Non-inferiority Trial on Treatments in Early COVID-19

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Sotrovimab; Drug: Tixagevimab Cilgavimab; Drug: Nirmatrelvir Ritonavir

• Study Type: Interventional
• Enrollment (Actual): 536
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Evelina Tacconelli; Phone Number: +39 0458128243; Email: evelina.tacconelli@univr.it
• Study Contact Backup: Name: Fulvia Mazzaferri; Phone Number: +39 3387310642; Email: fulvia.mazzaferri@aovr.veneto.it

Study Locations

• Italy
  • Bologna, Italy
    • RCCS Policlinico di S. Orsola
  • Cagliari, Italy
    • PO SS Trinità di Cagliari
  • Catania, Italy
    • Azienda Ospedaliera Cannizzaro
  • Catania, Italy
    • Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele
  • Catania, Italy
    • PO Garibaldi Nesima
  • Cremona, Italy
    • Azienda Socio-Sanitaria Territoriale di Cremona
  • Firenze, Italy
    • Ospedale S. Maria Annunziata
  • Milano, Italy
    • Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
  • Napoli, Italy
    • Azienda Ospedaliera dei Colli, presidio ospedaliero Cotugno
  • Padova, Italy
    • Azienda Ospedaliera di Padova
  • Palermo, Italy
    • AOU Policlinico
  • Perugia, Italy
    • Azienda Ospedaliera S. Maria della Misericordia
  • Pescara, Italy
    • Università degli Studi di Pescara
  • Roma, Italy
    • Fondazione Policlinico Universitario A. Gemelli
  • Savona, Italy
    • Ospedale San Paolo ASL 2 Savonese
  • Torino, Italy
    • AOU Città della Salute e Scienza, Presidio Molinette
  • Trieste, Italy
    • Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI)
  • Udine, Italy
    • Azienda Sanitaria Universitaria Friuli Centrale
  • Verona, Italy, 37134
    • Azienda Ospedaliera di Verona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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: tixagevimab 300mg/3mL (100mg/mL); 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

What is the study measuring?

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
Duration of symptoms	Days of symptoms within 90 days of randomization	90 days
90-day mortality	Death rate at 90 days of randomization	90 days

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Collaborators: Agenzia Italiana del Farmaco; Azienda Sanitaria-Universitaria Integrata di Udine

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2022
• Primary Completion (Actual): October 29, 2023
• Study Completion (Actual): October 29, 2023

Study Registration Dates

• First Submitted: April 7, 2022
• First Submitted That Met QC Criteria: April 7, 2022
• First Posted (Actual): April 11, 2022

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 5, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Coronavirus Infections; Monoclonal antibodies; Sotrovimab; Tixagevimab Cilgavimab; Nirmatrelvir Ritonavir
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Nirmatrelvir; Sotrovimab; Nirmatrelvir and ritonavir drug combination
• Other Study ID Numbers: MANTICO 2; 2021-002612-31 (EudraCT Number)

Drug and device information, study documents

• 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