<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/NCT04466241</url>
  </required_header>
  <id_info>
    <org_study_id>ANRS COV01 INTENSE COV</org_study_id>
    <nct_id>NCT04466241</nct_id>
  </id_info>
  <brief_title>Combination Therapies to Reduce Carriage of SARS-Cov-2 and Improve Outcome of COVID-19 in Ivory Coast: a Phase Randomized IIb Trial</brief_title>
  <acronym>INTENSE-COV</acronym>
  <official_title>Combination Therapies to Reduce the Nasopharyngeal Carriage of SARS-CoV-2 and Improve the Outcome of COVID-19 Infection in Ivory Coast (INTENSE-COV): a Phase IIb Randomized Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ANRS, Emerging Infectious Diseases</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Bordeaux</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>PACCI Program</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>ANRS, Emerging Infectious Diseases</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>
      In January 2020, the new SARS-CoV-2 coronavirus was identified in China. The disease caused&#xD;
      by this coronavirus was named COVID-19 by the World Health Organization (WHO). Since March&#xD;
      11, 2020, the WHO has described the global situation of COVID-19 as a pandemic. In Côte&#xD;
      d'Ivoire, as in other African countries, the number of cases is increasing exponentially.&#xD;
&#xD;
      Coronaviruses are a family of viruses that cause illnesses ranging from the common cold to&#xD;
      more severe pathologies. COVID-19 can result in fever or a feeling of fever (chills,&#xD;
      hot-cold), cough, headache, aches and pains, unusual tiredness, sudden loss of smell, total&#xD;
      disappearance of taste, or diarrhea. In severe forms, respiratory difficulties can lead to&#xD;
      hospitalization in intensive care or even death.&#xD;
&#xD;
      Numerous studies are currently being conducted around the world to seek effective treatment,&#xD;
      but few of them have started specifically in Africa. Moreover, most of these studies are&#xD;
      using a single drug to control the infection, whether these are repositioned drugs, i.e.&#xD;
      already being used for other diseases, or other newer drugs.&#xD;
&#xD;
      Currently in Côte d'Ivoire, the preferred treatment for COVID-19 is an antiviral:&#xD;
      lopinavir/ritonavir (LPV/r), usually directed against the Human Immunodeficiency Virus (HIV).&#xD;
&#xD;
      Since the number of viruses (viral load) is high in the respiratory tract during COVID-19&#xD;
      infection, we propose in INTENSE-COV (ICOV) clinical trial to study whether the combination&#xD;
      of two drugs is more effective than taking a single drug on reducing the viral load in the&#xD;
      respiratory tract but also on reducing inflammation.&#xD;
&#xD;
      These drugs include the LPV/r already in use in Côte d'Ivoire as well as an antihypertensive&#xD;
      drug - telmisartan, and a drug that lowers blood cholesterol - atorvastatin. All three have&#xD;
      been known for a long time and have been shown to be effective against other viruses. In&#xD;
      addition, they are generic, inexpensive and readily available in all countries.&#xD;
&#xD;
      The objectives of the ICOV study are therefore to improve viral eradication from the&#xD;
      patient's body and respiratory tract, to reduce inflammation, to improve more rapidly the&#xD;
      patient's state of health and to reduce the risk of transmission of the virus to others.&#xD;
&#xD;
      To participate in ICOV, patients must be over 18 years of age, have a COVID-19 infection&#xD;
      confirmed by a specific test, have clinical manifestations of the infection, and have signed&#xD;
      an informed consent. They will then be randomized into 3 treatment groups to ensure the&#xD;
      robustness of the study results. The reference group will be treated with LPV/r, according to&#xD;
      current recommendations in Côte d'Ivoire. The other 2 groups will be treated with LPV/r +&#xD;
      telmisartan and LPV/r + atorvastatin respectively. The treatment will last 10 days and&#xD;
      patients will be followed for a total of 28 days.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 27, 2020</start_date>
  <completion_date type="Anticipated">March 26, 2021</completion_date>
  <primary_completion_date type="Anticipated">March 26, 2021</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>Phase IIb, comparative, multicenter, randomized, superiority, parallel-group, open-label clinical trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients with undetectable nasopharyngeal swab SARS-CoV-2 PCR and C-reactive protein (CRP) &lt; 27 mg/L at Day 11</measure>
    <time_frame>Day 11</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with clinical improvement on the 7-point ordinal scale at Day 11 and Day 28</measure>
    <time_frame>Day 11 and Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kinetics of SARS-CoV-2 viral load</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death rate at Day 11 and Day 28</measure>
    <time_frame>Day 11 and Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All causes of death and Acute respiratory distress syndrome (ARDS) at Day 28</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to hospital discharge</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of oxygen supplementation</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of grade III or IV adverse events</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Residual concentration of lopinavir, telmisartan and atorvastatin</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of inflammatory and immunological markers (CRP, fibrinogen, ferritin, d-dimer, dosing of IgG, IgA, IgM; TCD4, CD8, B lymphocytes, NK lymphocytes; naïve/memory T lymphocytes)</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of endothelial activation markers (VEGF and soluble VEGF receptor,VE-cadherin, PECAM/CD31, CD42 and angiopoietin-2)</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with good results according to HIV status</measure>
    <time_frame>Up to Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of contact cases infected by COVID-19 at Day 28</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">294</enrollment>
  <condition>COVID-19</condition>
  <condition>COVID-19 Drug Treatment</condition>
  <condition>Severe Acute Respiratory Syndrome Coronavirus 2</condition>
  <arm_group>
    <arm_group_label>Lopinavir/ritonavir</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Lopinavir boosted by ritonavir 200mg/50mg: 2 tablets morning and evening from Day 1 to Day 10</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lopinavir/ritonavir + telmisartan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lopinavir boosted by ritonavir 200mg/50mg: 2 tablets morning and evening from Day 1 to Day 10&#xD;
Telmisartan 40 mg : 1 tablet daily from Day 1 to Day 10</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lopinavir/ritonavir + atorvastatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lopinavir boosted by ritonavir 200mg/50mg: 2 tablets morning and evening from Day 1 to Day 10&#xD;
Atorvastatin 20 mg : 1 tablet daily from Day 1 to Day 10</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lopinavir/Ritonavir 200 MG-50 MG Oral Tablet</intervention_name>
    <description>2 tablets morning and evening from Day 1 to Day 10</description>
    <arm_group_label>Lopinavir/ritonavir</arm_group_label>
    <arm_group_label>Lopinavir/ritonavir + atorvastatin</arm_group_label>
    <arm_group_label>Lopinavir/ritonavir + telmisartan</arm_group_label>
    <other_name>LPV/r</other_name>
    <other_name>Aluvia</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Telmisartan 40Mg Oral Tablet</intervention_name>
    <description>1 tablet daily from Day 1 to Day 10</description>
    <arm_group_label>Lopinavir/ritonavir + telmisartan</arm_group_label>
    <other_name>TMS</other_name>
    <other_name>Micardis</other_name>
    <other_name>Pritor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin 20 Mg Oral Tablet</intervention_name>
    <description>1 tablet daily from Day 1 to Day 10</description>
    <arm_group_label>Lopinavir/ritonavir + atorvastatin</arm_group_label>
    <other_name>ATV</other_name>
    <other_name>Tahor</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients over 18 years of age.&#xD;
&#xD;
          -  With SARS-CoV-2 infection confirmed by specific PCR.&#xD;
&#xD;
          -  With clinical manifestations of the infection, such as fever or cough, or&#xD;
             otolaryngologic (ORL) signs or respiratory difficulties, that started less than 7 days&#xD;
             ago.&#xD;
&#xD;
          -  COVID-19 specific treatment-naive.&#xD;
&#xD;
          -  Women of childbearing age should accept the use of mechanical contraception during the&#xD;
             study period.&#xD;
&#xD;
          -  Informed consent signed by the patient.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe form of infection requiring oxygen therapy &gt; 4l/min to achieve oxygen&#xD;
             saturation &gt; 94%.&#xD;
&#xD;
          -  Patient whose weight is &lt; 35kg.&#xD;
&#xD;
          -  Pharmacological investigation contraindicating the introduction of a CYP450 inhibitor,&#xD;
             in particular the CYP3A4 isoform.&#xD;
&#xD;
          -  Known hypersensitivity to lopinavir, ritonavir, telmisartan, atorvastatin or their&#xD;
             excipients.&#xD;
&#xD;
          -  Renal impairment (eGFR &lt;30 mL/min, CKD-EPI formulation).&#xD;
&#xD;
          -  Known cirrhosis.&#xD;
&#xD;
          -  Transaminases &gt; 3N.&#xD;
&#xD;
          -  Bilirubin &gt; 2.6N.&#xD;
&#xD;
          -  Electrocardiogram showing QTc&gt; 500 ms.&#xD;
&#xD;
          -  HIV-infected patient without treatment or treated with protease inhibitors (lopinavir,&#xD;
             darunavir, atazanavir).&#xD;
&#xD;
          -  Ongoing exposure to statins.&#xD;
&#xD;
          -  Contraindications to the use of statin:&#xD;
&#xD;
        CPK &gt; 5N, history of rhabdomyolysis or myopathies, increased risk when atorvastatin is&#xD;
        administered with strong CYP3A4 inhibitors or transport proteins (cyclosporin,&#xD;
        telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole,&#xD;
        itraconazole, posaconazole, letermovir, erythromycin, diltiazem, verapamil, fluconazole).&#xD;
&#xD;
          -  Ongoing exposure to sartans.&#xD;
&#xD;
          -  Contraindications to the use of telmisartan:&#xD;
&#xD;
        patient on angiotensin-converting enzyme (ACE) inhibitors, aliskiren or other angiotensin&#xD;
        receptor blockers (ARB).&#xD;
&#xD;
          -  Curatorship or guardianship.&#xD;
&#xD;
          -  Pregnancy or breastfeeding.&#xD;
&#xD;
          -  Dementia or any other condition that prevents informed consent.&#xD;
&#xD;
          -  Any reason that, at the discretion of the investigator, would compromise patient&#xD;
             safety and cooperation in the trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Serge Eholié, M.D., Ph.D.</last_name>
    <phone>+225 21 75 59 60</phone>
    <email>sergeholie@yahoo.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Fabrice Bonnet, M.D., Ph.D.</last_name>
    <phone>+335 56 79 58 26</phone>
    <email>fabrice.bonnet@u-bordeaux.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Service des Maladies Infectieuses et Tropicales, Centre Hospitalier et Universitaire (CHU) Treichville</name>
      <address>
        <city>Abidjan</city>
        <zip>01 BP V3</zip>
        <country>Côte D'Ivoire</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Adama Doumbia, MD</last_name>
      <phone>+225 07938209</phone>
      <email>adumbia@yahoo.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre de Traitement des Maladies Infectieuses (CTMI), CHU de Yopougon</name>
      <address>
        <city>Abidjan</city>
        <zip>21 BP 632</zip>
        <country>Côte D'Ivoire</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Baba Toumani Sidibé, MD</last_name>
      <phone>+225 01040306</phone>
      <email>babatoummy@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Côte D'Ivoire</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>July 6, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 10, 2020</study_first_posted>
  <last_update_submitted>February 3, 2021</last_update_submitted>
  <last_update_submitted_qc>February 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>Combination therapy</keyword>
  <keyword>Atorvastatin</keyword>
  <keyword>Telmisartan</keyword>
  <keyword>Lopinavir/ritonavir</keyword>
  <keyword>SARS-COV-2</keyword>
  <keyword>Viral load</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Severe Acute Respiratory Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Lopinavir</mesh_term>
    <mesh_term>Telmisartan</mesh_term>
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04466241
org study id: ANRS COV01 INTENSE COV
nct id: NCT04466241
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
In January 2020, the new SARS-CoV-2 coronavirus was identified in China. The disease caused
      by this coronavirus was named COVID-19 by the World Health Organization (WHO). Since March
      11, 2020, the WHO has described the global situation of COVID-19 as a pandemic. In Côte
      d'Ivoire, as in other African countries, the number of cases is increasing exponentially.

      Coronaviruses are a family of viruses that cause illnesses ranging from the common cold to
      more severe pathologies. COVID-19 can result in fever or a feeling of fever (chills,
      hot-cold), cough, headache, aches and pains, unusual tiredness, sudden loss of smell, total
      disappearance of taste, or diarrhea. In severe forms, respiratory difficulties can lead to
      hospitalization in intensive care or even death.

      Numerous studies are currently being conducted around the world to seek effective treatment,
      but few of them have started specifically in Africa. Moreover, most of these studies are
      using a single drug to control the infection, whether these are repositioned drugs, i.e.
      already being used for other diseases, or other newer drugs.

      Currently in Côte d'Ivoire, the preferred treatment for COVID-19 is an antiviral:
      lopinavir/ritonavir (LPV/r), usually directed against the Human Immunodeficiency Virus (HIV).

      Since the number of viruses (viral load) is high in the respiratory tract during COVID-19
      infection, we propose in INTENSE-COV (ICOV) clinical trial to study whether the combination
      of two drugs is more effective than taking a single drug on reducing the viral load in the
      respiratory tract but also on reducing inflammation.

      These drugs include the LPV/r already in use in Côte d'Ivoire as well as an antihypertensive
      drug - telmisartan, and a drug that lowers blood cholesterol - atorvastatin. All three have
      been known for a long time and have been shown to be effective against other viruses. In
      addition, they are generic, inexpensive and readily available in all countries.

      The objectives of the ICOV study are therefore to improve viral eradication from the
      patient's body and respiratory tract, to reduce inflammation, to improve more rapidly the
      patient's state of health and to reduce the risk of transmission of the virus to others.

      To participate in ICOV, patients must be over 18 years of age, have a COVID-19 infection
      confirmed by a specific test, have clinical manifestations of the infection, and have signed
      an informed consent. They will then be randomized into 3 treatment groups to ensure the
      robustness of the study results. The reference group will be treated with LPV/r, according to
      current recommendations in Côte d'Ivoire. The other 2 groups will be treated with LPV/r +
      telmisartan and LPV/r + atorvastatin respectively. The treatment will last 10 days and
      patients will be followed for a total of 28 days.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Phase IIb, comparative, multicenter, randomized, superiority, parallel-group, open-label clinical trial
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of patients with undetectable nasopharyngeal swab SARS-CoV-2 PCR and C-reactive protein (CRP) < 27 mg/L at Day 11
time frame: Day 11
measure: Proportion of patients with clinical improvement on the 7-point ordinal scale at Day 11 and Day 28
time frame: Day 11 and Day 28
measure: Kinetics of SARS-CoV-2 viral load
time frame: Up to Day 28
measure: Death rate at Day 11 and Day 28
time frame: Day 11 and Day 28
measure: All causes of death and Acute respiratory distress syndrome (ARDS) at Day 28
time frame: Day 28
measure: Time to hospital discharge
time frame: Up to Day 28
measure: Duration of oxygen supplementation
time frame: Up to Day 28
measure: Prevalence of grade III or IV adverse events
time frame: Up to Day 28
measure: Residual concentration of lopinavir, telmisartan and atorvastatin
time frame: Up to Day 28
measure: Evolution of inflammatory and immunological markers (CRP, fibrinogen, ferritin, d-dimer, dosing of IgG, IgA, IgM; TCD4, CD8, B lymphocytes, NK lymphocytes; naïve/memory T lymphocytes)
time frame: Up to Day 28
measure: Evolution of endothelial activation markers (VEGF and soluble VEGF receptor,VE-cadherin, PECAM/CD31, CD42 and angiopoietin-2)
time frame: Up to Day 28
measure: Proportion of patients with good results according to HIV status
time frame: Up to Day 28
measure: Number of contact cases infected by COVID-19 at Day 28
time frame: Day 28
arm group label: Lopinavir/ritonavir
arm group type: Active Comparator
description: Lopinavir boosted by ritonavir 200mg/50mg: 2 tablets morning and evening from Day 1 to Day 10
arm group label: Lopinavir/ritonavir + telmisartan
arm group type: Experimental
description: Lopinavir boosted by ritonavir 200mg/50mg: 2 tablets morning and evening from Day 1 to Day 10
Telmisartan 40 mg : 1 tablet daily from Day 1 to Day 10
arm group label: Lopinavir/ritonavir + atorvastatin
arm group type: Experimental
description: Lopinavir boosted by ritonavir 200mg/50mg: 2 tablets morning and evening from Day 1 to Day 10
Atorvastatin 20 mg : 1 tablet daily from Day 1 to Day 10
intervention type: Drug
intervention name: Lopinavir/Ritonavir 200 MG-50 MG Oral Tablet
description: 2 tablets morning and evening from Day 1 to Day 10
arm group label: Lopinavir/ritonavir
arm group label: Lopinavir/ritonavir + atorvastatin
arm group label: Lopinavir/ritonavir + telmisartan
other name: LPV/r
other name: Aluvia
intervention type: Drug
intervention name: Telmisartan 40Mg Oral Tablet
description: 1 tablet daily from Day 1 to Day 10
arm group label: Lopinavir/ritonavir + telmisartan
other name: TMS
other name: Micardis
other name: Pritor
intervention type: Drug
intervention name: Atorvastatin 20 Mg Oral Tablet
description: 1 tablet daily from Day 1 to Day 10
arm group label: Lopinavir/ritonavir + atorvastatin
other name: ATV
other name: Tahor
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Serge Eholié, M.D., Ph.D.
phone: +225 21 75 59 60
email: sergeholie@yahoo.fr
last name: Fabrice Bonnet, M.D., Ph.D.
phone: +335 56 79 58 26
email: fabrice.bonnet@u-bordeaux.fr
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Côte D'Ivoire
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Severe Acute Respiratory Syndrome
mesh term: Ritonavir
mesh term: Lopinavir
mesh term: Telmisartan
mesh term: Atorvastatin