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Non-inferiority Trial on Treatments in Early COVID-19

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05321394
Recruitment Status : Recruiting
First Posted : April 11, 2022
Last Update Posted : April 12, 2022
Sponsor:
Collaborators:
Agenzia Italiana del Farmaco
Azienda Sanitaria-Universitaria Integrata di Udine
Information provided by (Responsible Party):
Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona

Brief Summary:
The study aims at assessing the non-inferiority of tixagevimab plus cilgavimab and nirmatrelvir plus ritornavir vs. sotrovimab (reference standard due to the wider evidence gathered on its efficacy) on COVID-19 progression in a real-life setting of outpatients aged at least 50 years at an early stage of the disease. The progression of COVID-19 disease (hospitalization, need for supplementary oxygen therapy at home, death) within 14 days of randomisation is the composite outcome variable on which the calculation of the sample size is based. Based on available data regarding the reduction in the number of hospitalisations and medical visits with the use of sotrovimab at an early-stage of COVID-19, a disease progression of 1% has been estimated in the reference arm. 3% delta margin was considered clinically relevant, taking into account both the estimates of disease progression in the study population in absence of early treatment (7%, based on national data) and the efficacy of the reference standard. Therefore, 1095 participants will be randomly assigned in an equal ratio between the reference standard and each of the other two experimental arms (1:1:1). Randomization will be computer-generated in permuted blocks with a stratification based on site.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Sotrovimab Drug: Tixagevimab Cilgavimab Drug: Nirmatrelvir Ritonavir Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1095 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adaptive, Randomized, Non-inferiority Trial on the Use of Monoclonal Antibodies or Antivirals in Outpatients With Mild or Moderate COVID-19
Actual Study Start Date : March 7, 2022
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : October 30, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Ritonavir

Arm Intervention/treatment
Active Comparator: Sotrovimab
Sotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour
Drug: Sotrovimab
Single intravenous infusion of sotrovimab 500 mg (500 mg/8 mL), administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour.

Experimental: Tixagevimab Cilgavimab
300 mg of tixagevimab and 300 mg of cilgavimab administered as two separate consecutive intramuscular injections
Drug: Tixagevimab Cilgavimab

2 subsequent injections:

  1. tixagevimab 300mg/3mL (100mg/mL)
  2. cilgavimab 300mg/3mL (100mg/mL)

Experimental: Nirmatrelvir Ritonavir
300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together twice daily for 5 days
Drug: Nirmatrelvir Ritonavir
300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together twice daily for 5 days




Primary Outcome Measures :
  1. COVID-19 progression [ Time Frame: 14 days ]
    (1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation


Secondary Outcome Measures :
  1. Visits to the Emergency Room [ Time Frame: 28 days ]
    Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization

  2. Duration of supplemental oxygen therapy [ Time Frame: 90 days ]
    Days of supplemental oxygen therapy within 90 days of randomization

  3. Duration of hospitalization [ Time Frame: 90 days ]
    Days of any hospitalization within 90 days of randomization

  4. Non-invasive ventilation [ Time Frame: 28 days ]
    Rate of patients undergoing non-invasive ventilation within 28 days of randomization

  5. Duration of non-invasive ventilation [ Time Frame: 90 days ]
    Days of non-invasive ventilation within 90 days of randomization

  6. Mechanical ventilation [ Time Frame: 28 days ]
    Rate of patients undergoing mechanical ventilation within 28 of randomization

  7. Duration of mechanical ventilation [ Time Frame: 90 days ]
    Days of mechanical ventilation within 90 days of randomization

  8. 28-day mortality [ Time Frame: 28 days ]
    Death rate at 28 days of randomization

  9. 90-day mortality [ Time Frame: 90 days ]
    Death rate at 90 days of randomization

  10. Duration of symptoms [ Time Frame: 90 days ]
    Days of symptoms within 90 days of randomization



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 50 years
  • Informed consent by the subject or legally authorized representative
  • Laboratory-confirmed SARS-CoV-2 infection, as determined by PCR or other commercial or public health assay in any specimen, no more than 4 days prior to the study drug administration
  • Peripheral oxygen saturation ≥ 94% on room air and not requiring supplemental oxygen
  • Onset of symptom is no more than 4 days prior to the study drug administration. Onset time of symptom is defined as the time when the patient experienced the presence of at least one of the following (but not limited to) SARS-CoV-2 infection-associated symptom (FDA, September 2020): nasal obstruction or congestion, cough, fever > 37.3 °C, sore throat, body pain or muscle pain, headache, loss of taste or smell, nausea or vomiting, diarrhoea

Exclusion Criteria:

  • Previously or currently hospitalized or requiring hospitalization
  • Respiratory distress with respiratory rate ≥ 25 breaths/min
  • Heart rate ≥ 125 beats per minute
  • Peripheral oxygen saturation ≤ 93% on room air at sea level
  • Known allergies to any of the components used in the formulation of the interventions
  • Severe renal impairment (eGFR <30 mL/min)
  • Severe hepatic impairment (Child-Pugh Class C)
  • Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions
  • Co-administration with potent CYP3A inducers
  • Hemodynamic instability requiring use of pressors within 24 hours of randomization
  • Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that could potentially lead to hospitalization in within 30 days
  • Any co-morbidity requiring surgery within 7 days or that is considered life-threatening within 90 days
  • History of a positive SARS-CoV-2 test prior to the one serving as eligibility for this study
  • Other investigational intervention for SARS-CoV-2 prophylaxis within 30 days before dosing
  • Previous treatment with a SARS-CoV-2 specific monoclonal antibody
  • History of convalescent COVID-19 plasma treatment
  • Participation, within the last 30 days, in a clinical study involving an investigational intervention
  • Pregnancy or breast feeding
  • Investigator site personnel directly affiliated with this study
  • Sexually active women of childbearing potential or sexually active men who are unwilling to practice effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose
  • Inability to participate to the study follow-up

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): NCT05321394


Contacts
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Contact: Evelina Tacconelli 0458128243 ext +39 evelina.tacconelli@univr.it
Contact: Fulvia Mazzaferri 3387310642 ext +39 fulvia.mazzaferri@aovr.veneto.it

Locations
Show Show 19 study locations
Sponsors and Collaborators
Azienda Ospedaliera Universitaria Integrata Verona
Agenzia Italiana del Farmaco
Azienda Sanitaria-Universitaria Integrata di Udine
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Responsible Party: Evelina Tacconelli, Professor, Azienda Ospedaliera Universitaria Integrata Verona
ClinicalTrials.gov Identifier: NCT05321394    
Other Study ID Numbers: MANTICO 2
2021-002612-31 ( EudraCT Number )
First Posted: April 11, 2022    Key Record Dates
Last Update Posted: April 12, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona:
Coronavirus Infections
Monoclonal antibodies
Sotrovimab
Tixagevimab Cilgavimab
Nirmatrelvir Ritonavir
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Ritonavir
HIV Protease Inhibitors
Viral Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors