Non-inferiority Trial on Monoclonal Antibodies in COVID-19

NCT ID: NCT05205759

Last Updated: 2022-07-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 319 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-09
• Study Completion Date: 2022-04-05

Brief Summary

Currently, 3 anti-SARS-CoV-2 monoclonal antibody products have received Emergency Use Authorizations from the Italian Medicines Agency (AIFA) for the treatment of mild to moderate COVID-19 in non hospitalized patients with laboratory-confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease and/or hospitalization (bamlanivimab plus etesevimab, sotrovimab, and casirivimab plus imdevimab). Differently from casirivimab/imdevimab and sotrovimab, the European Medicines Agency (EMA) has never recommended authorising the combination bamlanivimab/etesevimab for treating COVID-19. Moreover, the evidence on sotrovimab relies on the interim analysis results of an ongoing randomised placebo-controlled clinical trial [1], unlike the combinations bamlanivimab/etesevimab and casirivimab/imdevimab, whose results of the randomised placebo-controlled trials were published after having completed the enrolment [2,3]. The study aims at assessing the non-inferiority of bamlanivimab plus etesevimab and sotrovimab vs. casirivimab plus imdevimab on COVID-19 progression in patients 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 casirivimab plus imdevimab at an early-stage of COVID-19, a disease progression of 5% has been estimated in the reference arm. 5% delta margin was considered clinically relevant, taking into account both the estimates of disease progression in the study population in absence of early treatment with monoclonal antibodies (20%, based on national data) and the efficacy of the reference standard. Therefore, 1260 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.

Detailed Description

Sample size. The parameters for the sample size estimation were derived from the only double-blind, randomised, placebo-controlled trial assessing the clinical efficacy of casirivimab/imdevimab (reference standard) [3]. Hospitalisation related to COVID-19 or all-cause mortality in this study occurred in 7 of 736 patients in the casirivimab/imdevimab 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomisation concurrently (3.2%) (relative risk reduction, 70.4%; P=0.002). Assuming a non-inferiority margin of 5%, 420 patients per group were needed to achieve 90% power with a 1-sided α level of .025, allowing for 5% dropout. A 5% non-inferiority margin was chosen as the maximal difference between treatments in COVID-19 progression that would be clinically acceptable by consultation with Infectious Diseases and clinical trial specialists involved in the protocol development.

Conditions

COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Bamlanivimab Etesevimab

Bamlanivimab 700 mg + Etesevimab 1400 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour

Group Type: EXPERIMENTAL

Bamlanivimab Etesevimab

Intervention Type: DRUG

Single intravenous infusion of bamlanivimab 700 mg and etesevimab 1400 mg, administered together \[1 bamlanivimab vial (700 mg/20 mL) and 2 etesevimab vials (700 mg/20 mL)\] in a 250-mL prefilled 0.9% Sodium Chloride infusion bag over one hour.

Sotrovimab

Sotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour

Group Type: EXPERIMENTAL

Sotrovimab

Intervention Type: DRUG

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.

Casirivimab Imdevimab

Casirivimab 600 mg + Imdevimab 600 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour

Group Type: ACTIVE_COMPARATOR

Casirivimab-Imdevimab

Intervention Type: DRUG

Single intravenous infusion of casirivimab 600 mg + imdevimab 600 mg, administered together in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour. Casirivimab and imdevimab are each supplied in individual single use vials. Casirivimab is available as 300 mg/2.5 mL (120 mg/mL) or 1332 mg/11.1 mL (120 mg/mL). Imdevimab is available as 300 mg/2.5 mL (120 mg/mL) or 1332 mg/11.1 mL (120 mg/mL).

Interventions

Bamlanivimab Etesevimab

Single intravenous infusion of bamlanivimab 700 mg and etesevimab 1400 mg, administered together \[1 bamlanivimab vial (700 mg/20 mL) and 2 etesevimab vials (700 mg/20 mL)\] in a 250-mL prefilled 0.9% Sodium Chloride infusion bag over one hour.

Intervention Type: 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.

Intervention Type: DRUG

Casirivimab-Imdevimab

Single intravenous infusion of casirivimab 600 mg + imdevimab 600 mg, administered together in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour. Casirivimab and imdevimab are each supplied in individual single use vials. Casirivimab is available as 300 mg/2.5 mL (120 mg/mL) or 1332 mg/11.1 mL (120 mg/mL). Imdevimab is available as 300 mg/2.5 mL (120 mg/mL) or 1332 mg/11.1 mL (120 mg/mL).

