<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04487964</url>
  </required_header>
  <id_info>
    <org_study_id>0925-0586</org_study_id>
    <nct_id>NCT04487964</nct_id>
  </id_info>
  <brief_title>Complementary Intervention for COVID-19</brief_title>
  <official_title>Evaluation of The Potential Therapeutic Effects of Licorice and Boswellia Serrata Gum in Egyptian Patients With COVID-19 as a Complementary Medicine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Egyptian Biomedical Research Network</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Egyptian Biomedical Research Network</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Boswellia Serrata gum and Licorice extract are two nutritional agents that have&#xD;
      pharmacological actions that could support the medical intervention for COVID-19. They have&#xD;
      broad antiviral activity, anti-inflammatory, anti-lung injury, antibacterial activity,&#xD;
      antithrombic formation, and immunomodulatory activity.&#xD;
&#xD;
      The study will be conducted after January 18, 2017&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Since last December 2019, a syndrome of severe pneumonia associated with the coronavirus&#xD;
      disease 2019 (COVID-19) emerged in Wuhan, Hubei Province, China. It is highly contagious and&#xD;
      rapidly spread to many other parts of China and almost all countries all over the world,&#xD;
      representing one of the most aggressive pandemics ever reported.&#xD;
&#xD;
      To date, April 21, 2020, More than 2.5 million persons were infected and more than 171.000&#xD;
      deaths with more fears all over the world from the multiplication of the total deaths. This&#xD;
      huge no. of patients made a horrible pressure on health care facilities in all countries and&#xD;
      lots of patients were not able to receive the appropriate medical care in hospitals WHO&#xD;
      declared that to date, there is no specific medicine recommended to prevent or treat the&#xD;
      novel coronavirus. However, in China, historically, when the outbreak started, Traditional&#xD;
      Chinese medicine (TCM) approaches including oral administration of preventive herbal&#xD;
      formulae, wearing TCM sachets, indoor herbal medicine fumigation, etc. were recommended for&#xD;
      prevention and treatment.&#xD;
&#xD;
      For example, in 2003, TCM approaches were used to prevent and treat severe acute respiratory&#xD;
      syndrome (SARS) which was the most serious infectious disease outbreak in China prior to the&#xD;
      COVID-19. In 2009, during the pandemic of H1N1 influenza around the world, the National&#xD;
      Administration of Traditional Chinese Medicine of China issued a CM prevention program, which&#xD;
      included 4 Chinese herbal medicine (CHM) formulae for adults of different CM body&#xD;
      constitutions and one for children. The current outbreak of COVID-19 resulted in many&#xD;
      provinces in China issuing CM prevention and control programs, among which the prevention&#xD;
      programs are mainly oral CHM formulae.&#xD;
&#xD;
      Glycyrrhizin, a component of many formulae, has reported having anti-inflammatory, antiviral&#xD;
      and antioxidant properties. Also, Boswellia Gum Resin has many active components that have&#xD;
      many medicinal properties such as antimicrobial, antioxidant, antifungal, anti-inflammatory,&#xD;
      immuno-modulatory.&#xD;
&#xD;
      Efficacy:&#xD;
&#xD;
        1. The two agents have broad-spectrum antiviral effects in-vitro and in in-vivo in&#xD;
           preclinical and clinical studies:&#xD;
&#xD;
           A. There are clinical studies about the efficacy of licorice in severe acute respiratory&#xD;
           syndrome-related coronavirus, This can be of major importance in the coronavirus&#xD;
           infections, since immunodeficiency patients may be particularly at risk.&#xD;
&#xD;
           B. There are traditional use and clinical experience of Chinese traditional Medicine&#xD;
           containing licorice in the treatment of COVID 19.&#xD;
&#xD;
        2. The two agents have anti-inflammatory effects and blocking the production of cytokines&#xD;
           which are the main causes for the severity of diseases.&#xD;
&#xD;
        3. The two agents have antioxidant effects, prevent tissue damages in the lungs.&#xD;
&#xD;
        4. The two agents inhibit the airway mass hyperplasia so, they alleviate anoxia state and&#xD;
           improve clinical symptoms.&#xD;
&#xD;
        5. The two agents are used in the treatment of bronchial asthma and respiratory&#xD;
           inflammatory disorders.&#xD;
&#xD;
        6. Licorice has antithrombin and antiplatelet effects so, it alleviates the&#xD;
           hypercoagulation induced by COVID 19.&#xD;
&#xD;
        7. Licorice enhances the production of interferon-gamma that has high activity against the&#xD;
           replication of the virus.&#xD;
&#xD;
      Safety:&#xD;
&#xD;
        1. Licorice and Boswellia Gum Resin had been considered as a food supplement or nutritional&#xD;
           agents, so they have high safety margins in recommended doses, However, there is a&#xD;
           contraindication for the use of licorice in non controlled hypertensive patients.&#xD;
&#xD;
        2. Hypertensive patients and patients sensitive to hypokalemia are excluded from this&#xD;
           study. Regarding other patients, many studies documented that Hypertension may develop&#xD;
           as an adverse reaction after chronic use of large doses.&#xD;
&#xD;
        3. Excessive consumption of licorice for a long time (more than 2 mg/kg/day of pure&#xD;
           glycyrrhizinic acid, a licorice component) may result in adverse effects, such as&#xD;
           hypokalemia, increased blood pressure, and muscle weakness. People with previously&#xD;
           existing heart or kidney problems may be more susceptible to GZA and licorice poisoning.&#xD;
           It is important to monitor the amount of licorice consumed in order to prevent toxicity.&#xD;
&#xD;
      More interesting, It has been shown that monoammonium glycyrrhizinate injection or&#xD;
      glycyrrhizic acid exerts a protective influence on myocardial ischemic injury induced by&#xD;
      isoproterenol by inhibiting oxidative stress and regulating Ca2+ homeostasis, therefore, it&#xD;
      may be useful in the management of myocardial ischemic injury.&#xD;
&#xD;
      Isoliquiritigenin has reported having a significant anti-platelet action in vivo by&#xD;
      inhibiting cyclooxygenase and lipoxygenase or peroxidase activity in platelets.&#xD;
&#xD;
      Glycyrrhizin (GL) elicits effective antithrombotic action (prevent thrombosis), as it was&#xD;
      considered as an effective thrombin inhibitor.&#xD;
&#xD;
      However, the most important side effect is the induction of hypertension, and it can induce&#xD;
      what appears to be pseudohyperaldosteronism, due to glycyrrhetinic acid the main active&#xD;
      component of the root. Glycyrrhetinic acid and metabolites block the 11 beta-hydroxysteroid&#xD;
      dehydrogenase type 2 and also bind mineralocorticoid receptors directly, acting as agonists.&#xD;
&#xD;
      Boswellia serrate (B.serrata) is used traditionally to treat chronic inflammatory diseases&#xD;
      such as in acute systemic inflammation, accompanied liver dysfunction, and chronic&#xD;
      inflammatory diseases. Recent studies show that Boswellia serrate can improve the clinical&#xD;
      outcomes along with conventional therapies in ischaemic stroke. This action is due to the&#xD;
      anti-inflammatory properties of the main bioactive compounds Boswellic acids (BAs). It&#xD;
      inhibits the pro-inflammatory cytokines such as interleukin-1 β (IL-1 β), tumor necrosis&#xD;
      factor-α (TNF-α), interferon-gamma (IFN-γ), and inhibit 5-lipoxygenase (5-LOX) and therefore&#xD;
      shuts down mechanisms of leukotrienes, which are inflammatory mediators.&#xD;
&#xD;
      Many studies investigate the role of Boswellia serrata for the treatment of various&#xD;
      inflammatory conditions of respiratory disorders such as asthma, bronchitis, and laryngitis,&#xD;
      and cough. The anti-asthmatic potential of Boswellic acid which possesses significant&#xD;
      anti-inflammatory activities, the data suggest that the mechanism by which it effectively&#xD;
      treats bronchial asthma is based on reductions of Th2 cytokines via inhibition of a signal&#xD;
      transducer and activator of transcription (pSTAT6) and GATA-3 expression and inhibit&#xD;
      leukotriene biosynthesis which suppressed allergic airway inflammation. This treatment showed&#xD;
      improvement of disease as evidenced by the disappearance of physical symptoms and signs such&#xD;
      as dyspnea, rhonchi, number of attacks, as well as a decrease in the eosinophilic count.&#xD;
&#xD;
      The antiviral effect of Boswellia serrata and its components as boswellic acid was&#xD;
      investigated against HSV-1, Chikungunya virus (CHIKV) and vesicular stomatitis virus, the&#xD;
      mechanism of the effect of Boswellia acids against Herpes Simplex Virus (HSV) may through the&#xD;
      inhibition of nuclear factor - kappa B (NF-κB), essential for virus replication, and observed&#xD;
      significant down-regulation of NF-κB, and the mitogen-activated protein kinase (p38&#xD;
      MAP-kinase) activation, in addition, to reduce expression of tumor necrosis factor (TNF)-α,&#xD;
      Interleukin (IL)-1β and IL-6. Also, boswellic acid had been used in the outbreak of&#xD;
      Chikungunya virus (CHIKV) a broad antiviral agent by blocking of entry of CHIKV&#xD;
      Env-pseudotyped lentiviral vectors and inhibited CHIKV infection in vitro.&#xD;
&#xD;
      . Pharmacokinetic studies&#xD;
&#xD;
      Aim of the work:&#xD;
&#xD;
      To evaluate the therapeutic role of Licorice extract and Boswellia serrate gum as a&#xD;
      complementary intervention in addition to conventional therapy in Egyptian patients with&#xD;
      COVID-19.&#xD;
&#xD;
      All included patients will be diagnosed according to the Egyptian Ministry of Health and&#xD;
      population criteria for COVID-19 diagnosis:&#xD;
&#xD;
      Epidemiological history:&#xD;
&#xD;
        1. History of travel to or residence in communities where cases reported within 14 days&#xD;
           prior to the onset of the disease&#xD;
&#xD;
        2. In contact with viral RNA positive people within 14 days prior to disease onset.&#xD;
&#xD;
        3. In contact with patients who have a fever or respiratory symptoms from communities&#xD;
           confirmed cases reported within 14 days before disease onset Clinical features:&#xD;
&#xD;
      1. Fever and/or respiratory symptoms. 2. Imaging characteristics. 3. The white blood cell&#xD;
      count was normal or decreased, with lymphocyte decreased.&#xD;
&#xD;
      Diagnosis of any suspected patient should follow the following criteria:&#xD;
&#xD;
        1. Anyone of the epidemiological history with any of the clinical features. OR&#xD;
&#xD;
        2. All three clinical features. OR&#xD;
&#xD;
        3. Severe Acute Respiratory Infection (SARI) with no other obvious cause.&#xD;
&#xD;
      Confirmed Cases:&#xD;
&#xD;
        1. RT-PCR indicates positive for novel coronavirus RNA&#xD;
&#xD;
        2. Viral specific IgM and IgG are detectable in serum&#xD;
&#xD;
        3. Viral specific IgG is detectable from negative to positive, OR&#xD;
&#xD;
        4. Viral specific IgG antibody reaches a titration of at least 4-fold higher in the&#xD;
           recovery stage than in the acute stage.&#xD;
&#xD;
      All patients will have the following investigations:&#xD;
&#xD;
        1. X-ray chest/CT chest&#xD;
&#xD;
        2. CBC with differential count&gt;, total blood picture&#xD;
&#xD;
        3. Arterial Blood Gas Test (ABG).&#xD;
&#xD;
        4. C-reactive protein (CRP)&#xD;
&#xD;
        5. D-Dimer.&#xD;
&#xD;
        6. Serum ferritin.&#xD;
&#xD;
        7. Triglycerides.&#xD;
&#xD;
        8. Fibrinogen.&#xD;
&#xD;
        9. Serum aspartate aminotransferase.&#xD;
&#xD;
       10. Renal functions.&#xD;
&#xD;
       11. Troponin T, Troponin I, if myocarditis is suspected. The study will be launched in at&#xD;
           least one center related to the Ministry of Health and following the protocol&#xD;
           recommended by the Scientific Committee and its dynamic changes that occur from time to&#xD;
           time.&#xD;
&#xD;
      The study population will be divided into two groups of patients:&#xD;
&#xD;
      A- Group 1: Will include patients who are receiving conventional therapy according to the MOH&#xD;
      protocol.&#xD;
&#xD;
      B- Group 2: Will include patients who will receive Licorice and Boswellia Serrata gum in&#xD;
      addition to conventional therapy.&#xD;
&#xD;
      Dosage form:&#xD;
&#xD;
      LICORICE CAPSULES; 250 mg standardized extract (25% Glycyrrhizin - 62.5 mg).&#xD;
&#xD;
      Dose:&#xD;
&#xD;
      One capsule, Two times daily, before meals For 10 days, with measuring blood pressure daily.&#xD;
&#xD;
      Boswellia serrata Gum Resin; B. serrate contains volatile oils (5-15%), pure resin (55-66%),&#xD;
      and mucus (12-23%). The resin contains terpenoids, phenolic compounds, flavonoids, and&#xD;
      phenylpropanoids. More than 12 different Boswellic acids have been identified, the amounts of&#xD;
      11-keto-β-boswellic acid KBA is 3-4.7% and acetyl-11-keto-β-boswellic acid(AKBA) is 2.2-2.9%,&#xD;
      Dose: 2 gm, 4 times daily For 15 days, Boswellia Gum Resin is administered by chewing for the&#xD;
      half-hour&#xD;
&#xD;
      Statistical analysis:&#xD;
&#xD;
      All data will be analyzed statistically by using Statistical Product and Service Solutions&#xD;
      (SPSS) version 18, to detect any statistically significant differences between the two groups&#xD;
      which include comparing the 2 groups in all clinical and laboratory variables and statistical&#xD;
      significance was considered when p-value &lt;0.05, also will use univariate and multivariate&#xD;
      analysis to show if any differences in the 2 groups.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2020</start_date>
  <completion_date type="Actual">December 1, 2021</completion_date>
  <primary_completion_date type="Actual">November 1, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Pilot study</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Increased number of people recovering from COVID-19</measure>
    <time_frame>14 days</time_frame>
    <description>Conversion of RT-PCR indicates positive for novel coronavirus RNA to negative</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Decrease number of patients that require respiratory support ,</measure>
    <time_frame>14 days</time_frame>
    <description>Decrease number of patients that require respiratory support , management in the Intensive Care Unit (ICU) and need Mechanical Ventilation Support with endotracheal intubation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decrease duration of hospital stay</measure>
    <time_frame>7 days</time_frame>
    <description>Rapid recovery</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>the conventional therapy according to the MOH protocol.</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients who are receiving conventional therapy according to the MOH protocol.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>conventional therapy +Liquorice cap and Boswellia Serrata gum</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive Liquorice cap and Boswellia Serrata gum in addition to conventional therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Licorice extract</intervention_name>
    <description>LICORICE CAPSULES; 250 mg standardized extract (25% Glycyrrhizin - 62.5 mg) For 10 days, with measuring blood pressure daily.&#xD;
Dose:&#xD;
One capsule, twice daily, before meals. Boswellia serrata Gum Resin; B. serrate contains volatile oils (5-15%), pure resin (55-66%), and mucus (12-23%). The resin contains terpenoids, phenolic compounds, flavonoids, and phenylpropanoids. More than 12 different Boswellic acids have been identified, the amounts of 11-keto-β-boswellic acid KBA is 3-4.7% and acetyl-11-keto-β-boswellic acid(AKBA) is 2.2-2.9%, Dose: 2 gm, 4 times daily For 15 days, Boswellia Gum Resin is administered by chewing for a half-hour</description>
    <arm_group_label>conventional therapy +Liquorice cap and Boswellia Serrata gum</arm_group_label>
    <arm_group_label>the conventional therapy according to the MOH protocol.</arm_group_label>
    <other_name>Boswellia serrata Gum</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Symptomatic and laboratory-confirmed diagnosis of COVID-19.&#xD;
&#xD;
          -  RT-PCR indicates positive for novel coronavirus RNA&#xD;
&#xD;
          -  Viral specific IgM and IgG are detectable in serum&#xD;
&#xD;
          -  Viral specific IgG is detectable from negative to positive, OR&#xD;
&#xD;
          -  Viral specific IgG antibody reaches a titration of at least 4-fold higher in the&#xD;
             recovery stage than in the acute stage&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are not fulfilling the diagnostic criteria for COVOID-19.&#xD;
&#xD;
          -  Pregnant women.&#xD;
&#xD;
          -  Critically ill patients who are mechanically ventilated since admission.&#xD;
&#xD;
          -  Hypertensive patients.&#xD;
&#xD;
          -  Congestive heart failure patients&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adel A. Gomaa, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Professor of Medical pharmacology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Faculty of Medicine, Assiut University</name>
      <address>
        <city>Assiut</city>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
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  </reference>
  <reference>
    <citation>Guo A, He D, Xu HB, Geng CA, Zhao J. Promotion of regulatory T cell induction by immunomodulatory herbal medicine licorice and its two constituents. Sci Rep. 2015 Sep 15;5:14046. doi: 10.1038/srep14046.</citation>
    <PMID>26370586</PMID>
  </reference>
  <reference>
    <citation>Li X, He X, Liu B, Xu L, Lu C, Zhao H, Niu X, Chen S, Lu A. Maturation of murine bone marrow-derived dendritic cells induced by Radix Glycyrrhizae polysaccharide. Molecules. 2012 May 30;17(6):6557-68. doi: 10.3390/molecules17066557.</citation>
    <PMID>22728353</PMID>
  </reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>July 24, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>March 21, 2022</last_update_submitted>
  <last_update_submitted_qc>March 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Egyptian Biomedical Research Network</investigator_affiliation>
    <investigator_full_name>Adel Gomaa</investigator_full_name>
    <investigator_title>Professor of medical pharmacology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>A pilot study for evaluation of the potential therapeutic effect of food supplement, licorice extract, and Boswellia Serrata gum</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
  </patient_data>
  <study_docs>
    <study_doc>
      <doc_id>EgyptianBiomedicalRN</doc_id>
      <doc_type>Study Protocol</doc_type>
      <doc_url>https://drive.google.com/file/d/1JF9GMByaEHNRiKMssyEchmPTV_V5dRp_/view?usp=sharing</doc_url>
      <doc_comment>this link describ the study protocol</doc_comment>
    </study_doc>
  </study_docs>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04487964
org study id: 0925-0586
nct id: NCT04487964
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Boswellia Serrata gum and Licorice extract are two nutritional agents that have
      pharmacological actions that could support the medical intervention for COVID-19. They have
      broad antiviral activity, anti-inflammatory, anti-lung injury, antibacterial activity,
      antithrombic formation, and immunomodulatory activity.

      The study will be conducted after January 18, 2017
Since last December 2019, a syndrome of severe pneumonia associated with the coronavirus
      disease 2019 (COVID-19) emerged in Wuhan, Hubei Province, China. It is highly contagious and
      rapidly spread to many other parts of China and almost all countries all over the world,
      representing one of the most aggressive pandemics ever reported.

      To date, April 21, 2020, More than 2.5 million persons were infected and more than 171.000
      deaths with more fears all over the world from the multiplication of the total deaths. This
      huge no. of patients made a horrible pressure on health care facilities in all countries and
      lots of patients were not able to receive the appropriate medical care in hospitals WHO
      declared that to date, there is no specific medicine recommended to prevent or treat the
      novel coronavirus. However, in China, historically, when the outbreak started, Traditional
      Chinese medicine (TCM) approaches including oral administration of preventive herbal
      formulae, wearing TCM sachets, indoor herbal medicine fumigation, etc. were recommended for
      prevention and treatment.

      For example, in 2003, TCM approaches were used to prevent and treat severe acute respiratory
      syndrome (SARS) which was the most serious infectious disease outbreak in China prior to the
      COVID-19. In 2009, during the pandemic of H1N1 influenza around the world, the National
      Administration of Traditional Chinese Medicine of China issued a CM prevention program, which
      included 4 Chinese herbal medicine (CHM) formulae for adults of different CM body
      constitutions and one for children. The current outbreak of COVID-19 resulted in many
      provinces in China issuing CM prevention and control programs, among which the prevention
      programs are mainly oral CHM formulae.

