<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/NCT04454307</url>
  </required_header>
  <id_info>
    <org_study_id>TRAM/COVID19</org_study_id>
    <nct_id>NCT04454307</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Tramadol in COVID-19 Egyptian Patients</brief_title>
  <official_title>Safety and Efficacy of Tramadol Adjuvant Therapy to Standard Care for COVID-19 Egyptian Patients: A Randomized Double Blind Controlled Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tanta University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tanta University</source>
  <oversight_info>
    <has_dmc>Yes</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>
      The rationale of the use of tramadol for COVID-19 patients is attributed to its&#xD;
      anti-inflammatory, hypocagulatory, antioxidant, cardio-protective, analgesic, antitussive,&#xD;
      bactericidal and antidepressant effect.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and Rationale:&#xD;
&#xD;
      T cells play a critical role in antiviral immunity, their level was dramatically reduced in&#xD;
      COVID-19 patients. There is a negative correlation between T cell numbers and cytokines serum&#xD;
      level in COVID-19 patients. In those patients, there is up-regulation of inflammatory&#xD;
      cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and interferon&#xD;
      γ. This makes the use of tramadol reasonable in such patients because it has&#xD;
      anti-inflammatory effect decreasing plasma level of TNF-α after treatment with a dose of 100&#xD;
      mg every 12 hours for 10 days, which may result in a subsequent increase in T cell numbers.&#xD;
&#xD;
      Besides, COVID-19 patients with acute respiratory failure present with severe&#xD;
      hypercoagulability due to hyperfibrinogenemia resulting in increased fibrin formation and&#xD;
      polymerization that may predispose to thrombosis. It has been reported that tramadol has a&#xD;
      hypocoagulable effect in the blood of women with gynecologic malignancies. Consequently,&#xD;
      tramadol may be useful for patients who have a tendency toward a hypercoagulable status and&#xD;
      thromboembolic complications. Moreover, tramadol could affect hemostatic parameters in favor&#xD;
      of bleeding tendency in rats.&#xD;
&#xD;
      On the other hand, the severity and mortality risk of COVID-19 have been associated with the&#xD;
      age. This age-related mortality is attributed to the shortage of antioxidant mechanisms and&#xD;
      increased oxidative damage. Tramadol increased the antioxidant enzymes superoxide dismutase&#xD;
      and glutathione peroxidase while diminished the oxidative stress marker malondialdehyde in&#xD;
      testicular ischemia-reperfusion injury in rats. Owing to its antioxidant properties, tramadol&#xD;
      could reduce complications in COVID-19 patients.&#xD;
&#xD;
      Moreover, tramadol was reported to significantly lower lactate dehydrogenase (LDH) level and&#xD;
      to provide a cardio-protective effect. This property of tramadol seems beneficial since it&#xD;
      was found that, about 60% of COVID-19 patients are presented with elevated LDH levels.&#xD;
      Tramadol has also antitussive property. Tramadol is a unique analgesic offering moderate,&#xD;
      dose-related pain relief through its action at multiple sites. In contrast to pure opioid&#xD;
      agonists, it has a low risk of respiratory depression, tolerance, and dependence. Previous&#xD;
      studies confirmed that tramadol dependence may occur when it is used daily for more than a&#xD;
      few weeks/months.&#xD;
&#xD;
      More interestingly, patients infected with COVID-19 may experience intense emotional and&#xD;
      behavioral reactions, such as fear, loneliness, anxiety, insomnia, or anger. These conditions&#xD;
      can be especially prevalent in quarantined patients. Tramadol is a centrally acting analgesic&#xD;
      drug with a dual mechanism of action: binding to μ-opioid receptors and the inhibition of&#xD;
      serotonin and norepinephrine reuptake. Through its ability to inhibit serotonin and&#xD;
      norepinephrine reuptake, tramadol may exhibit antidepressant activity. In this context, the&#xD;
      analgesic and antidepressant effects of tramadol may favor its use for COVID-19 patients.&#xD;
      Tramadol also was found to have dose- and time-dependent bactericidal activity against&#xD;
      Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas&#xD;
      aeruginosa pathogens in vitro.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">July 2020</start_date>
  <completion_date type="Anticipated">October 2020</completion_date>
  <primary_completion_date type="Anticipated">August 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</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>A randomized Double Blind Controlled Clinical Trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>A randomized Double Blind Controlled Clinical Trial</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of COVID-19 PCR negative cases</measure>
    <time_frame>10 days</time_frame>
    <description>PCR analysis of nasal swabs from COVID-19 patients</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Tramadol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>tramadol 100 mg twice daily for 10 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>standard care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>standard care plus (placebo twice daily for 10 days).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tramadol</intervention_name>
    <description>tramadol 100 mg twice daily for 10 days</description>
    <arm_group_label>Tramadol</arm_group_label>
    <other_name>tramal</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard care delivered in the isolation hospitals.</intervention_name>
    <description>Oxygen ventilation.</description>
    <arm_group_label>standard care</arm_group_label>
    <other_name>nasal oxygen</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Newly diagnosed symptomatic COVID-19 patients with mild to moderate respiratory&#xD;
             manifestations, adults (18-65 Years old), and both sexes.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with abnormal liver function (ALT, AST), chronic kidney disease or dialysis&#xD;
             (CrCl&lt; 30 ml/min)&#xD;
&#xD;
          -  Pregnant women or women who are breastfeeding&#xD;
&#xD;
          -  Immunocompromised patients taking medication upon screening&#xD;
&#xD;
          -  Subjects with comorbid condition like hypertension, cardiovascular disease, diabetes&#xD;
             mellites, asthma, COPD, malignancy&#xD;
&#xD;
          -  Patients having allergy to Hydroxychloroquine and/or Nitazoxanide&#xD;
&#xD;
          -  Patients with contraindication towards the study medication including retinopathy,&#xD;
             G6PD deficiency and QT prolongation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nahla Elashmawy, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tanta University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Nahla Elashmawy, PhD</last_name>
    <phone>201116721982</phone>
    <email>nahla.elashmawi@pharm.tanta.edu.eg</email>
  </overall_contact>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>June 30, 2020</last_update_submitted>
  <last_update_submitted_qc>June 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 2, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tanta University</investigator_affiliation>
    <investigator_full_name>Prof. Dr. Nahla El-Ashmawy</investigator_full_name>
    <investigator_title>Dean of Faculty of Pharmacy</investigator_title>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tramadol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04454307
org study id: TRAM/COVID19
nct id: NCT04454307
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The rationale of the use of tramadol for COVID-19 patients is attributed to its
      anti-inflammatory, hypocagulatory, antioxidant, cardio-protective, analgesic, antitussive,
      bactericidal and antidepressant effect.
Background and Rationale:

