Non-inferiority Trial on Monoclonal Antibodies in COVID-19

NCT05205759 | Terminated Phase 3 DMC FDA Drug

• 2 other identifiers: MANTICO2021-002612-31
• Study Type: interventional
• Target: 319
• Locations: 1 country
• Sites: 20

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.

Conditions

COVID-19

Keywords

Coronavirus Infections; Monoclonal antibodies; Bamlanivimab Etesevimab; Casirivimab Imdevimab; Sotrovimab

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Visits to the Emergency Room

  28 days

• Duration of supplemental oxygen therapy

  90 days

• Duration of hospitalization

  90 days

• Non-invasive ventilation

  28 days

• Duration of non-invasive ventilation

  90 days

Study Arms (3)

Bamlanivimab Etesevimab

EXPERIMENTAL

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

Drug: Bamlanivimab Etesevimab

Sotrovimab

EXPERIMENTAL

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

Drug: Sotrovimab

Casirivimab Imdevimab

ACTIVE COMPARATOR

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

Drug: Casirivimab-Imdevimab

Interventions

Bamlanivimab Etesevimab 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.

Bamlanivimab Etesevimab

Sotrovimab 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.

Sotrovimab

Casirivimab-Imdevimab 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).

Casirivimab Imdevimab

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Azienda Ospedaliera Universitaria Integrata Verona: lead
• Agenzia Italiana del Farmaco: collaborator
• Azienda Sanitaria-Universitaria Integrata di Udine: collaborator

Study Sites (20)

IRCCS Policlinico di S. Orsola

Bologna, Italy

Location

PO SS Trinità di Cagliari

Cagliari, Italy

Location

Azienda Ospedaliera Cannizzaro

Catania, Italy

Location

Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele

Catania, Italy

Location

PO Garibaldi Nesima

Catania, Italy

Location

Azienda Socio-Sanitaria Territoriale di Cremona

Cremona, Italy

Location

Ospedale S. Maria Annunziata

Florence, Italy

Location

Covid Hospital Jesolo

Jesolo, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Italy

Location

Azienda Ospedaliera dei Colli, presidio ospedaliero Cotugno

Napoli, Italy

Location

Azienda Ospedaliera di Padova

Padua, Italy

Location

AOU Policlinico

Palermo, Italy

Location

Azienda Ospedaliera S. Maria della Misericordia

Perugia, Italy

Location

Università degli Studi di Pescara

Pescara, Italy

Location

Fondazione Policlinico Universitario A. Gemelli

Roma, Italy

Location

Ospedale San Paolo ASL 2 Savonese

Savona, Italy

Location

AOU Città della Salute e Scienza, Presidio Molinette

Torino, Italy

Location

Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI)

Trieste, Italy

Location

Azienda Sanitaria Universitaria Friuli Centrale

Udine, Italy

Location

Azienda Ospedaliera di Verona

Verona, 37134, Italy

Location

Related Publications (5)

• Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL, Hebner CM, Sager J, Mogalian E, Tipple C, Peppercorn A, Alexander E, Pang PS, Free A, Brinson C, Aldinger M, Shapiro AE; COMET-ICE Investigators. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941-1950. doi: 10.1056/NEJMoa2107934. Epub 2021 Oct 27.

  PMID: 34706189 BACKGROUND

• 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.

  PMID: 34260849 BACKGROUND

• Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Xiao J, Hooper AT, Hamilton JD, Musser BJ, Rofail D, Hussein M, Im J, Atmodjo DY, Perry C, Pan C, Mahmood A, Hosain R, Davis JD, Turner KC, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Roque-Guerrero L, Acloque G, Aazami H, Cannon K, Simon-Campos JA, Bocchini JA, Kowal B, DiCioccio AT, Soo Y, Geba GP, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD; Trial Investigators. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. N Engl J Med. 2021 Dec 2;385(23):e81. doi: 10.1056/NEJMoa2108163. Epub 2021 Sep 29.

  PMID: 34587383 BACKGROUND

• 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.

  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.

  PMID: 36413383 DERIVED

MeSH Terms

Conditions

COVID-19; Coronavirus Infections

Interventions

bamlanivimab and etesevimab drug combination; sotrovimab; casirivimab and imdevimab drug combination

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 15, 2022
• First Posted: January 25, 2022
• Study Start: December 9, 2021
• Primary Completion: February 5, 2022
• Study Completion: April 5, 2022
• Last Updated: July 26, 2022

Record last verified: 2022-07

Locations

IT (20)