COVID-19Phase 3NCT05321394
Non-inferiority Trial on Treatments in Early COVID-19
A Phase 3 study testing Sotrovimab, Tixagevimab Cilgavimab and Nirmatrelvir Ritonavir in people with COVID-19, run by Azienda Ospedaliera Universitaria Integrata Verona at 19 sites in Italy.
Trial summary
The study aims at assessing the non-inferiority of tixagevimab plus cilgavimab and nirmatrelvir plus ritornavir vs. sotrovimab (reference standard due to the wider evidence gathered on its efficacy) on COVID-19 progression in a real-life setting of outpatients aged at least 50 years at an early stage of the disease. Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- COVID-19
- What is being tested?
- Sotrovimab, Tixagevimab Cilgavimab and Nirmatrelvir Ritonavir
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 536 participants
- Where
- 19 sitesItaly
- Study dates
- 7 Mar 2022to 29 Oct 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 50 years
- Informed consent by the subject or legally authorized representative
- Laboratory-confirmed SARS-CoV-2 infection, as determined by PCR or other commercial or public health assay in any specimen, no more than 4 days prior to the study drug administration
- Peripheral oxygen saturation ≥ 94% on room air and not requiring supplemental oxygen
- Onset of symptom is no more than 4 days prior to the study drug administration. Onset time of symptom is defined as the time when the patient experienced the presence of at least one of the following (but not limited to) SARS-CoV-2 infection-associated symptom (FDA, September 2020): nasal obstruction or congestion, cough, fever > 37.3 °C, sore throat, body pain or muscle pain, headache, loss of taste or smell, nausea or vomiting, diarrhoea
Who cannot join
- 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 interventions
- Severe renal impairment (eGFR <30 mL/min)
Show all 21Show fewer
- Severe hepatic impairment (Child-Pugh Class C)
- Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions
- Co-administration with potent CYP3A inducers
- 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 in within 30 days
- Any co-morbidity requiring surgery within 7 days or that is considered life-threatening within 90 days
- History of a positive SARS-CoV-2 test prior to the one serving as eligibility for this study
- Other investigational intervention for SARS-CoV-2 prophylaxis within 30 days before dosing
- Previous treatment with a SARS-CoV-2 specific monoclonal antibody
- History of convalescent COVID-19 plasma treatment
- Participation, within the last 30 days, in a clinical study involving an investigational intervention
- 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
Trial locations and contacts
19 sites in 1 country.
19 sites in 1 country
Italy19 sites
RCCS Policlinico di S. Orsola
Bologna
PO SS Trinità di Cagliari
Cagliari
Azienda Ospedaliera Cannizzaro
Catania
Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele
Catania
PO Garibaldi Nesima
Catania
Azienda Socio-Sanitaria Territoriale di Cremona
Cremona
Ospedale S. Maria Annunziata
Florence
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan
Azienda Ospedaliera dei Colli, presidio ospedaliero Cotugno
Naples
Azienda Ospedaliera di Padova
Padova
AOU Policlinico
Palermo
Azienda Ospedaliera S. Maria della Misericordia
Perugia
Università degli Studi di Pescara
Pescara
Fondazione Policlinico Universitario A. Gemelli
Roma
Ospedale San Paolo ASL 2 Savonese
Savona
AOU Città della Salute e Scienza, Presidio Molinette
Torino
Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI)
Trieste
Azienda Sanitaria Universitaria Friuli Centrale
Udine
Azienda Ospedaliera di Verona
Verona, 37134
About this study
Official title: Adaptive, Randomized, Non-inferiority Trial on the Use of Monoclonal Antibodies or Antivirals in Outpatients With Mild or Moderate COVID-19
The study aims at assessing the non-inferiority of tixagevimab plus cilgavimab and nirmatrelvir plus ritornavir vs. sotrovimab (reference standard due to the wider evidence gathered on its efficacy) on COVID-19 progression in a real-life setting of outpatients 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 sotrovimab at an early-stage of COVID-19, a disease progression of 1% has been estimated in the reference arm. 3% delta margin was considered clinically relevant, taking into account both the estimates of disease progression in the study population in absence of early treatment (7%, based on national data) and the efficacy of the reference standard. Therefore, 1095 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
- Being tested
- Sotrovimab, Tixagevimab Cilgavimab, Nirmatrelvir Ritonavir
- Keywords
- Coronavirus Infections, Monoclonal antibodies, Sotrovimab, Tixagevimab Cilgavimab, Nirmatrelvir Ritonavir
- Medical subject headings
- COVID-19, Coronavirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SotrovimabDrug
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.
Tixagevimab CilgavimabDrug
2 subsequent injections:
- tixagevimab 300mg/3mL (100mg/mL)
- cilgavimab 300mg/3mL (100mg/mL)
Nirmatrelvir RitonavirDrug
300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together twice daily for 5 days
| Study group | Role | What they receive |
|---|---|---|
| Sotrovimab | Active comparator | Sotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour Receives: Drug: Sotrovimab |
| Tixagevimab Cilgavimab | Experimental | 300 mg of tixagevimab and 300 mg of cilgavimab administered as two separate consecutive intramuscular injections Receives: Drug: Tixagevimab Cilgavimab |
| Nirmatrelvir Ritonavir | Experimental | 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together twice daily for 5 days Receives: Drug: Nirmatrelvir Ritonavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
COVID-19 progression
(1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation
Measured: 14 days
Secondary outcomes (10)
Visits to the Emergency Room
Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization
Measured: 28 days
Duration of supplemental oxygen therapy
Days of supplemental oxygen therapy within 90 days of randomization
Measured: 90 days
Duration of hospitalization
Days of any hospitalization within 90 days of randomization
Measured: 90 days
Non-invasive ventilation
Rate of patients undergoing non-invasive ventilation within 28 days of randomization
Measured: 28 days
Duration of non-invasive ventilation
Days of non-invasive ventilation within 90 days of randomization
Measured: 90 days
Mechanical ventilation
Rate of patients undergoing mechanical ventilation within 28 of randomization
Measured: 28 days
Duration of mechanical ventilation
Days of mechanical ventilation within 90 days of randomization
Measured: 90 days
28-day mortality
Death rate at 28 days of randomization
Measured: 28 days
90-day mortality
Death rate at 90 days of randomization
Measured: 90 days
Duration of symptoms
Days of symptoms within 90 days of randomization
Measured: 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2022
- Study start7 Mar 2022
- Primary completion29 Oct 2023
- Study completion29 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 536 participants (actual)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliera Universitaria Integrata Verona
- Sponsor type
- University, hospital or other
- Collaborators
- Agenzia Italiana del Farmaco, Azienda Sanitaria-Universitaria Integrata di Udine
- Responsible party
- Principal investigator, Evelina Tacconelli, Azienda Ospedaliera Universitaria Integrata Verona
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05321394
- Sponsor's protocol ID
- MANTICO 2
- Other IDs
- 2021-002612-31
- Status last verified
- Nov 2023
- First submitted
- 7 Apr 2022
- Last updated
- 7 Nov 2023
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Mazzotta V, Mazzaferri F, Lanini S, Mirandola M, Cozzi Lepri A, Vergori A, Savoldi A, Santoro A, Maccarrone G, Mastrorosa I, Simonetti O, Zottis F, Nicastri E, Rosini G, Rovigo L, Tavernaro L, Sarmati L, Tascini C, Girardi E, Cattelan AM, Antinori A, Tacconelli E; MANTICO2/MONET study group. Pooled analysis of the MANTICO2 and MONET randomized controlled trials comparing drug efficacy for early treatment of COVID-19 during Omicron waves. J Infect. 2024 Nov;89(5):106294. doi: 10.1016/j.jinf.2024.106294. Epub 2024 Sep 27.
PubMed 39343244
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Adaptive, Randomized, Non-inferiority Trial on the Use of Monoclonal Antibodies or Antivirals in Outpatients With Mild or Moderate COVID-19
- ClinicalTrials.gov ID
- NCT05321394
- Acronym / sponsor ID
- MANTICO 2
- Conditions
- COVID-19
- Keywords
- Coronavirus Infections, Monoclonal antibodies, Sotrovimab, Tixagevimab Cilgavimab, Nirmatrelvir Ritonavir
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 536 participants (actual)
- Lead sponsor
- Azienda Ospedaliera Universitaria Integrata VeronaUniversity, hospital or other
- Collaborators
- Agenzia Italiana del Farmaco, Azienda Sanitaria-Universitaria Integrata di Udine
- Study start
- 7 Mar 2022 (actual)
- Primary completion
- 29 Oct 2023 (actual)
- Study completion
- 29 Oct 2023 (actual)
- First posted
- 11 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study aims at assessing the non-inferiority of tixagevimab plus cilgavimab and nirmatrelvir plus ritornavir vs. sotrovimab (reference standard due to the wider evidence gathered on its efficacy) on COVID-19 progression in a real-life setting of outpatients 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 sotrovimab at an early-stage of COVID-19, a disease progression of 1% has been estimated in the reference arm. 3% delta margin was considered clinically relevant, taking into account both the estimates of disease progression in the study population in absence of early treatment (7%, based on national data) and the efficacy of the reference standard. Therefore, 1095 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Sotrovimab | Active comparator | Drug: SotrovimabSotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour |
| Tixagevimab Cilgavimab | Experimental | Drug: Tixagevimab Cilgavimab300 mg of tixagevimab and 300 mg of cilgavimab administered as two separate consecutive intramuscular injections |
| Nirmatrelvir Ritonavir | Experimental | Drug: Nirmatrelvir Ritonavir300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together twice daily for 5 days |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age ≥ 50 years
- Informed consent by the subject or legally authorized representative
- Laboratory-confirmed SARS-CoV-2 infection, as determined by PCR or other commercial or public health assay in any specimen, no more than 4 days prior to the study drug administration
- Peripheral oxygen saturation ≥ 94% on room air and not requiring supplemental oxygen
- Onset of symptom is no more than 4 days prior to the study drug administration. Onset time of symptom is defined as the time when the patient experienced the presence of at least one of the following (but not limited to) SARS-CoV-2 infection-associated symptom (FDA, September 2020): nasal obstruction or congestion, cough, fever > 37.3 °C, sore throat, body pain or muscle pain, headache, loss of taste or smell, nausea or vomiting, diarrhoea
Key exclusion criteria (21 listed)
- 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 interventions
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SotrovimabSingle 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 | Sotrovimab |
| Tixagevimab Cilgavimab2 subsequent injections: 1. tixagevimab 300mg/3mL (100mg/mL) 2. cilgavimab 300mg/3mL (100mg/mL) | Drug | Tixagevimab Cilgavimab |
| Nirmatrelvir Ritonavir300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together twice daily for 5 days | Drug | Nirmatrelvir Ritonavir |
Primary outcome
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
10 secondary outcomes
Visits to the Emergency Room
Time frame: 28 days
Duration of supplemental oxygen therapy
Time frame: 90 days
Duration of hospitalization
Time frame: 90 days
Non-invasive ventilation
Time frame: 28 days
Duration of non-invasive ventilation
Time frame: 90 days
Mechanical ventilation
Time frame: 28 days
Duration of mechanical ventilation
Time frame: 90 days
28-day mortality
Time frame: 28 days
90-day mortality
Time frame: 90 days
Duration of symptoms
Time frame: 90 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2023.
- Derived from this study: PubMed 39343244Mazzotta V, Mazzaferri F, Lanini S, Mirandola M, Cozzi Lepri A, Vergori A, Savoldi A, Santoro A, Maccarrone G, Mastrorosa I, Simonetti O, Zottis F, Nicastri E, Rosini G, Rovigo L, Tavernaro L, Sarmati L, Tascini C, Girardi E, Cattelan AM, Antinori A, Tacconelli E; MANTICO2/MONET study group. Pooled analysis of the MANTICO2 and MONET randomized controlled trials comparing drug efficacy for early treatment of COVID-19 during Omicron waves. J Infect. 2024 Nov;89(5):106294. doi: 10.1016/j.jinf.2024.106294. Epub 2024 Sep 27.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
19 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Sotrovimab, Tixagevimab Cilgavimab and Nirmatrelvir Ritonavir in people with COVID-19, run by Azienda Ospedaliera Universitaria Integrata Verona at 19 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
COVID-19 progression (time frame: 14 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05321394, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2023.