      Glycyrrhizin, a component of many formulae, has reported having anti-inflammatory, antiviral
      and antioxidant properties. Also, Boswellia Gum Resin has many active components that have
      many medicinal properties such as antimicrobial, antioxidant, antifungal, anti-inflammatory,
      immuno-modulatory.

      Efficacy:

        1. The two agents have broad-spectrum antiviral effects in-vitro and in in-vivo in
           preclinical and clinical studies:

           A. There are clinical studies about the efficacy of licorice in severe acute respiratory
           syndrome-related coronavirus, This can be of major importance in the coronavirus
           infections, since immunodeficiency patients may be particularly at risk.

           B. There are traditional use and clinical experience of Chinese traditional Medicine
           containing licorice in the treatment of COVID 19.

        2. The two agents have anti-inflammatory effects and blocking the production of cytokines
           which are the main causes for the severity of diseases.

        3. The two agents have antioxidant effects, prevent tissue damages in the lungs.

        4. The two agents inhibit the airway mass hyperplasia so, they alleviate anoxia state and
           improve clinical symptoms.

        5. The two agents are used in the treatment of bronchial asthma and respiratory
           inflammatory disorders.

        6. Licorice has antithrombin and antiplatelet effects so, it alleviates the
           hypercoagulation induced by COVID 19.

        7. Licorice enhances the production of interferon-gamma that has high activity against the
           replication of the virus.

      Safety:

        1. Licorice and Boswellia Gum Resin had been considered as a food supplement or nutritional
           agents, so they have high safety margins in recommended doses, However, there is a
           contraindication for the use of licorice in non controlled hypertensive patients.

        2. Hypertensive patients and patients sensitive to hypokalemia are excluded from this
           study. Regarding other patients, many studies documented that Hypertension may develop
           as an adverse reaction after chronic use of large doses.

        3. Excessive consumption of licorice for a long time (more than 2 mg/kg/day of pure
           glycyrrhizinic acid, a licorice component) may result in adverse effects, such as
           hypokalemia, increased blood pressure, and muscle weakness. People with previously
           existing heart or kidney problems may be more susceptible to GZA and licorice poisoning.
           It is important to monitor the amount of licorice consumed in order to prevent toxicity.

      More interesting, It has been shown that monoammonium glycyrrhizinate injection or
      glycyrrhizic acid exerts a protective influence on myocardial ischemic injury induced by
      isoproterenol by inhibiting oxidative stress and regulating Ca2+ homeostasis, therefore, it
      may be useful in the management of myocardial ischemic injury.

      Isoliquiritigenin has reported having a significant anti-platelet action in vivo by
      inhibiting cyclooxygenase and lipoxygenase or peroxidase activity in platelets.

      Glycyrrhizin (GL) elicits effective antithrombotic action (prevent thrombosis), as it was
      considered as an effective thrombin inhibitor.

      However, the most important side effect is the induction of hypertension, and it can induce
      what appears to be pseudohyperaldosteronism, due to glycyrrhetinic acid the main active
      component of the root. Glycyrrhetinic acid and metabolites block the 11 beta-hydroxysteroid
      dehydrogenase type 2 and also bind mineralocorticoid receptors directly, acting as agonists.

      Boswellia serrate (B.serrata) is used traditionally to treat chronic inflammatory diseases
      such as in acute systemic inflammation, accompanied liver dysfunction, and chronic
      inflammatory diseases. Recent studies show that Boswellia serrate can improve the clinical
      outcomes along with conventional therapies in ischaemic stroke. This action is due to the
      anti-inflammatory properties of the main bioactive compounds Boswellic acids (BAs). It
      inhibits the pro-inflammatory cytokines such as interleukin-1 β (IL-1 β), tumor necrosis
      factor-α (TNF-α), interferon-gamma (IFN-γ), and inhibit 5-lipoxygenase (5-LOX) and therefore
      shuts down mechanisms of leukotrienes, which are inflammatory mediators.

      Many studies investigate the role of Boswellia serrata for the treatment of various
      inflammatory conditions of respiratory disorders such as asthma, bronchitis, and laryngitis,
      and cough. The anti-asthmatic potential of Boswellic acid which possesses significant
      anti-inflammatory activities, the data suggest that the mechanism by which it effectively
      treats bronchial asthma is based on reductions of Th2 cytokines via inhibition of a signal
      transducer and activator of transcription (pSTAT6) and GATA-3 expression and inhibit
      leukotriene biosynthesis which suppressed allergic airway inflammation. This treatment showed
      improvement of disease as evidenced by the disappearance of physical symptoms and signs such
      as dyspnea, rhonchi, number of attacks, as well as a decrease in the eosinophilic count.

      The antiviral effect of Boswellia serrata and its components as boswellic acid was
      investigated against HSV-1, Chikungunya virus (CHIKV) and vesicular stomatitis virus, the
      mechanism of the effect of Boswellia acids against Herpes Simplex Virus (HSV) may through the
      inhibition of nuclear factor - kappa B (NF-κB), essential for virus replication, and observed
      significant down-regulation of NF-κB, and the mitogen-activated protein kinase (p38
      MAP-kinase) activation, in addition, to reduce expression of tumor necrosis factor (TNF)-α,
      Interleukin (IL)-1β and IL-6. Also, boswellic acid had been used in the outbreak of
      Chikungunya virus (CHIKV) a broad antiviral agent by blocking of entry of CHIKV
      Env-pseudotyped lentiviral vectors and inhibited CHIKV infection in vitro.

      . Pharmacokinetic studies

      Aim of the work:

      To evaluate the therapeutic role of Licorice extract and Boswellia serrate gum as a
      complementary intervention in addition to conventional therapy in Egyptian patients with
      COVID-19.

      All included patients will be diagnosed according to the Egyptian Ministry of Health and
      population criteria for COVID-19 diagnosis:

      Epidemiological history:

        1. History of travel to or residence in communities where cases reported within 14 days
           prior to the onset of the disease

        2. In contact with viral RNA positive people within 14 days prior to disease onset.

        3. In contact with patients who have a fever or respiratory symptoms from communities
           confirmed cases reported within 14 days before disease onset Clinical features:

      1. Fever and/or respiratory symptoms. 2. Imaging characteristics. 3. The white blood cell
      count was normal or decreased, with lymphocyte decreased.

      Diagnosis of any suspected patient should follow the following criteria:

        1. Anyone of the epidemiological history with any of the clinical features. OR

        2. All three clinical features. OR

        3. Severe Acute Respiratory Infection (SARI) with no other obvious cause.

      Confirmed Cases:

        1. RT-PCR indicates positive for novel coronavirus RNA

        2. Viral specific IgM and IgG are detectable in serum

        3. Viral specific IgG is detectable from negative to positive, OR

        4. Viral specific IgG antibody reaches a titration of at least 4-fold higher in the
           recovery stage than in the acute stage.

      All patients will have the following investigations:

        1. X-ray chest/CT chest

        2. CBC with differential count>, total blood picture

        3. Arterial Blood Gas Test (ABG).

        4. C-reactive protein (CRP)

        5. D-Dimer.

        6. Serum ferritin.

        7. Triglycerides.

        8. Fibrinogen.

        9. Serum aspartate aminotransferase.

       10. Renal functions.

       11. Troponin T, Troponin I, if myocarditis is suspected. The study will be launched in at
           least one center related to the Ministry of Health and following the protocol
           recommended by the Scientific Committee and its dynamic changes that occur from time to
           time.

      The study population will be divided into two groups of patients:

      A- Group 1: Will include patients who are receiving conventional therapy according to the MOH
      protocol.

      B- Group 2: Will include patients who will receive Licorice and Boswellia Serrata gum in
      addition to conventional therapy.

      Dosage form:

      LICORICE CAPSULES; 250 mg standardized extract (25% Glycyrrhizin - 62.5 mg).

      Dose:

      One capsule, Two times daily, before meals For 10 days, with measuring blood pressure daily.

      Boswellia serrata Gum Resin; B. serrate contains volatile oils (5-15%), pure resin (55-66%),
      and mucus (12-23%). The resin contains terpenoids, phenolic compounds, flavonoids, and
      phenylpropanoids. More than 12 different Boswellic acids have been identified, the amounts of
      11-keto-β-boswellic acid KBA is 3-4.7% and acetyl-11-keto-β-boswellic acid(AKBA) is 2.2-2.9%,
      Dose: 2 gm, 4 times daily For 15 days, Boswellia Gum Resin is administered by chewing for the
      half-hour

      Statistical analysis:

      All data will be analyzed statistically by using Statistical Product and Service Solutions
      (SPSS) version 18, to detect any statistically significant differences between the two groups
      which include comparing the 2 groups in all clinical and laboratory variables and statistical
      significance was considered when p-value <0.05, also will use univariate and multivariate
      analysis to show if any differences in the 2 groups.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Pilot study
primary purpose: Prevention
masking: None (Open Label)
measure: Increased number of people recovering from COVID-19
time frame: 14 days
description: Conversion of RT-PCR indicates positive for novel coronavirus RNA to negative
measure: Decrease number of patients that require respiratory support ,
time frame: 14 days
description: Decrease number of patients that require respiratory support , management in the Intensive Care Unit (ICU) and need Mechanical Ventilation Support with endotracheal intubation.
measure: Decrease duration of hospital stay
time frame: 7 days
description: Rapid recovery
arm group label: the conventional therapy according to the MOH protocol.
arm group type: Active Comparator
description: Patients who are receiving conventional therapy according to the MOH protocol.
arm group label: conventional therapy +Liquorice cap and Boswellia Serrata gum
arm group type: Active Comparator
description: Patients will receive Liquorice cap and Boswellia Serrata gum in addition to conventional therapy
intervention type: Dietary Supplement
intervention name: Licorice extract
description: LICORICE CAPSULES; 250 mg standardized extract (25% Glycyrrhizin - 62.5 mg) For 10 days, with measuring blood pressure daily.
Dose:
One capsule, twice daily, before meals. Boswellia serrata Gum Resin; B. serrate contains volatile oils (5-15%), pure resin (55-66%), and mucus (12-23%). The resin contains terpenoids, phenolic compounds, flavonoids, and phenylpropanoids. More than 12 different Boswellic acids have been identified, the amounts of 11-keto-β-boswellic acid KBA is 3-4.7% and acetyl-11-keto-β-boswellic acid(AKBA) is 2.2-2.9%, Dose: 2 gm, 4 times daily For 15 days, Boswellia Gum Resin is administered by chewing for a half-hour
arm group label: conventional therapy +Liquorice cap and Boswellia Serrata gum
arm group label: the conventional therapy according to the MOH protocol.
other name: Boswellia serrata Gum
criteria: 
gender: All
minimum age: 12 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Adel A. Gomaa, Ph.D.
role: Principal Investigator
affiliation: Professor of Medical pharmacology
facility: 
country: Egypt
citation: Yu X, Bao Y, Meng X, Wang S, Li T, Chang X, Xu W, Yang G, Bo T. Multi-pathway integrated adjustment mechanism of licorice flavonoids presenting anti-inflammatory activity. Oncol Lett. 2019 Nov;18(5):4956-4963. doi: 10.3892/ol.2019.10793. Epub 2019 Sep 4.
PMID: 31612007
citation: Mollica L, De Marchis F, Spitaleri A, Dallacosta C, Pennacchini D, Zamai M, Agresti A, Trisciuoglio L, Musco G, Bianchi ME. Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem Biol. 2007 Apr;14(4):431-41. doi: 10.1016/j.chembiol.2007.03.007.
PMID: 17462578
citation: Kong D, Wang Z, Tian J, Liu T, Zhou H. Glycyrrhizin inactivates toll-like receptor (TLR) signaling pathway to reduce lipopolysaccharide-induced acute lung injury by inhibiting TLR2. J Cell Physiol. 2019 Apr;234(4):4597-4607. doi: 10.1002/jcp.27242. Epub 2018 Sep 10.
PMID: 30203548
citation: Ammon HP. Modulation of the immune system by Boswellia serrata extracts and boswellic acids. Phytomedicine. 2010 Sep;17(11):862-7. doi: 10.1016/j.phymed.2010.03.003. Epub 2010 Aug 8. Erratum In: Phytomedicine. 2011 Feb 15;18(4):334.
PMID: 20696559
citation: Ammon HP. Boswellic Acids and Their Role in Chronic Inflammatory Diseases. Adv Exp Med Biol. 2016;928:291-327. doi: 10.1007/978-3-319-41334-1_13.
PMID: 27671822
citation: Baram SM, Karima S, Shateri S, Tafakhori A, Fotouhi A, Lima BS, Rajaei S, Mahdavi M, Tehrani HS, Aghamollaii V, Aghamiri SH, Mansouri B, Gharahje S, Kabiri S, Hosseinizadeh M, Shahamati SZ, Alborzi AT. Functional improvement and immune-inflammatory cytokines profile of ischaemic stroke patients after treatment with boswellic acids: a randomized, double-blind, placebo-controlled, pilot trial. Inflammopharmacology. 2019 Dec;27(6):1101-1112. doi: 10.1007/s10787-019-00627-z. Epub 2019 Aug 12.