      T cells play a critical role in antiviral immunity, their level was dramatically reduced in
      COVID-19 patients. There is a negative correlation between T cell numbers and cytokines serum
      level in COVID-19 patients. In those patients, there is up-regulation of inflammatory
      cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and interferon
      γ. This makes the use of tramadol reasonable in such patients because it has
      anti-inflammatory effect decreasing plasma level of TNF-α after treatment with a dose of 100
      mg every 12 hours for 10 days, which may result in a subsequent increase in T cell numbers.

      Besides, COVID-19 patients with acute respiratory failure present with severe
      hypercoagulability due to hyperfibrinogenemia resulting in increased fibrin formation and
      polymerization that may predispose to thrombosis. It has been reported that tramadol has a
      hypocoagulable effect in the blood of women with gynecologic malignancies. Consequently,
      tramadol may be useful for patients who have a tendency toward a hypercoagulable status and
      thromboembolic complications. Moreover, tramadol could affect hemostatic parameters in favor
      of bleeding tendency in rats.

      On the other hand, the severity and mortality risk of COVID-19 have been associated with the
      age. This age-related mortality is attributed to the shortage of antioxidant mechanisms and
      increased oxidative damage. Tramadol increased the antioxidant enzymes superoxide dismutase
      and glutathione peroxidase while diminished the oxidative stress marker malondialdehyde in
      testicular ischemia-reperfusion injury in rats. Owing to its antioxidant properties, tramadol
      could reduce complications in COVID-19 patients.

      Moreover, tramadol was reported to significantly lower lactate dehydrogenase (LDH) level and
      to provide a cardio-protective effect. This property of tramadol seems beneficial since it
      was found that, about 60% of COVID-19 patients are presented with elevated LDH levels.
      Tramadol has also antitussive property. Tramadol is a unique analgesic offering moderate,
      dose-related pain relief through its action at multiple sites. In contrast to pure opioid
      agonists, it has a low risk of respiratory depression, tolerance, and dependence. Previous
      studies confirmed that tramadol dependence may occur when it is used daily for more than a
      few weeks/months.

      More interestingly, patients infected with COVID-19 may experience intense emotional and
      behavioral reactions, such as fear, loneliness, anxiety, insomnia, or anger. These conditions
      can be especially prevalent in quarantined patients. Tramadol is a centrally acting analgesic
      drug with a dual mechanism of action: binding to μ-opioid receptors and the inhibition of
      serotonin and norepinephrine reuptake. Through its ability to inhibit serotonin and
      norepinephrine reuptake, tramadol may exhibit antidepressant activity. In this context, the
      analgesic and antidepressant effects of tramadol may favor its use for COVID-19 patients.
      Tramadol also was found to have dose- and time-dependent bactericidal activity against
      Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas
      aeruginosa pathogens in vitro.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A randomized Double Blind Controlled Clinical Trial
primary purpose: Treatment
masking: Double (Participant, Care Provider)
masking description: A randomized Double Blind Controlled Clinical Trial
measure: Number of COVID-19 PCR negative cases
time frame: 10 days
description: PCR analysis of nasal swabs from COVID-19 patients
arm group label: Tramadol
arm group type: Experimental
description: tramadol 100 mg twice daily for 10 days
arm group label: standard care
arm group type: Active Comparator
description: standard care plus (placebo twice daily for 10 days).
intervention type: Drug
intervention name: Tramadol
description: tramadol 100 mg twice daily for 10 days
arm group label: Tramadol
other name: tramal
intervention type: Other
intervention name: Standard care delivered in the isolation hospitals.
description: Oxygen ventilation.
arm group label: standard care
other name: nasal oxygen
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Nahla Elashmawy, PhD
role: Principal Investigator
affiliation: Tanta University
last name: Nahla Elashmawy, PhD
phone: 201116721982
email: nahla.elashmawi@pharm.tanta.edu.eg
responsible party type: Principal Investigator
investigator affiliation: Tanta University
investigator full name: Prof. Dr. Nahla El-Ashmawy
investigator title: Dean of Faculty of Pharmacy
mesh term: COVID-19
mesh term: Tramadol
sharing ipd: No