<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/NCT04483830</url>
  </required_header>
  <id_info>
    <org_study_id>Clidm/Vas/2020-05-01</org_study_id>
    <nct_id>NCT04483830</nct_id>
  </id_info>
  <brief_title>Suloexide in the Treatment of Early Stages of COVID-19</brief_title>
  <acronym>SulES-COVID</acronym>
  <official_title>Sulodexide in the Treatment of Early Stages of COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Clinedem</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Alfasigma S.p.A.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Clinedem</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>
      Problem:&#xD;
&#xD;
      The COVID- 19 pandemic has not only affected our healthcare system, but the impact on the&#xD;
      worldwide financial systems and our &quot;normal&quot; way of life is still to be determined.&#xD;
&#xD;
      Although the percentage of patients infected with COVID-19 that need hospital care is low,&#xD;
      Its high rate of contagiousness makes the total number of patients in need of hospital care&#xD;
      cripple any healthcare system, limiting the space available for other patients in need of&#xD;
      critical care, who cannot be admitted or even prefer not to attend the hospital in fear of&#xD;
      infection.&#xD;
&#xD;
      Early investigations report an Increase risk of thromboembolic complications, and a systemic&#xD;
      inflammatory response not clearly understood. There is a possible vascular endothelial&#xD;
      dysfunction due to chronic comorbidities (Hypertension, diabetes, obesity, chronic kidney&#xD;
      disease, lung disease) as a risk factor for a more severe presentation.&#xD;
&#xD;
      Justification:&#xD;
&#xD;
      Sulodexide is a two-compound drug, each of them with different endothelial action that can be&#xD;
      beneficial in COVID-19 patients.&#xD;
&#xD;
      Glycosaminoglycans: Can help restore venous and arterial endothelial glycocalyx which can&#xD;
      downregulate or limit the response to inflammatory molecules, by maintaining the integrity&#xD;
      lost in certain chronic diseases (high blood pressure, diabetes).&#xD;
&#xD;
      Heparin compound: It has an antithrombotic effect that could help reduce the incidence of&#xD;
      thromboembolic complications, and also add to the anti-inflammatory response due to it&#xD;
      anti-thrombin action (similar or a bit less to that of low molecular weight heparin) with&#xD;
      less risk of major bleeding.&#xD;
&#xD;
      It's a medication that can be used orally with minimal adverse effects and is less expensive&#xD;
      than low molecular weight heparin.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      We hypothesize that sulodexide instituted early in populations at significant risk and&#xD;
      symptomatic patients affected with COVID-19 (shortness of breath, fever, weakness, diarrhoea)&#xD;
      and risk factors of diabetes, hypertension, COPD, atherosclerosis, chronic kidney disease,&#xD;
      will provide improvement in endothelial integrity, decrease inflammatory responses, and&#xD;
      improved clinical outcomes with decreased hospital admission, decrease VTE and arterial&#xD;
      complications, morbidity, and mortality.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To use sulodexide in patients that have early onset of COVID-19 symptoms to mitigate the&#xD;
      progression of the disease process that can allow them to recover at home, and limit the need&#xD;
      of hospital care and a more severe clinical manifestation&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objective:&#xD;
&#xD;
      To use sulodexide in patients that have early onset of COVID-19 symptoms to mitigate the&#xD;
      progression of the disease process that can allow them to recover at home, and limit the need&#xD;
      for hospital care and the more severe manifestation which includes fulminant respiratory&#xD;
      failure, acute kidney injury, cardiomyopathy, and thrombosis.&#xD;
&#xD;
      Target study population:&#xD;
&#xD;
      COVID-19 positives in the early but symptomatic stages of the disease (fever, cough,&#xD;
      shortness of breath, malaise, diarrhoea, nausea, vomiting, anosmia). High risk of developing&#xD;
      a severe presentation of the disease (due to chronic comorbidities).&#xD;
&#xD;
      Research methodology Prospectively, information collection will be carried out in COVID-19&#xD;
      patients, who are in early stages of the disease, defined as a beginning of symptoms of 3&#xD;
      days or less, who attend the CLINEDEM medical unit, located in San Luis Rio Colorado, Sonora,&#xD;
      Mexico, in the period from June 15, 2020, to 30 August 2020. Demographic and clinical data&#xD;
      will be collected digitally and physically and kept in the clinical record individually the&#xD;
      researcher.&#xD;
&#xD;
      This is a clinical, prospective, one-centre, randomized, controlled study. The collaboration&#xD;
      of the participants in the protocol will be a minimum of 3 weeks. Selection Period: the time&#xD;
      during which candidates will be reviewed, selected, and randomized. Contact will be made with&#xD;
      primary health services, both government and private, for a prompt reference of suspected&#xD;
      cases, contact with family members of known COVID-19 patients to seek evaluation if&#xD;
      developing symptoms, and social media recruitment. Candidates will be evaluated for inclusion&#xD;
      criteria by the researcher (or the assigned person), explain the protocol, confirm the&#xD;
      availability and/or willingness to participate, the signature of informed consent will be&#xD;
      obtained for follow-up and laboratory sampling, from then on patients will be considered&#xD;
      inscribed in the clinical trial. The physician (or assigned person) will collect general&#xD;
      demographic information, relevant medical history, measurement of patient weight and height&#xD;
      for body mass index (BMI) calculation, send to a clinical laboratory that will perform&#xD;
      baseline examination blood samples, and COVID-19 testing.&#xD;
&#xD;
      2 groups will be formed: Group A: COVID-19 positive patients with early-stage symptoms who&#xD;
      will receive placebo doses of sulodexide. Group B: COVID-19 positive patients with&#xD;
      early-stage symptoms receiving doses of sulodexide.&#xD;
&#xD;
      Treatment period: time from when patients initiate the oral dose of sulodexide. Patients in&#xD;
      groups A and B will receive the recommended initial stage treatment protocol which consists&#xD;
      of rest, measures of home isolation, and use of acetaminophen in case of pain or fever. if&#xD;
      the participant is indicated another medicine by their treating physician, it will be&#xD;
      recorded in their file, but will not be an elimination criterion.&#xD;
&#xD;
      Group A: will be granted supply for 7 days of placebo medicine in the same packaging and&#xD;
      appearance as the original sulodexide. A first follow-up appointment will be scheduled, which&#xD;
      will be made according to the participant's preference, either virtually (phone, cell phone,&#xD;
      videoconference) or physically with a visit to the patient's home by the researcher or a&#xD;
      study collaborator, which will be repeated every 7 days for 21 days, questions will be asked&#xD;
      about the general health condition and will report adverse symptoms related to drug intake.&#xD;
      During this period, extra visits will be made at the request of the patient or consideration&#xD;
      of the investigator. At each visit, symptomatic progression will be asses. At the end of the&#xD;
      21 days, a control blood sample will be carried out including dimer-D and C-reactive protein&#xD;
      and the study variables will be analyzed.&#xD;
&#xD;
      In case of need for hospital care, the authorization will be requested from the physician is&#xD;
      charged to obtain daily information about the general evolution during the stay, without&#xD;
      interfering with the specific treatment protocol. This information will be collected and&#xD;
      emptied into a database electronically and physically. Despite being part of the initial&#xD;
      informed consent, follow-up authorization will be confirmed during a hospital stay, which can&#xD;
      be denied at any time by the patient or family member, in case the participant is not in a&#xD;
      position to make decisions. The use of a placebo will be ruled out at that time. Group B: the&#xD;
      same protocol as group A + Sulodexide dose of 500 LRU will be added every 12hrs (two&#xD;
      capsules).&#xD;
&#xD;
      Measures to prevent or minimize bias: Control group will be receiving a placebo.&#xD;
      Randomization will be performed according to the Castor EDU computing program. Only the&#xD;
      research leader will be known as randomization allocation.&#xD;
&#xD;
      Premature interruption of the study: The study may be suspended prematurely if significant&#xD;
      safety problems are detected, if new scientific knowledge arises, or if other conditions&#xD;
      arise that place subjects at undue risk if they continue in the study. The sponsor or the&#xD;
      Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or the competent&#xD;
      authorities may terminate the study before its scheduled time.&#xD;
&#xD;
      Drug compliance The dates of the first and last intake, as well as any interruption of&#xD;
      treatment, if any, will be recorded in the participant's file. The number of tablets&#xD;
      dispensed and the number of tablets returned by the participant must be counted by the&#xD;
      researcher or a designated person on his/her team and registered. If the participant does not&#xD;
      bring back their medication box, the number of tablets taken and the number of days in which&#xD;
      the means have been applied will be estimated by the investigator interrogating the&#xD;
      participant. If the information is available on an upcoming visit, the data should be&#xD;
      corrected. Compliance will be evaluated weekly for the duration of your participation.&#xD;
      Compliance shall be calculated based on the relationship between the number of tablets taken&#xD;
      and the theoretical number of tablets required by the number of treatment days. If compliance&#xD;
      is not satisfactory during the study (e.g. less than 80% or more than 120%), the participant&#xD;
      should be questioned to identify the reason for the study.&#xD;
&#xD;
      Universe With a population in the area of San Luis Rio Colorado and its surroundings&#xD;
      approximately 1,000,000. 60% in the age range between 20 and 70 years and 55% female sex.&#xD;
&#xD;
      There is difficulty in defining the current number of positive cases given the presence of&#xD;
      asymptomatic carriers of the disease, as well as a lack of openness for diagnostic tests in&#xD;
      the health sector, limiting an adequate sample calculation required for the study.&#xD;
&#xD;
      A COVID-19 patient has an 80% probability of developing a self-limited presentation that will&#xD;
      not warrant hospital care, but in the presence of comorbidities, the risk can increase. This&#xD;
      trial is focused on high-risk patients that can develop the need for hospital care given by&#xD;
      the calculator risk assessment software, increasing the risk of hospital care in our&#xD;
      population to 30-50%. In the severe presentation, the risk of mechanical ventilation can be&#xD;
      20% and a 6.7% mortality rate, however, these data can be modified according to different&#xD;
      countries and by the presence of risk factors given by chronic commodities.&#xD;
&#xD;
      In Mexico, as of June 07, 2020, the national mortality rate is reported at 11.8% and in the&#xD;
      state of Sonora of 9.7%. In the town of San Luis Rio Colorado, Sonora, of the cases confirmed&#xD;
      37.7% has required hospital management.&#xD;
&#xD;
      Sample size:&#xD;
&#xD;
      The sample size was determined using G*Power 3.1.9.2 program by taking an error type I with a&#xD;
      value of 5% (alpha-0.05), a type II error of 20% (beta-0.20) giving a 95% confidence value&#xD;
      and a statistical power of 80%. Obtaining a No. 102 participants per group to which 10% was&#xD;
      added for possible patient loss/abandonment by defining a total sample of 112 patients per&#xD;
      study group.&#xD;
&#xD;
      Statistical analysis The data will be emptied into Excel sheets (Office 360, Microsoft) and&#xD;
      transferred to the Statistical Package for Social Sciences (SPSS) version 25 (IBM) operating&#xD;
      program for statistical analysis.&#xD;
&#xD;
      The study looks for a superior effect in group B (sulodexide) compared to group A (control),&#xD;
      a significant level will be set to 5% (p &lt; 0.05) with a 95% confidence interval.&#xD;
&#xD;
      Descriptive variables will be presented as mean, standard deviation (SD), minimum, maximum&#xD;
      for continuous data, and a number of cases and percentages for categorical data. The student&#xD;
      t-test and chi-square will be used to compare the differences between the two groups&#xD;
      accordingly.&#xD;
&#xD;
      Variable Classification Dependents: the need for hospital care, days needed supplemental&#xD;
      oxygen, need for hemodialysis, need for mechanical ventilation, mortality, presence of major&#xD;
      bleeding, presence of thromboembolic complications, Serum levels of D- dimer, serum levels of&#xD;
      C-reactive protein, serum levels of creatinine.&#xD;
&#xD;
      Independent: Use of sulodexide General precautions of sulodexide: If anticoagulants are used&#xD;
      simultaneously, the doses of the anticoagulants should be readjusted.&#xD;
&#xD;
      Restrictions on use during pregnancy and lactation: Although fetal toxicity studies did not&#xD;
      show embryo or fetal-toxic effects, use during pregnancy or lactation is not recommended.&#xD;
&#xD;
      Secondary and adverse reactions: Epigastric pain, nausea, vomiting, and skin rash have rarely&#xD;
      been reported. Local manifestations have occasionally been reported at the site of redness&#xD;
      injection or small bruising. In control group research, the frequency of side effects is&#xD;
      similar to placebo.&#xD;
&#xD;
      Adverse Events:&#xD;
&#xD;
      All adverse events and other situations relevant to the safety of participants should be&#xD;
      followed and documented completely and accurately to ensure that the sponsor has the&#xD;
      information necessary to continuously assess the benefit-risk balance of the Clinical Trial.&#xD;
      An adverse event is defined as any unfavourable medical occurrence in a subject participating&#xD;
      in a clinical study, whether or not there is a causal relationship with the medicinal product&#xD;
      understudy, and/or experimental procedures, which occur or are detected from the date on&#xD;
      which the participant signs the consent form, regardless of the study period (e.g. the&#xD;
      selection period, they also refer).&#xD;
&#xD;
      Therefore, an adverse event may be:&#xD;
&#xD;
        -  Any unwanted signs, including an abnormal finding of an additional examination&#xD;
           (laboratory tests, x-rays, ECG, etc.) that is considered clinically relevant by the&#xD;
           researcher&#xD;
&#xD;
        -  Any symptoms or illnesses not related to the underlying disease.&#xD;
&#xD;
      Ethical and Regulatory Aspects&#xD;
&#xD;
      Helsinki Declaration from the World Medical Association: The Global Medical Association has&#xD;
      promulgated the Helsinki Declaration as a proposal for ethical principles for medical&#xD;
      research in humans, including research of identifiable human material and information.&#xD;
&#xD;
      According to ethical principles for medical research in human beings, the physician has to&#xD;
      protect life, health, dignity, integrity, the right to self-determination, privacy and&#xD;
      confidentiality of information; Following this principle, the confidentiality of the&#xD;
      information will be maintained the participating patients, only medical and administrative&#xD;
      personnel related to the protocol will have access to the clinical record where the patient's&#xD;