PMID: 31407195
citation: Beghelli D, Isani G, Roncada P, Andreani G, Bistoni O, Bertocchi M, Lupidi G, Alunno A. Antioxidant and Ex Vivo Immune System Regulatory Properties of Boswellia serrata Extracts. Oxid Med Cell Longev. 2017;2017:7468064. doi: 10.1155/2017/7468064. Epub 2017 Mar 13.
PMID: 28386311
citation: Eltahir HM, Fawzy MA, Mohamed EM, Alrehany MA, Shehata AM, Abouzied MM. Antioxidant, anti-inflammatory and anti-fibrotic effects of Boswellia serrate gum resin in CCl4-induced hepatotoxicity. Exp Ther Med. 2020 Feb;19(2):1313-1321. doi: 10.3892/etm.2019.8353. Epub 2019 Dec 19.
PMID: 32010304
citation: Goswami D, Mahapatra AD, Banerjee S, Kar A, Ojha D, Mukherjee PK, Chattopadhyay D. Boswellia serrata oleo-gum-resin and beta-boswellic acid inhibits HSV-1 infection in vitro through modulation of NF-small ka, CyrillicB and p38 MAP kinase signaling. Phytomedicine. 2018 Dec 1;51:94-103. doi: 10.1016/j.phymed.2018.10.016. Epub 2018 Oct 16.
PMID: 30466633
citation: Zhou X, Cai JG, Zhu WW, Zhao HY, Wang K, Zhang XF. Boswellic acid attenuates asthma phenotype by downregulation of GATA3 via nhibition of PSTAT6. Genet Mol Res. 2015 Jul 6;14(3):7463-8. doi: 10.4238/2015.July.3.22.
PMID: 26214425
citation: Loeser K, Seemann S, Konig S, Lenhardt I, Abdel-Tawab M, Koeberle A, Werz O, Lupp A. Protective Effect of Casperome(R), an Orally Bioavailable Frankincense Extract, on Lipopolysaccharide- Induced Systemic Inflammation in Mice. Front Pharmacol. 2018 Apr 20;9:387. doi: 10.3389/fphar.2018.00387. eCollection 2018.
PMID: 29731716
citation: Roy NK, Parama D, Banik K, Bordoloi D, Devi AK, Thakur KK, Padmavathi G, Shakibaei M, Fan L, Sethi G, Kunnumakkara AB. An Update on Pharmacological Potential of Boswellic Acids against Chronic Diseases. Int J Mol Sci. 2019 Aug 22;20(17):4101. doi: 10.3390/ijms20174101.
PMID: 31443458
citation: Soni KK, Meshram D, Lawal TO, Patel U, Mahady GB. Fractions of Boswellia Serrata Suppress LTA4, LTC4, Cyclooxygenase-2 Activities and mRNA in HL-60 Cells and Reduce Lung Inflammation in BALB/c Mice. Curr Drug Discov Technol. 2021;18(1):95-104. doi: 10.2174/1570163817666200127112928.
PMID: 31985381
citation: von Rhein C, Weidner T, Henss L, Martin J, Weber C, Sliva K, Schnierle BS. Curcumin and Boswellia serrata gum resin extract inhibit chikungunya and vesicular stomatitis virus infections in vitro. Antiviral Res. 2016 Jan;125:51-7. doi: 10.1016/j.antiviral.2015.11.007. Epub 2015 Dec 2.
PMID: 26611396
citation: Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003 Jun 14;361(9374):2045-6. doi: 10.1016/s0140-6736(03)13615-x.
PMID: 12814717
citation: Redeploying plant defences. Nat Plants. 2020 Mar;6(3):177. doi: 10.1038/s41477-020-0628-0.
PMID: 32170291
citation: Wang L, Yang R, Yuan B, Liu Y, Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm Sin B. 2015 Jul;5(4):310-5. doi: 10.1016/j.apsb.2015.05.005. Epub 2015 Jun 17.
PMID: 26579460
citation: Sun ZG, Zhao TT, Lu N, Yang YA, Zhu HL. Research Progress of Glycyrrhizic Acid on Antiviral Activity. Mini Rev Med Chem. 2019;19(10):826-832. doi: 10.2174/1389557519666190119111125.
PMID: 30659537
citation: Luo P, Liu D, Li J. Pharmacological perspective: glycyrrhizin may be an efficacious therapeutic agent for COVID-19. Int J Antimicrob Agents. 2020 Jun;55(6):105995. doi: 10.1016/j.ijantimicag.2020.105995. Epub 2020 Apr 24.
PMID: 32335281
citation: Guo A, He D, Xu HB, Geng CA, Zhao J. Promotion of regulatory T cell induction by immunomodulatory herbal medicine licorice and its two constituents. Sci Rep. 2015 Sep 15;5:14046. doi: 10.1038/srep14046.
PMID: 26370586
citation: Li X, He X, Liu B, Xu L, Lu C, Zhao H, Niu X, Chen S, Lu A. Maturation of murine bone marrow-derived dendritic cells induced by Radix Glycyrrhizae polysaccharide. Molecules. 2012 May 30;17(6):6557-68. doi: 10.3390/molecules17066557.
PMID: 22728353
responsible party type: Principal Investigator
investigator affiliation: Egyptian Biomedical Research Network
investigator full name: Adel Gomaa
investigator title: Professor of medical pharmacology
mesh term: COVID-19
sharing ipd: Yes
ipd description: A pilot study for evaluation of the potential therapeutic effect of food supplement, licorice extract, and Boswellia Serrata gum
ipd info type: Study Protocol
study doc: 