in the treatment and symptomatic management of patients 
with COVID-19. It was aimed at providing an overview of the available evidence and 
ongoing trials concerning the effects of CHMs for the treatment of COVID-19. Methods: 
This is a narrative review of relevant studies. Searches were conducted to identify 
documents published till April 22, 2020. Electronic databases, evidence-based 
collections, websites of relevant organizations, and trial registries were consulted. 
Results: A total of 25 guidelines on the treatment of patients with COVID-19 were 
identified. Four guidelines provided recommendations on the use of CHMs; these 
guidelines were developed in China and South Korea and were based on the consensus 
of experts exclusively. The remaining 21 guidelines provided no guidance on CHMs. No 
finished RCTs of CHMs for the treatment of patients with COVID-19 was found. 
According to the evidence evaluated in this review, a Cochrane review of CHMs for 
severe acute respiratory syndrome and five uncontrolled observational studies of the 
effects of CHMs in patients with COVID-19, the effects of CHMs for COVID-19 are 
unknown. A total of 52 ongoing clinical trials of CHM interventions for the treatment of 
COVID-19 were found. These trials will be carried out mostly in China (n = 51). Forty 
(77%) of the ongoing trials will be randomized, whereas 12 (23%) have an unclear 
sequence generation procedure. Forty-seven trials (90%) will have a sample size <400 
participants. Conclusions: To the authors' knowledge, only the Chinese and the South 
Korean guidelines recommend CHMs as a treatment option for patients with COVID-19. 
These guidelines base their recommendations on the consensus of experts. Clinical 
guidelines or health authorities from other countries do not provide advice on CHMs. 

6 
 
Due to the absence of RCT, there is currently no reliable evidence on the effects of any 
specific CHM intervention for the treatment of patients with COVID-19. A high number 
of clinical trials of different herbal products are being currently conducted in China. 
(Lopez-Alcalde, J., et al, 2020).  
Coronavirus disease 2019(COVID-19) refers to the pneumonia caused by novel 
coronavirus(2019-nCoV) infection in 2019. It is highly infectious, with quick spreading 
and a wide range of impact. It has been broken out in many countries around the world 
and has become a public health emergency of international concern. Chinese medicine 
has a long history in treating plague, and viral disease is the clinical advantage in Chinese 
medicine. Under the premise that there is currently no specific drug treatment, Chinese 
medicine has achieved certain effects in the treatment of COVID-19, which has 
attracted much attention and has been upgraded to a national strategy. Regarding the 
treatment of COVID-19 with Chinese medicine, it is believed that in terms of the name 
of Chinese medicine, the modern connotation of &quot;uniform of typhoid and febrile 
disease&quot; should be re-recognized, and it is advisable to use drugs based on 
specific clinical prescriptions and indications. In terms of pathogenesis, the COVID-19 
has the pathogenesis rules including from the mild to severe conditions, from the 
surface to the inside, from the excess syndrome to the deficiency syndrome. We should 
pay attention to the Taiyang syndrome damaged by wet disease in initial stage, 
Shaoyang syndrome complicated with Yangming syndrome in the middle stage, 
phlegm-heat obstructing lung in critical period, lung and spleen deficiency in the 
recovery stage. In terms of clinical treatment strategies, Dayuan Yin is recommended 
to induce sweat and disperse the stasis in early stage. Xiaochaihu Decoction and Maxing 
Shigan Decoction is used to relieve both exterior and interior symptoms in middle stage. 
In critical stage, Tingli Dazao Xiefei Decoction, Weijing Decoction, Xuanbai Chengqi 
Decoction, Xiaoxianxiong Decoction, and Sanzi Yangqin Decoction are considered to 
reduce phlegm and clear heat. We should pay attention to nourishing Qi and 
strengthening the spleen by Zhuye Shigao Decoction, Sha-shen Maidong Decoction, and 
Liujunzi Decoction in the later recovery period. It shall be noted that, no matter in the 

