Clinical trial NCT05321394: Non-inferiority Trial on Treatments in Early COVID-19
Official title: Adaptive, Randomized, Non-inferiority Trial on the Use of Monoclonal Antibodies or Antivirals in Outpatients With Mild or Moderate COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Coronavirus Infections
Monoclonal antibodies
Sotrovimab
Tixagevimab Cilgavimab
Nirmatrelvir Ritonavir
Lead sponsor: Azienda Ospedaliera Universitaria Integrata Verona
Sponsor class: OTHER
Collaborators: name: Agenzia Italiana del Farmaco
name: Azienda Sanitaria-Universitaria Integrata di Udine
First posted: 2022-04-11
Enrollment: 536
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: COVID-19 progression
timeFrame: 14 days
Secondary outcomes:
measure: Visits to the Emergency Room
timeFrame: 28 days
measure: Duration of supplemental oxygen therapy
timeFrame: 90 days
measure: Duration of hospitalization
timeFrame: 90 days
measure: Non-invasive ventilation
timeFrame: 28 days
measure: Duration of non-invasive ventilation
timeFrame: 90 days
measure: Mechanical ventilation
timeFrame: 28 days
measure: Duration of mechanical ventilation
timeFrame: 90 days
measure: 28-day mortality
timeFrame: 28 days
measure: 90-day mortality
timeFrame: 90 days
measure: Duration of symptoms
timeFrame: 90 days
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: RCCS Policlinico di S. Orsola
city: Cagliari
country: Italy
facility: PO SS Trinità di Cagliari
city: Catania
country: Italy
facility: Azienda Ospedaliera Cannizzaro
city: Catania
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele
city: Catania
country: Italy
facility: PO Garibaldi Nesima
city: Cremona
country: Italy
facility: Azienda Socio-Sanitaria Territoriale di Cremona
city: Firenze
country: Italy
facility: Ospedale S. Maria Annunziata
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: Azienda Ospedaliera dei Colli, presidio ospedaliero Cotugno
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Palermo
country: Italy
facility: AOU Policlinico
city: Perugia
country: Italy
facility: Azienda Ospedaliera S. Maria della Misericordia
city: Pescara
country: Italy
facility: Università degli Studi di Pescara
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli
city: Savona
country: Italy
facility: Ospedale San Paolo ASL 2 Savonese
city: Torino
country: Italy
facility: AOU Città della Salute e Scienza, Presidio Molinette
city: Trieste
country: Italy
facility: Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI)
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Friuli Centrale
city: Verona
country: Italy
facility: Azienda Ospedaliera di Verona
Study officials:
References: