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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05205759
Recruitment Status : Terminated (Stop for futility after the onset of the omicron wave)
First Posted : January 25, 2022
Last Update Posted : July 26, 2022
Sponsor:
Collaborators:
Agenzia Italiana del Farmaco
Azienda Sanitaria-Universitaria Integrata di Udine
Information provided by (Responsible Party):
Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona

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.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Bamlanivimab Etesevimab Drug: Sotrovimab Drug: Casirivimab-Imdevimab Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 319 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Adaptive, Randomized, Non-inferiority Trial to Evaluate the Efficacy of Monoclonal Antibodies in Outpatients With Mild or Moderate COVID-19
Actual Study Start Date : December 9, 2021
Actual Primary Completion Date : February 5, 2022
Actual Study Completion Date : April 5, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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).




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Visits to the Emergency Room [ Time Frame: 28 days ]
    Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization

  2. Duration of supplemental oxygen therapy [ Time Frame: 90 days ]
    Days of supplemental oxygen therapy within 90 days of randomization

  3. Duration of hospitalization [ Time Frame: 90 days ]
    Days of any hospitalization within 90 days of randomization

  4. Non-invasive ventilation [ Time Frame: 28 days ]
    Rate of patients undergoing non-invasive ventilation within 28 days of randomization

  5. Duration of non-invasive ventilation [ Time Frame: 90 days ]
    Days of non-invasive ventilation within 90 days of randomization

  6. Mechanical ventilation [ Time Frame: 28 days ]
    Rate of patients undergoing mechanical ventilation within 28 of randomization

  7. Duration of mechanical ventilation [ Time Frame: 90 days ]
    Days of mechanical ventilation within 90 days of randomization

  8. 28-day mortality [ Time Frame: 28 days ]
    Death rate at 28 days of randomization

  9. Duration of symptoms [ Time Frame: 90 days ]
    Days of symptoms within 90 days of randomization



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05205759


Locations
Show Show 20 study locations
Sponsors and Collaborators
Azienda Ospedaliera Universitaria Integrata Verona
Agenzia Italiana del Farmaco
Azienda Sanitaria-Universitaria Integrata di Udine
Publications:
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.

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Responsible Party: Evelina Tacconelli, Professor, Azienda Ospedaliera Universitaria Integrata Verona
ClinicalTrials.gov Identifier: NCT05205759    
Other Study ID Numbers: MANTICO
2021-002612-31 ( EudraCT Number )
First Posted: January 25, 2022    Key Record Dates
Last Update Posted: July 26, 2022
Last Verified: July 2022

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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
Keywords provided by Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona:
Coronavirus Infections
Monoclonal antibodies
Bamlanivimab Etesevimab
Casirivimab Imdevimab
Sotrovimab
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Bamlanivimab
Antiviral Agents
Anti-Infective Agents