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

July 24, 2022 updated by: Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona

Adaptive, Randomized, Non-inferiority Trial to Evaluate the Efficacy of Monoclonal Antibodies in Outpatients With Mild or Moderate COVID-19

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
319

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Bologna, Italy
        • IRCCS 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
      • Jesolo, Italy
        • Covid Hospital Jesolo
      • 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

50 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Bamlanivimab Etesevimab
Bamlanivimab 700 mg + Etesevimab 1400 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour
Drug: 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.
Experimental: 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.
Active Comparator: Casirivimab Imdevimab
Casirivimab 600 mg + Imdevimab 600 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour
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).

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
COVID-19 progression
Time Frame: 14 days
(1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation
14 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Visits to the Emergency Room
Time Frame: 28 days
Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization
28 days
Duration of supplemental oxygen therapy
Time Frame: 90 days
Days of supplemental oxygen therapy within 90 days of randomization
90 days
Duration of hospitalization
Time Frame: 90 days
Days of any hospitalization within 90 days of randomization
90 days
Non-invasive ventilation
Time Frame: 28 days
Rate of patients undergoing non-invasive ventilation within 28 days of randomization
28 days
Duration of non-invasive ventilation
Time Frame: 90 days
Days of non-invasive ventilation within 90 days of randomization
90 days
Mechanical ventilation
Time Frame: 28 days
Rate of patients undergoing mechanical ventilation within 28 of randomization
28 days
Duration of mechanical ventilation
Time Frame: 90 days
Days of mechanical ventilation within 90 days of randomization
90 days
28-day mortality
Time Frame: 28 days
Death rate at 28 days of randomization
28 days
Duration of symptoms
Time Frame: 90 days
Days of symptoms within 90 days of randomization
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Azienda Ospedaliera Universitaria Integrata Verona

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Agenzia Italiana del Farmaco
Azienda Sanitaria-Universitaria Integrata di Udine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 9, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 5, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 5, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 15, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 22, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 25, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 26, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 24, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • MANTICO
  • 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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