Non-inferiority Trial on Treatments in Early COVID-19

Study Overview
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Brief Summary
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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.

Official Title
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Adaptive, Randomized, Non-inferiority Trial on the Use of Monoclonal Antibodies or Antivirals in Outpatients With Mild or Moderate COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Sotrovimab
* Drug: Tixagevimab Cilgavimab
* Drug: Nirmatrelvir Ritonavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sotrovimab<br>Sotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour | Drug: Sotrovimab<br>* 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.<br>|
| Experimental: Tixagevimab Cilgavimab<br>300 mg of tixagevimab and 300 mg of cilgavimab administered as two separate consecutive intramuscular injections | Drug: Tixagevimab Cilgavimab<br>* 2 subsequent injections: tixagevimab 300mg/3mL (100mg/mL) cilgavimab 300mg/3mL (100mg/mL)<br>|
| Experimental: Nirmatrelvir Ritonavir<br>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<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID-19 progression | (1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visits to the Emergency Room | Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization | 28 days | 
| Duration of supplemental oxygen therapy | Days of supplemental oxygen therapy within 90 days of randomization | 90 days | 
| Duration of hospitalization | Days of any hospitalization within 90 days of randomization | 90 days | 
| Non-invasive ventilation | Rate of patients undergoing non-invasive ventilation within 28 days of randomization | 28 days | 
| Duration of non-invasive ventilation | Days of non-invasive ventilation within 90 days of randomization | 90 days | 
| Mechanical ventilation | Rate of patients undergoing mechanical ventilation within 28 of randomization | 28 days | 
| Duration of mechanical ventilation | Days of mechanical ventilation within 90 days of randomization | 90 days | 
| 28-day mortality | Death rate at 28 days of randomization | 28 days | 
| 90-day mortality | Death rate at 90 days of randomization | 90 days | 
| Duration of symptoms | Days of symptoms within 90 days of randomization | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus Infections, Monoclonal antibodies, Sotrovimab, Tixagevimab Cilgavimab, Nirmatrelvir Ritonavir