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Combination Therapies to Reduce Carriage of SARS-Cov-2 and Improve Outcome of COVID-19 in Ivory Coast: a Phase Randomized IIb Trial (INTENSE-COV)

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ClinicalTrials.gov Identifier: NCT04466241
Recruitment Status : Recruiting
First Posted : July 10, 2020
Last Update Posted : February 4, 2021
Sponsor:
Collaborators:
University of Bordeaux
PACCI Program
Information provided by (Responsible Party):
ANRS, Emerging Infectious Diseases

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
COVID-19 COVID-19 Drug Treatment Severe Acute Respiratory Syndrome Coronavirus 2 Drug: Lopinavir/Ritonavir 200 MG-50 MG Oral Tablet Drug: Telmisartan 40Mg Oral Tablet Drug: Atorvastatin 20 Mg Oral Tablet Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 294 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase IIb, comparative, multicenter, randomized, superiority, parallel-group, open-label clinical trial
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 27, 2020
Estimated Primary Completion Date : March 26, 2021
Estimated Study Completion Date : March 26, 2021


Arm Intervention/treatment
Active Comparator: Lopinavir/ritonavir
Lopinavir boosted by ritonavir 200mg/50mg: 2 tablets morning and evening from Day 1 to Day 10
Drug: Lopinavir/Ritonavir 200 MG-50 MG Oral Tablet
2 tablets morning and evening from Day 1 to Day 10
Other Names:
  • LPV/r
  • Aluvia

Experimental: Lopinavir/ritonavir + telmisartan
  • 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
Drug: Lopinavir/Ritonavir 200 MG-50 MG Oral Tablet
2 tablets morning and evening from Day 1 to Day 10
Other Names:
  • LPV/r
  • Aluvia

Drug: Telmisartan 40Mg Oral Tablet
1 tablet daily from Day 1 to Day 10
Other Names:
  • TMS
  • Micardis
  • Pritor

Experimental: Lopinavir/ritonavir + atorvastatin
  • 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
Drug: Lopinavir/Ritonavir 200 MG-50 MG Oral Tablet
2 tablets morning and evening from Day 1 to Day 10
Other Names:
  • LPV/r
  • Aluvia

Drug: Atorvastatin 20 Mg Oral Tablet
1 tablet daily from Day 1 to Day 10
Other Names:
  • ATV
  • Tahor




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. Kinetics of SARS-CoV-2 viral load [ Time Frame: Up to Day 28 ]
  3. Death rate at Day 11 and Day 28 [ Time Frame: Day 11 and Day 28 ]
  4. All causes of death and Acute respiratory distress syndrome (ARDS) at Day 28 [ Time Frame: Day 28 ]
  5. Time to hospital discharge [ Time Frame: Up to Day 28 ]
  6. Duration of oxygen supplementation [ Time Frame: Up to Day 28 ]
  7. Prevalence of grade III or IV adverse events [ Time Frame: Up to Day 28 ]
  8. Residual concentration of lopinavir, telmisartan and atorvastatin [ Time Frame: Up to Day 28 ]
  9. 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 ]
  10. Evolution of endothelial activation markers (VEGF and soluble VEGF receptor,VE-cadherin, PECAM/CD31, CD42 and angiopoietin-2) [ Time Frame: Up to Day 28 ]
  11. Proportion of patients with good results according to HIV status [ Time Frame: Up to Day 28 ]
  12. Number of contact cases infected by COVID-19 at Day 28 [ Time Frame: Day 28 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients over 18 years of age.
  • With SARS-CoV-2 infection confirmed by specific PCR.
  • With clinical manifestations of the infection, such as fever or cough, or otolaryngologic (ORL) signs or respiratory difficulties, that started less than 7 days ago.
  • COVID-19 specific treatment-naive.
  • Women of childbearing age should accept the use of mechanical contraception during the study period.
  • Informed consent signed by the patient.

Exclusion Criteria:

  • Severe form of infection requiring oxygen therapy > 4l/min to achieve oxygen saturation > 94%.
  • Patient whose weight is < 35kg.
  • Pharmacological investigation contraindicating the introduction of a CYP450 inhibitor, in particular the CYP3A4 isoform.
  • Known hypersensitivity to lopinavir, ritonavir, telmisartan, atorvastatin or their excipients.
  • Renal impairment (eGFR <30 mL/min, CKD-EPI formulation).
  • Known cirrhosis.
  • Transaminases > 3N.
  • Bilirubin > 2.6N.
  • Electrocardiogram showing QTc> 500 ms.
  • HIV-infected patient without treatment or treated with protease inhibitors (lopinavir, darunavir, atazanavir).
  • Ongoing exposure to statins.
  • Contraindications to the use of statin:

CPK > 5N, history of rhabdomyolysis or myopathies, increased risk when atorvastatin is administered with strong CYP3A4 inhibitors or transport proteins (cyclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, erythromycin, diltiazem, verapamil, fluconazole).

  • Ongoing exposure to sartans.
  • Contraindications to the use of telmisartan:

patient on angiotensin-converting enzyme (ACE) inhibitors, aliskiren or other angiotensin receptor blockers (ARB).

  • Curatorship or guardianship.
  • Pregnancy or breastfeeding.
  • Dementia or any other condition that prevents informed consent.
  • Any reason that, at the discretion of the investigator, would compromise patient safety and cooperation in the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04466241


Contacts
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Contact: Serge Eholié, M.D., Ph.D. +225 21 75 59 60 sergeholie@yahoo.fr
Contact: Fabrice Bonnet, M.D., Ph.D. +335 56 79 58 26 fabrice.bonnet@u-bordeaux.fr

Locations
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Côte D'Ivoire
Service des Maladies Infectieuses et Tropicales, Centre Hospitalier et Universitaire (CHU) Treichville Recruiting
Abidjan, Côte D'Ivoire, 01 BP V3
Contact: Adama Doumbia, MD    +225 07938209    adumbia@yahoo.fr   
Centre de Traitement des Maladies Infectieuses (CTMI), CHU de Yopougon Recruiting
Abidjan, Côte D'Ivoire, 21 BP 632
Contact: Baba Toumani Sidibé, MD    +225 01040306    babatoummy@gmail.com   
Sponsors and Collaborators
ANRS, Emerging Infectious Diseases
University of Bordeaux
PACCI Program
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Responsible Party: ANRS, Emerging Infectious Diseases
ClinicalTrials.gov Identifier: NCT04466241    
Other Study ID Numbers: ANRS COV01 INTENSE COV
First Posted: July 10, 2020    Key Record Dates
Last Update Posted: February 4, 2021
Last Verified: February 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ANRS, Emerging Infectious Diseases:
COVID-19
Combination therapy
Atorvastatin
Telmisartan
Lopinavir/ritonavir
SARS-COV-2
Viral load
Additional relevant MeSH terms:
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Severe Acute Respiratory Syndrome
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Ritonavir
Lopinavir
Telmisartan
Atorvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
HIV Protease Inhibitors
Protease Inhibitors
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists