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Non-inferiority Trial on Monoclonal Antibodies in COVID-19 (MANTICO)

Primary Purpose

COVID-19

Status
Terminated
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Bamlanivimab Etesevimab
Sotrovimab
Casirivimab-Imdevimab
Sponsored by
Azienda Ospedaliera Universitaria Integrata Verona
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring Coronavirus Infections, Monoclonal antibodies, Bamlanivimab Etesevimab, Casirivimab Imdevimab, Sotrovimab

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • IRCCS Policlinico di S. Orsola
  • PO SS Trinità di Cagliari
  • Azienda Ospedaliera Cannizzaro
  • Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele
  • PO Garibaldi Nesima
  • Azienda Socio-Sanitaria Territoriale di Cremona
  • Ospedale S. Maria Annunziata
  • Covid Hospital Jesolo
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Azienda Ospedaliera dei Colli, presidio ospedaliero Cotugno
  • Azienda Ospedaliera di Padova
  • AOU Policlinico
  • Azienda Ospedaliera S. Maria della Misericordia
  • Università degli Studi di Pescara
  • Fondazione Policlinico Universitario A. Gemelli
  • Ospedale San Paolo ASL 2 Savonese
  • AOU Città della Salute e Scienza, Presidio Molinette
  • Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI)
  • Azienda Sanitaria Universitaria Friuli Centrale
  • Azienda Ospedaliera di Verona

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Bamlanivimab Etesevimab

Sotrovimab

Casirivimab Imdevimab

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

COVID-19 progression
(1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation

Secondary Outcome Measures

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

Full Information

First Posted
January 15, 2022
Last Updated
July 24, 2022
Sponsor
Azienda Ospedaliera Universitaria Integrata Verona
Collaborators
Agenzia Italiana del Farmaco, Azienda Sanitaria-Universitaria Integrata di Udine
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1. Study Identification

Unique Protocol Identification Number
NCT05205759
Brief Title
Non-inferiority Trial on Monoclonal Antibodies in COVID-19
Acronym
MANTICO
Official Title
Adaptive, Randomized, Non-inferiority Trial to Evaluate the Efficacy of Monoclonal Antibodies in Outpatients With Mild or Moderate COVID-19
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Terminated
Why Stopped
Stop for futility after the onset of the omicron wave
Study Start Date
December 9, 2021 (Actual)
Primary Completion Date
February 5, 2022 (Actual)
Study Completion Date
April 5, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Azienda Ospedaliera Universitaria Integrata Verona
Collaborators
Agenzia Italiana del Farmaco, Azienda Sanitaria-Universitaria Integrata di Udine

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19
Keywords
Coronavirus Infections, Monoclonal antibodies, Bamlanivimab Etesevimab, Casirivimab Imdevimab, Sotrovimab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
319 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bamlanivimab Etesevimab
Arm Type
Experimental
Arm Description
Bamlanivimab 700 mg + Etesevimab 1400 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour
Arm Title
Sotrovimab
Arm Type
Experimental
Arm Description
Sotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour
Arm Title
Casirivimab Imdevimab
Arm Type
Active Comparator
Arm Description
Casirivimab 600 mg + Imdevimab 600 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour
Intervention Type
Drug
Intervention Name(s)
Bamlanivimab Etesevimab
Intervention Description
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
Intervention Name(s)
Sotrovimab
Intervention Description
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
Intervention Name(s)
Casirivimab-Imdevimab
Intervention Description
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).
Primary Outcome Measure Information:
Title
COVID-19 progression
Description
(1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation
Time Frame
14 days
Secondary Outcome Measure Information:
Title
Visits to the Emergency Room
Description
Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization
Time Frame
28 days
Title
Duration of supplemental oxygen therapy
Description
Days of supplemental oxygen therapy within 90 days of randomization
Time Frame
90 days
Title
Duration of hospitalization
Description
Days of any hospitalization within 90 days of randomization
Time Frame
90 days
Title
Non-invasive ventilation
Description
Rate of patients undergoing non-invasive ventilation within 28 days of randomization
Time Frame
28 days
Title
Duration of non-invasive ventilation
Description
Days of non-invasive ventilation within 90 days of randomization
Time Frame
90 days
Title
Mechanical ventilation
Description
Rate of patients undergoing mechanical ventilation within 28 of randomization
Time Frame
28 days
Title
Duration of mechanical ventilation
Description
Days of mechanical ventilation within 90 days of randomization
Time Frame
90 days
Title
28-day mortality
Description
Death rate at 28 days of randomization
Time Frame
28 days
Title
Duration of symptoms
Description
Days of symptoms within 90 days of randomization
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
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
Facility Information:
Facility Name
IRCCS Policlinico di S. Orsola
City
Bologna
Country
Italy
Facility Name
PO SS Trinità di Cagliari
City
Cagliari
Country
Italy
Facility Name
Azienda Ospedaliera Cannizzaro
City
Catania
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele
City
Catania
Country
Italy
Facility Name
PO Garibaldi Nesima
City
Catania
Country
Italy
Facility Name
Azienda Socio-Sanitaria Territoriale di Cremona
City
Cremona
Country
Italy
Facility Name
Ospedale S. Maria Annunziata
City
Firenze
Country
Italy
Facility Name
Covid Hospital Jesolo
City
Jesolo
Country
Italy
Facility Name
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
City
Milano
Country
Italy
Facility Name
Azienda Ospedaliera dei Colli, presidio ospedaliero Cotugno
City
Napoli
Country
Italy
Facility Name
Azienda Ospedaliera di Padova
City
Padova
Country
Italy
Facility Name
AOU Policlinico
City
Palermo
Country
Italy
Facility Name
Azienda Ospedaliera S. Maria della Misericordia
City
Perugia
Country
Italy
Facility Name
Università degli Studi di Pescara
City
Pescara
Country
Italy
Facility Name
Fondazione Policlinico Universitario A. Gemelli
City
Roma
Country
Italy
Facility Name
Ospedale San Paolo ASL 2 Savonese
City
Savona
Country
Italy
Facility Name
AOU Città della Salute e Scienza, Presidio Molinette
City
Torino
Country
Italy
Facility Name
Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI)
City
Trieste
Country
Italy
Facility Name
Azienda Sanitaria Universitaria Friuli Centrale
City
Udine
Country
Italy
Facility Name
Azienda Ospedaliera di Verona
City
Verona
ZIP/Postal Code
37134
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
34706189
Citation
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.
Results Reference
background
PubMed Identifier
34260849
Citation
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.
Results Reference
background
PubMed Identifier
34587383
Citation
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.
Results Reference
background
Citation
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.
Results Reference
background

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Non-inferiority Trial on Monoclonal Antibodies in COVID-19

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