7 
 
initial mild stage, the middle and critical stages, or in the later recovery stage, Chinese 
medicine plays an important role, including preventing mild to severe disease, 
shortening the fever time, improving cough symptoms, increasing blood oxygen 
saturation and reducing mortality. Many studies have shown that the classical herbal 
formulae can alleviate the cytokine storm, regulate the immune imbalance, and 
produce the potential effect of synergistic treatment for COVID-19 through multiple 
components, multiple targets, and multiple pathways. (Su, K. L. and X. J. Xiong, 2021).  
Background: In January, national guidelines were developed and recommended for use 
throughout China to fight coronavirus disease 2019 (COVID-19). Chinese herbal 
medicine (CHM) was also included as part of the treatment plans at various stages of 
COVID-19. Methods: We conducted a pilot randomized, controlled trial in patients with 
severe COVID-19 in Wuhan, China. Eligible adult patients were randomly assigned in a 
2:1 ratio to receive either CHM plus standard care or standard care alone for 7 days. 
The primary outcome was the change in the disease severity category of COVID-19 after 
treatment. Results: Between Jan 31, 2020, and Feb 19, 2020, 42 out of 100 screened 
patients were included in the trial: 28 in the CHM plus standard care group and 14 in 
the standard care alone group. Among 42 participants who were randomized (mean 
[SD] age 60.43 years [12.69 years]), 21 (21/42, 50%) were aged >/=65 years, 35 (35/42, 
83%) were women, and 42 (42/42, 100%) had data available for the primary outcome. 
For the primary outcome, one patient from each group died during treatment; the odds 
of a shift toward death was lower in the CHM plus group than in the standard care alone 
group (common OR 0.59, 95% CI 0.148-2.352, P = 0.454). Three (two from the CHM 
plus group and one from the standard care alone group) patients progressed from 
severe to critical illness. After treatment, mild, moderate, and severe COVID-19 disease 
accounted for 17.86% (5/28) vs. 14.29% (2/28), 71.43% (20/28) vs. 64.29% (9/28), and 
0% (0) vs. 7.14% (1/28) of the patients treated with CHM plus standard care vs. standard 
care alone. Conclusions: For the first time, the G-CHAMPS trial provided valuable 
information for the national guideline-based CHM treatment of hospitalized patients 
with severe COVID-19. The effects of CHM in COVID-19 may be clinically important and 

8 
 
warrant 
further 
consideration 
and 
studies. 
Clinical 
Trial 
Registration: 
http://www.chictr.org.cn/index.aspx. Uniqueidentifier: ChiCTR2000029418. (Ye, Y. A. 
and G. C. C. Group, 2020). 
STUDY DESCRIPTION: 
The study has retrospectively investigated outcome of patients with Covid-19 who have 
been tested positive for Covid-19 and immediately after that treated with a herbal-
compound called Xagrotin. The outcome is compared to the outcome of patients in 
same situation who have treated with standard treatment for Covid-19, but not 
including Xagrotin. 361 patients included in the first group and 178 in the second group. 
We analyzed the effect of drug, and also investigated impact of different factors, for 
instance gender, age, duration of disease, smoking habits and concomitant diseases on 
the outcome. Adverse events were also registered. 
Key word: Covid-19, Herbal Compound, Xagrotin 
STUDY DESIGN 
This is an interventional, multi-center, randomized study in adult patients with Covid-
19 that was conducted for 5 months (June 2020 – December 2020). The present study 
was performed to treat the risks of coronavirus disease. This study consisted of two 
phases and in parallel. Informed consent was obtained from all patients. In this study, 
539 adults with laboratory or clinically confirmed Covid-19 disease in an outpatient 
setting were enrolled and divided into two groups: the study group (n=361) treated 
with Xagrotin extract 2 grams three times a day, plus the standard of care for covid-19, 
and the control group (n=178) was treated with the standard of care for covid-19, 
respectively. Patients enrolled in the current study at approximately 20 cities. 
Inclusion Criteria 
All adult patients in an outpatient setting who were confirmed as coronavirus patients 
were eligible to be included in the study. 

9 
 
Exclusion Criteria 
In this study, we excluded the patients with the following criteria; age under 18 years, 
patients with incomplete information regarding sex, age, duration of disease, any drug 
usage, symptoms, …etc. 
Safety endpoints 
The herbal medicine Xagrotin is a combination of several local plants from the Zagros 
Mountains located in Kurdistan. In various studies, these plants have been studied 
individually for different pathological conditions. The side effects have been reported 
safe, but the results showed that it is somewhat capable of affecting CYP3A4. Therefore, 
Combined usage of Xagrotin with drug should be closely monitored. The level of LC50 
1844±2/34 mg/kg was obtained. In this study, by examining the doses of these plants 
in previous studies, their safest dose was calculated. These safe dosages combined to 
formulate Xagrotin. Due to the unavailability of Covid-19 vaccination in Iran and the 
deadly outbreak of the virus, Xagrotin was made available to the local population along 
with this study. 
 
 
 
 
 
 
 
 
 
 

10 
 
OUTCOME MEASURES 
This outcome e study has the following three main criteria. 
 
Row 
Outcome 
Title 
Time Frame 
Description 
1 
Primary 
Outcome 
Measure: 
Mortality 
30 days 
Survival at 30th day time point 
2 
Primary 
Outcome 
Measure: 
Duration of 
disease 
30 days 
Number 
of 
days 
the 
patient 
has 
experienced the symptoms 
3 
Secondary 
Outcome 
Measure:   
Hospitalization 
30 days 
Number of participants who have been 
hospitalized for Covid-19 
 
Eligibility Criteria:  
The participants in this study are of both sexes (male-female) and the target age is 
between 18-94 years. 
• Inclusion Criteria:Age 18 or higher, Newly diagnosed (no longer than 10 days), 
PCR or clinically confirmed Covid-19 
• Exclusion Criteria: Severe pulmonary disease, Severe cardiovascular disease, 
Severe hepatic disease, Severe renal disease,  
• Diabetes mellitus type one, Metabolic acidosis, Oxygen saturation <70%, 
Pregnancy, Breast feeding, Concomitant treatment with anticoagulation drugs, 
Concomitant treatment with CYP3A4 medicines with narrow therapeutic 
window 
 
 
 

11 
 
 
CONTACTS 
 
Central Contact Person:  Dana Omer1 – Seyed Mohammad Hosseini2 
Facility Contact: Mani Avrin3  
Investigators: Hemen Moradi-Sardareh4 
 
Reference 
1. Andersen DO, Weber ND, Wood SG, Hughes BG, Murray BK, North JA. In vitro virucidal 
activity of selected anthraquinones and anthraquinone derivatives. Antiviral Res 1991; 
16: 185–196. 
2. Ang, L., et al. (2020). "Herbal Medicine for the Treatment of Coronavirus Disease 2019 
(COVID-19): A Systematic Review and Meta-Analysis of Randomized Controlled Trials." 
J Clin Med 9(5). 
3. Dzobo, K., et al. (2021). "Coronavirus Disease-2019 Treatment Strategies Targeting 
Interleukin-6 Signaling and Herbal Medicine." OMICS 25(1): 13-22. 
4. Field AK, Biron KK. The end of innocerice revisited: resistance of herpes virus to antiviral 
drugs. Clin Microbiol Rev 1994; 7: 1-13. 
5. Hayashi K, Hayashi T, Morita N. Mechanism of action of the anti-herpesvirus biflavone 
ginketin. Antimicrob Agents Chemother 1992; 36:1890–1893. 
6. Hayashi K, Hayashi T, Otsuka H, Takeda Y. Antiviral activity of 5, 6, 7-trimethoxyflavone 
and its potentiation of the anti-herpes activity of acyclovir. J Antimicrob Chemother 
1997; 39:821–824. 
 
1 . Dana Omer, PhD of Hematology, Hiwa Hospital – Sulaimani, danaomar1979@gmail.com, 
+964  7701586707 
2 . Seyed Mohammad Hosseini, PhD of microbiology, Tehran University of Research 
Sciences, scpmicro@gmail.com, +989141676041 
3 . mani.avrin@gmail.com, +4745806145 
4 .  Hemen Moradi-Sardareh,  PhD of Clinical Biochemistry 

12 
 
7.   Huang, S. T., et al. (2020). "Principles and treatment strategies for the use of Chinese 
herbal medicine in patients at different stages of coronavirus infection." Am J Cancer 
Res 10(7): 2010-2031. 
8. Lopez-Alcalde, J., et al. (2020). "Current State of Research About Chinese Herbal 
Medicines (CHM) for the Treatment of Coronavirus Disease 2019 (COVID-19): A Scoping 
Review." J Altern Complement Med 26(7): 557-570. 
9. Robert Yuan, Yuan Lin; Traditional Chinese Medicine: an approach to scientific proof 
and clinical validation. Pharmacology & Therapeutics 2000, 86: 191–198. 
10. Schinazi, RF, Chu CK, Babu JR, Oswald BJ, Saalmann V, Cannon DL, Eriksson BFH., Nasar 
M. Anthraquinones as a new class of antiviral agents against human immunodeficiency 
virus. Antiviral Res 1990; 13: 265–272. 
11. Sindambiwe JB, Calomme M, Cos P, Totte J, Pieters L, Vlietinck A, Vanden Berghe D. 
Screening of seven selected Rwandan medicinal plants for antimicrobial and antiviral 
activities. Journal of Ethnopharmacology 1999; 65: 71–77. 
12. Su, K. L. and X. J. Xiong (2021). "[Treatment strategy and thought on classical herbal 
formulae for coronavirus disease 2019]." Zhongguo Zhong Yao Za Zhi 46(2): 494-503. 
13. Sydiskis RJ, Owen DG, Lohr JL, Rosler KH, Blomster RN. Inactivation of enveloped viruses 
by anthraquinones extracted from plants. Antimicrob Agents Chemother 1991; 35: 
2463–2466. 
14. Vlietinck AJ, Vanden Berghe DA. Can ethnopharmacology contribute to the 
development of antiviral drugs J Ethnopharmacol 1991; 32: 141-53. 
15.  Ye, Y. A. and G. C. C. Group (2020). "Guideline-Based Chinese Herbal Medicine 
Treatment Plus Standard Care for Severe Coronavirus Disease 2019 (G-CHAMPS): 
Evidence from China." Front Med (Lausanne) 7: 256.