Intervention Type: DRUG

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 antigen or nucleic acid identification in any specimen, within 4 days of eligibility assessment
• Peripheral oxygen saturation ≥ 94% on room air and not requiring supplemental oxygen
• Onset of symptoms within 4 days of eligibility assessment. Onset time of symptoms is defined as the time when the patient experienced the presence of at least one of the following SARS-CoV-2 infection-associated symptoms for the first time [4]: cough, nasal congestion, sore throat, feeling hot or feverish, myalgia, fatigue, headache, anosmia/ageusia, nausea, vomiting, and/or 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 trial drugs
• 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 within 30 days
• Any co-morbidity requiring surgery within 7 days or that is considered life-threatening within 90 days
• History of positive SARS-CoV-2 test prior to 4 days of the eligibility assessment
• Previous treatment with a SARS-CoV-2 specific monoclonal antibody
• History of convalescent COVID-19 plasma treatment
• Participation in a clinical study involving an investigational intervention within the last 30 days
• 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

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Agenzia Italiana del Farmaco

OTHER_GOV

Sponsor Role: collaborator

Azienda Sanitaria-Universitaria Integrata di Udine

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera Universitaria Integrata Verona

OTHER

Sponsor Role: lead

Responsible Party

Evelina Tacconelli

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

IRCCS Policlinico di S. Orsola

Bologna, , Italy

PO SS Trinità di Cagliari

Cagliari, , Italy

Azienda Ospedaliera Cannizzaro

Catania, , Italy

Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele

Catania, , Italy

PO Garibaldi Nesima

Catania, , Italy

Azienda Socio-Sanitaria Territoriale di Cremona

Cremona, , Italy

Ospedale S. Maria Annunziata

Florence, , Italy

Covid Hospital Jesolo

Jesolo, , Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Azienda Ospedaliera dei Colli, presidio ospedaliero Cotugno

Napoli, , Italy

Azienda Ospedaliera di Padova

Padua, , Italy

AOU Policlinico

Palermo, , Italy

Azienda Ospedaliera S. Maria della Misericordia

Perugia, , Italy

Università degli Studi di Pescara

Pescara, , Italy

Fondazione Policlinico Universitario A. Gemelli

Roma, , Italy

Ospedale San Paolo ASL 2 Savonese

Savona, , Italy

AOU Città della Salute e Scienza, Presidio Molinette

Torino, , Italy

Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI)

Trieste, , Italy

Azienda Sanitaria Universitaria Friuli Centrale

Udine, , Italy

Azienda Ospedaliera di Verona

Verona, , Italy

Countries

Italy

References

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Reference Type: BACKGROUND

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Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, Hebert C, Perry R, Boscia J, Heller B, Morris J, Crystal C, Igbinadolor A, Huhn G, Cardona J, Shawa I, Kumar P, Adams AC, Van Naarden J, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Dabora MC, Klekotka P, Shen L, Skovronsky DM; BLAZE-1 Investigators. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021 Oct 7;385(15):1382-1392. doi: 10.1056/NEJMoa2102685. Epub 2021 Jul 14.

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Reference Type: BACKGROUND

PMID: 34587383 (View on PubMed)

U.S. Department of Health and Human Services Food and Drug Administration. Assessing COVID19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-covid-19-related-symptoms-outpatient-adult-and-adolescent-subjects-clinical-trials-drugs. Accessed 30 March 2022.

Reference Type: BACKGROUND

Mazzaferri F, Mirandola M, Savoldi A, De Nardo P, Morra M, Tebon M, Armellini M, De Luca G, Calandrino L, Sasset L, D'Elia D, Sozio E, Danese E, Gibellini D, Monne I, Scroccaro G, Magrini N, Cattelan A, Tascini C; MANTICO Working Group; Tacconelli E. Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern. Elife. 2022 Nov 22;11:e79639. doi: 10.7554/eLife.79639.

Reference Type: DERIVED

PMID: 36413383 (View on PubMed)

Other Identifiers

2021-002612-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MANTICO

Identifier Type: -

Identifier Source: org_study_id