      name and information are located. For third parties who require access to the data, mainly&#xD;
      for the final statistical analysis or collaboration of some information regarding the study,&#xD;
      this will be sent, subject to authorization by the principal investigator, but under special&#xD;
      coding that replaces the name of the participant and not including personal-work information&#xD;
      not related to the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 5, 2020</start_date>
  <completion_date type="Actual">September 7, 2020</completion_date>
  <primary_completion_date type="Actual">August 6, 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</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>prospective, single centre, randomized, placebo-control trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>placebo control</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>hospital care</measure>
    <time_frame>21 days since start of trial participation</time_frame>
    <description>need for hospital care admission</description>
  </primary_outcome>
  <primary_outcome>
    <measure>days of hospital care</measure>
    <time_frame>21 days since start of trial participation</time_frame>
    <description>number of total days in hospital care</description>
  </primary_outcome>
  <primary_outcome>
    <measure>days of need suplemental oxigen</measure>
    <time_frame>21 days since the start of trial participation</time_frame>
    <description>total days in need of supplemental oxigen via facial mask or nasal</description>
  </primary_outcome>
  <primary_outcome>
    <measure>serum level of d-dimmer</measure>
    <time_frame>change betwen basal level and at 14 day follow-up</time_frame>
    <description>total value in ng/dl of d-dimmer</description>
  </primary_outcome>
  <primary_outcome>
    <measure>serum level of creatinine</measure>
    <time_frame>change between basal level ans at 14 day followup</time_frame>
    <description>total value in mg/dl</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>thromboembolic event</measure>
    <time_frame>21 days from start of trial</time_frame>
    <description>presence of a tromboembolic event</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>need for mechanical ventilation</measure>
    <time_frame>21 days from the start of the trial</time_frame>
    <description>the need for the use of endotraqueal tube mechanical ventilation</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">243</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>group A</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>patient with the early stages of COVID-19 to received an oral dose of placebo twice a day for 21 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>group B</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>patient in the early stages of COVID-19 to received an oral dose of 500LRU of sulodexide twice a day for 21 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sulodexide</intervention_name>
    <description>an oral dose of 2 capsules each day for 21 days</description>
    <arm_group_label>group B</arm_group_label>
    <other_name>vessel due f</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>an oral dose of 2 capsules each day for 21 days</description>
    <arm_group_label>group A</arm_group_label>
    <other_name>vessel due f -placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  3 days or less with clinical COVID-19 symptoms (fever, cough, sour throat, headache,&#xD;
             body ache, anosmia, diarrhoea, vomiting).&#xD;
&#xD;
          -  sign inform consent.&#xD;
&#xD;
          -  &gt;50% risk developing a severe clinical presentation of COVID-19 according to risk&#xD;
             calculator&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  COVID-19 negative test&#xD;
&#xD;
          -  known pregnancy&#xD;
&#xD;
          -  chronic use of steroid medication&#xD;
&#xD;
          -  deep vein thrombosis in the last 6 months&#xD;
&#xD;
          -  extended anticoagulation in the last 3 months.&#xD;
&#xD;
          -  known allergy to sulodexide.&#xD;
&#xD;
          -  severe symptoms that warrant hospital care at initial screening&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alejandro j Gonzalez-Ochoa, md</last_name>
    <role>Principal Investigator</role>
    <affiliation>Clinedem</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinedem</name>
      <address>
        <city>San Luis Rio Colorado</city>
        <state>Sonora</state>
        <zip>83449</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 23, 2020</study_first_posted>
  <last_update_submitted>September 7, 2020</last_update_submitted>
  <last_update_submitted_qc>September 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Clinedem</investigator_affiliation>
    <investigator_full_name>alejandro jose gonzalez ochoa</investigator_full_name>
    <investigator_title>Vascular and endovascular surgery</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glucuronyl glucosamine glycan sulfate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>individual participant data will be confidential</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>March 17, 2022</submitted>
    <returned>April 5, 2022</returned>
  </pending_results>
  <!-- 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/NCT04483830
org study id: Clidm/Vas/2020-05-01
nct id: NCT04483830
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Problem:

      The COVID- 19 pandemic has not only affected our healthcare system, but the impact on the
      worldwide financial systems and our "normal" way of life is still to be determined.

      Although the percentage of patients infected with COVID-19 that need hospital care is low,
      Its high rate of contagiousness makes the total number of patients in need of hospital care
      cripple any healthcare system, limiting the space available for other patients in need of
      critical care, who cannot be admitted or even prefer not to attend the hospital in fear of
      infection.

      Early investigations report an Increase risk of thromboembolic complications, and a systemic
      inflammatory response not clearly understood. There is a possible vascular endothelial
      dysfunction due to chronic comorbidities (Hypertension, diabetes, obesity, chronic kidney
      disease, lung disease) as a risk factor for a more severe presentation.

      Justification:

      Sulodexide is a two-compound drug, each of them with different endothelial action that can be
      beneficial in COVID-19 patients.

      Glycosaminoglycans: Can help restore venous and arterial endothelial glycocalyx which can
      downregulate or limit the response to inflammatory molecules, by maintaining the integrity
      lost in certain chronic diseases (high blood pressure, diabetes).

      Heparin compound: It has an antithrombotic effect that could help reduce the incidence of
      thromboembolic complications, and also add to the anti-inflammatory response due to it
      anti-thrombin action (similar or a bit less to that of low molecular weight heparin) with
      less risk of major bleeding.

      It's a medication that can be used orally with minimal adverse effects and is less expensive
      than low molecular weight heparin.

