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

• ClinicalTrials.gov Identifier: NCT05205759
• Recruitment Status: Terminated
• First Posted: January 25, 2022
• Last Update Posted: July 26, 2022
• Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Collaborators: Agenzia Italiana del Farmaco; Azienda Sanitaria-Universitaria Integrata di Udine
• Information provided by (Responsible Party): Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona

Tracking Information

• First Submitted Date: January 15, 2022
• First Posted Date: January 25, 2022
• Last Update Posted Date: July 26, 2022
• Actual Study Start Date: December 9, 2021
• Actual Primary Completion Date: February 5, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 22, 2022)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 17, 2022)

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

Original Secondary Outcome Measures (submitted: January 22, 2022)

• Visits to the Emergency Room [ Time Frame: 28 days ]
  Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization
• Duration of supplemental oxygen therapy [ Time Frame: 90 days ]
  Days of supplemental oxygen therapy within 90 days of randomization
• Duration of hospitalization [ Time Frame: 90 days ]
  Days of any hospitalization within 90 days of randomization
• Non-invasive ventilation [ Time Frame: 28 days ]
  Rate of patients undergoing non-invasive ventilation within 28 days of randomization
• Duration of non-invasive ventilation [ Time Frame: 90 days ]
  Days of non-invasive ventilation within 90 days of randomization
• Mechanical ventilation [ Time Frame: 28 days ]
  Rate of patients undergoing mechanical ventilation within 28 of randomization
• Duration of mechanical ventilation [ Time Frame: 90 days ]
  Days of mechanical ventilation within 90 days of randomization
• 28-day mortality [ Time Frame: 28 days ]
  Death rate at 28 days of randomization
• 90-day mortality [ Time Frame: 90 days ]
  Death rate at 90 days of randomization
• Duration of fever [ Time Frame: 90 days ]
  Days of fever within 90 days of randomization
• Duration of symptoms [ Time Frame: 90 days ]
  Days of symptoms within 90 days of randomization
• Duration of absence from work [ Time Frame: 90 days ]
  Days of absence from work (including smart working) within 90 days of randomization (only in the case of employment)
• Adverse events [ Time Frame: 90 days ]
  Rate of adverse events leading to interruption of the drug infusion or serious adverse events within 90 days of randomization

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Non-inferiority Trial on Monoclonal Antibodies in COVID-19
• Official Title: Adaptive, Randomized, Non-inferiority Trial to Evaluate the Efficacy of Monoclonal Antibodies in Outpatients With Mild or Moderate COVID-19
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: COVID-19

Intervention

• 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.
• 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.
• 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).

Study Arms

• Experimental: Bamlanivimab Etesevimab
  Bamlanivimab 700 mg + Etesevimab 1400 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour
  Intervention: Drug: Bamlanivimab Etesevimab
• Experimental: Sotrovimab
  Sotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour
  Intervention: Drug: Sotrovimab
• 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
  Intervention: Drug: Casirivimab-Imdevimab

Publications *

• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 24, 2022): 319
• Original Estimated Enrollment (submitted: January 22, 2022): 1260
• Actual Study Completion Date: April 5, 2022
• Actual Primary Completion Date: February 5, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT05205759
• Other Study ID Numbers: MANTICO; 2021-002612-31 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona
• Original Responsible Party: Same as current
• Current Study Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Original Study Sponsor: Same as current

Collaborators

• Agenzia Italiana del Farmaco
• Azienda Sanitaria-Universitaria Integrata di Udine

• Investigators: Not Provided
• PRS Account: Azienda Ospedaliera Universitaria Integrata Verona
• Verification Date: July 2022