      Hypothesis:

      We hypothesize that sulodexide instituted early in populations at significant risk and
      symptomatic patients affected with COVID-19 (shortness of breath, fever, weakness, diarrhoea)
      and risk factors of diabetes, hypertension, COPD, atherosclerosis, chronic kidney disease,
      will provide improvement in endothelial integrity, decrease inflammatory responses, and
      improved clinical outcomes with decreased hospital admission, decrease VTE and arterial
      complications, morbidity, and mortality.

      Objective:

      To use sulodexide in patients that have early onset of COVID-19 symptoms to mitigate the
      progression of the disease process that can allow them to recover at home, and limit the need
      of hospital care and a more severe clinical manifestation
Objective:

      To use sulodexide in patients that have early onset of COVID-19 symptoms to mitigate the
      progression of the disease process that can allow them to recover at home, and limit the need
      for hospital care and the more severe manifestation which includes fulminant respiratory
      failure, acute kidney injury, cardiomyopathy, and thrombosis.

      Target study population:

      COVID-19 positives in the early but symptomatic stages of the disease (fever, cough,
      shortness of breath, malaise, diarrhoea, nausea, vomiting, anosmia). High risk of developing
      a severe presentation of the disease (due to chronic comorbidities).

      Research methodology Prospectively, information collection will be carried out in COVID-19
      patients, who are in early stages of the disease, defined as a beginning of symptoms of 3
      days or less, who attend the CLINEDEM medical unit, located in San Luis Rio Colorado, Sonora,
      Mexico, in the period from June 15, 2020, to 30 August 2020. Demographic and clinical data
      will be collected digitally and physically and kept in the clinical record individually the
      researcher.

      This is a clinical, prospective, one-centre, randomized, controlled study. The collaboration
      of the participants in the protocol will be a minimum of 3 weeks. Selection Period: the time
      during which candidates will be reviewed, selected, and randomized. Contact will be made with
      primary health services, both government and private, for a prompt reference of suspected
      cases, contact with family members of known COVID-19 patients to seek evaluation if
      developing symptoms, and social media recruitment. Candidates will be evaluated for inclusion
      criteria by the researcher (or the assigned person), explain the protocol, confirm the
      availability and/or willingness to participate, the signature of informed consent will be
      obtained for follow-up and laboratory sampling, from then on patients will be considered
      inscribed in the clinical trial. The physician (or assigned person) will collect general
      demographic information, relevant medical history, measurement of patient weight and height
      for body mass index (BMI) calculation, send to a clinical laboratory that will perform
      baseline examination blood samples, and COVID-19 testing.

      2 groups will be formed: Group A: COVID-19 positive patients with early-stage symptoms who
      will receive placebo doses of sulodexide. Group B: COVID-19 positive patients with
      early-stage symptoms receiving doses of sulodexide.

      Treatment period: time from when patients initiate the oral dose of sulodexide. Patients in
      groups A and B will receive the recommended initial stage treatment protocol which consists
      of rest, measures of home isolation, and use of acetaminophen in case of pain or fever. if
      the participant is indicated another medicine by their treating physician, it will be
      recorded in their file, but will not be an elimination criterion.

      Group A: will be granted supply for 7 days of placebo medicine in the same packaging and
      appearance as the original sulodexide. A first follow-up appointment will be scheduled, which
      will be made according to the participant's preference, either virtually (phone, cell phone,
      videoconference) or physically with a visit to the patient's home by the researcher or a
      study collaborator, which will be repeated every 7 days for 21 days, questions will be asked
      about the general health condition and will report adverse symptoms related to drug intake.
      During this period, extra visits will be made at the request of the patient or consideration
      of the investigator. At each visit, symptomatic progression will be asses. At the end of the
      21 days, a control blood sample will be carried out including dimer-D and C-reactive protein
      and the study variables will be analyzed.

      In case of need for hospital care, the authorization will be requested from the physician is
      charged to obtain daily information about the general evolution during the stay, without
      interfering with the specific treatment protocol. This information will be collected and
      emptied into a database electronically and physically. Despite being part of the initial
      informed consent, follow-up authorization will be confirmed during a hospital stay, which can
      be denied at any time by the patient or family member, in case the participant is not in a
      position to make decisions. The use of a placebo will be ruled out at that time. Group B: the
      same protocol as group A + Sulodexide dose of 500 LRU will be added every 12hrs (two
      capsules).

      Measures to prevent or minimize bias: Control group will be receiving a placebo.
      Randomization will be performed according to the Castor EDU computing program. Only the
      research leader will be known as randomization allocation.

      Premature interruption of the study: The study may be suspended prematurely if significant
      safety problems are detected, if new scientific knowledge arises, or if other conditions
      arise that place subjects at undue risk if they continue in the study. The sponsor or the
      Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or the competent
      authorities may terminate the study before its scheduled time.

      Drug compliance The dates of the first and last intake, as well as any interruption of
      treatment, if any, will be recorded in the participant's file. The number of tablets
      dispensed and the number of tablets returned by the participant must be counted by the
      researcher or a designated person on his/her team and registered. If the participant does not
      bring back their medication box, the number of tablets taken and the number of days in which
      the means have been applied will be estimated by the investigator interrogating the
      participant. If the information is available on an upcoming visit, the data should be
      corrected. Compliance will be evaluated weekly for the duration of your participation.
      Compliance shall be calculated based on the relationship between the number of tablets taken
      and the theoretical number of tablets required by the number of treatment days. If compliance
      is not satisfactory during the study (e.g. less than 80% or more than 120%), the participant
      should be questioned to identify the reason for the study.

      Universe With a population in the area of San Luis Rio Colorado and its surroundings
      approximately 1,000,000. 60% in the age range between 20 and 70 years and 55% female sex.

      There is difficulty in defining the current number of positive cases given the presence of
      asymptomatic carriers of the disease, as well as a lack of openness for diagnostic tests in
      the health sector, limiting an adequate sample calculation required for the study.

      A COVID-19 patient has an 80% probability of developing a self-limited presentation that will
      not warrant hospital care, but in the presence of comorbidities, the risk can increase. This
      trial is focused on high-risk patients that can develop the need for hospital care given by
      the calculator risk assessment software, increasing the risk of hospital care in our
      population to 30-50%. In the severe presentation, the risk of mechanical ventilation can be
      20% and a 6.7% mortality rate, however, these data can be modified according to different
      countries and by the presence of risk factors given by chronic commodities.

      In Mexico, as of June 07, 2020, the national mortality rate is reported at 11.8% and in the
      state of Sonora of 9.7%. In the town of San Luis Rio Colorado, Sonora, of the cases confirmed
      37.7% has required hospital management.

      Sample size:

      The sample size was determined using G*Power 3.1.9.2 program by taking an error type I with a
      value of 5% (alpha-0.05), a type II error of 20% (beta-0.20) giving a 95% confidence value
      and a statistical power of 80%. Obtaining a No. 102 participants per group to which 10% was
      added for possible patient loss/abandonment by defining a total sample of 112 patients per
      study group.

      Statistical analysis The data will be emptied into Excel sheets (Office 360, Microsoft) and
      transferred to the Statistical Package for Social Sciences (SPSS) version 25 (IBM) operating
      program for statistical analysis.

      The study looks for a superior effect in group B (sulodexide) compared to group A (control),
      a significant level will be set to 5% (p < 0.05) with a 95% confidence interval.

      Descriptive variables will be presented as mean, standard deviation (SD), minimum, maximum
      for continuous data, and a number of cases and percentages for categorical data. The student
      t-test and chi-square will be used to compare the differences between the two groups
      accordingly.

      Variable Classification Dependents: the need for hospital care, days needed supplemental
      oxygen, need for hemodialysis, need for mechanical ventilation, mortality, presence of major
      bleeding, presence of thromboembolic complications, Serum levels of D- dimer, serum levels of
      C-reactive protein, serum levels of creatinine.

      Independent: Use of sulodexide General precautions of sulodexide: If anticoagulants are used
      simultaneously, the doses of the anticoagulants should be readjusted.

      Restrictions on use during pregnancy and lactation: Although fetal toxicity studies did not
      show embryo or fetal-toxic effects, use during pregnancy or lactation is not recommended.

      Secondary and adverse reactions: Epigastric pain, nausea, vomiting, and skin rash have rarely
      been reported. Local manifestations have occasionally been reported at the site of redness
      injection or small bruising. In control group research, the frequency of side effects is
      similar to placebo.

      Adverse Events:

      All adverse events and other situations relevant to the safety of participants should be
      followed and documented completely and accurately to ensure that the sponsor has the
      information necessary to continuously assess the benefit-risk balance of the Clinical Trial.
      An adverse event is defined as any unfavourable medical occurrence in a subject participating
      in a clinical study, whether or not there is a causal relationship with the medicinal product
      understudy, and/or experimental procedures, which occur or are detected from the date on
      which the participant signs the consent form, regardless of the study period (e.g. the
      selection period, they also refer).

      Therefore, an adverse event may be:

        -  Any unwanted signs, including an abnormal finding of an additional examination
           (laboratory tests, x-rays, ECG, etc.) that is considered clinically relevant by the
           researcher

        -  Any symptoms or illnesses not related to the underlying disease.

      Ethical and Regulatory Aspects

      Helsinki Declaration from the World Medical Association: The Global Medical Association has
      promulgated the Helsinki Declaration as a proposal for ethical principles for medical
      research in humans, including research of identifiable human material and information.

      According to ethical principles for medical research in human beings, the physician has to
      protect life, health, dignity, integrity, the right to self-determination, privacy and
      confidentiality of information; Following this principle, the confidentiality of the
      information will be maintained the participating patients, only medical and administrative
      personnel related to the protocol will have access to the clinical record where the patient's
      name and information are located. For third parties who require access to the data, mainly
      for the final statistical analysis or collaboration of some information regarding the study,
      this will be sent, subject to authorization by the principal investigator, but under special
      coding that replaces the name of the participant and not including personal-work information
      not related to the study.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: prospective, single centre, randomized, placebo-control trial
primary purpose: Treatment
masking: Single (Participant)
masking description: placebo control
measure: hospital care
time frame: 21 days since start of trial participation
description: need for hospital care admission
measure: days of hospital care
time frame: 21 days since start of trial participation
description: number of total days in hospital care
measure: days of need suplemental oxigen
time frame: 21 days since the start of trial participation
description: total days in need of supplemental oxigen via facial mask or nasal
measure: serum level of d-dimmer
time frame: change betwen basal level and at 14 day follow-up
description: total value in ng/dl of d-dimmer
measure: serum level of creatinine
time frame: change between basal level ans at 14 day followup
description: total value in mg/dl
measure: thromboembolic event
time frame: 21 days from start of trial
description: presence of a tromboembolic event
measure: need for mechanical ventilation
time frame: 21 days from the start of the trial
description: the need for the use of endotraqueal tube mechanical ventilation
arm group label: group A
arm group type: Placebo Comparator
description: patient with the early stages of COVID-19 to received an oral dose of placebo twice a day for 21 days
arm group label: group B
arm group type: Active Comparator
description: patient in the early stages of COVID-19 to received an oral dose of 500LRU of sulodexide twice a day for 21 days.
intervention type: Drug
intervention name: Sulodexide
description: an oral dose of 2 capsules each day for 21 days
arm group label: group B
other name: vessel due f
intervention type: Drug
intervention name: Placebo
description: an oral dose of 2 capsules each day for 21 days
arm group label: group A
other name: vessel due f -placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Alejandro j Gonzalez-Ochoa, md
role: Principal Investigator
affiliation: Clinedem
facility: 
country: Mexico
responsible party type: Principal Investigator
investigator affiliation: Clinedem
investigator full name: alejandro jose gonzalez ochoa
investigator title: Vascular and endovascular surgery
mesh term: COVID-19
mesh term: Glucuronyl glucosamine glycan sulfate
sharing ipd: No
ipd description: individual participant data will be confidential
submitted: March 17, 2022
returned: April 5, 2022