Covid-19Phase 2COMBAT-19NCT04397497
Mavrilimumab in Severe COVID-19 Pneumonia and Hyper-inflammation (COMBAT-19)
A Phase 2 study testing Mavrilimumab in people with Covid-19 and Acute Respiratory Failure, run by Ospedale San Raffaele at 3 sites in Italy.
Trial summary
This study is a prospective, phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of mavrilimumab in hospitalized patients with acute respiratory failure requiring oxygen supplementation in COVID- 19 pneumonia and a hyper-inflammatory status. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Covid-19, Acute Respiratory Failure, ARDS, Human
- What is being tested?
- Mavrilimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 3 sitesItaly
- Study dates
- 22 May 2020to 22 Nov 2020
- Phase
- Phase 2
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults (≥ 18 years of age)
- Signed informed consent by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representative or according to local guidelines
- Patients clinically diagnosed with SARS-CoV-2 virus by PCR or by other approved diagnostic methodology
- Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray or CT scan with pulmonary infiltrates
- Patient requiring oxygen supplementation (i.e. with a SpO2 ≤ 92% while breathing room air) and having a PAO2/FIO2 ratio ≤ 300 mmHg
- Lactate dehydrogenase (LDH) > normal range and at least one of the following:
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- fever > 38.0 °C;
- increased levels of C-reactive Protein (CRP) ≥ 10x UNL mg/L (≥ 60 mg/l);
- increased levels of ferritin ≥ 2.5x UNL ( ≥ 1000 μg/L)
Who cannot join
- Onset of COVID-19 pneumonia symptoms (i.e. dyspnea/respiratory insufficiency) >14 days
- On mechanical ventilation at the time of randomization
- A PaO2/FiO2 < 100 mmHg
- Uncontrolled systemic infection (other than COVID-19)
- Hypersensitivity to the active substance or to any of the excipients of the experimental drug
- Total neutrophil count < 1500/mm3
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- Severe hepatic cirrhosis
- History of chronic HBV or HCV infection
- Known or active tuberculosis (TB) or a history of incompletely treated TB; suspected or known extrapulmonary tuberculosis
- Moderate/severe heart failure (NYHA Class 3 or 4)
- Any prior (within the defined periods below) or concurrent use of immunosuppressive therapies including but not limited to the following:
- Anti-IL-6, anti-IL-6R antagonists or Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period;
- Cell-depleting agents (e.g., anti CD20) without evidence of recovery of B cells to baseline level;
- Anakinra within 1 week of baseline; canakinumab within 8 weeks of baseline; abatacept within 8 weeks of baseline.
- Tumor necrosis factor (TNF) inhibitors within 2-8 weeks (etanercept within 2 weeks, infliximab, certolizumab, golimumab, or adalimumab within 8 weeks), or after at least 5 half-lives have elapsed, whichever is longer;
- Alkylating agents including cyclophosphamide (CYC) within 6 months of baseline;
- Cyclosporine (CsA), azathioprine (AZA) or mycophenolate mofetil (MMF) or leflunomide or methotrexate within 4 weeks of baseline.
- Pregnancy or lactation (Note: Women of childbearing age should use effective contraception/abstinence after treatment with mavrilimumab and for 3 months after the dosing)
- Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
- In the opinion of the investigator, progression to death is imminent and highly likely within the next 24 hours, irrespective of the provision of treatments
- Current participation in any other interventional investigational trials
Trial locations and contacts
3 sites in 1 country.
Italy3 sites
IRCCS Ospedale San Raffaele
Milan, 20132
Giacomo De Luca, MD
IRCCS Istituto Ortopedico Galeazzi
Milan, 20161
IRCCS Policlinico San Donato
San Donato, MI, 20097
About this study
Official title: A Randomized, Double Blind, Placebo-controlled Trial of Mavrilimumab for Acute Respiratory Failure Due to COVID-19 Pneumonia With Hyper-inflammation (the COMBAT-19 Trial)
This study is a prospective, phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of mavrilimumab in hospitalized patients with acute respiratory failure requiring oxygen supplementation in COVID- 19 pneumonia and a hyper-inflammatory status. The study will randomize patients to mavrilimumab or placebo, in addition to standard of care per local practice. The total trial duration will be 12 weeks after single mavrilimumab or placebo dose.
Read the detailed description
To evaluate the efficacy and safety of mavrilimumab versus placebo in addition to best standard of care (SoC) in the treatment of COVID-19 pneumonia.
As of May 13, 2020, COVID-19 has been confirmed in more than 4.2 million people worldwide. Mortality rate has been reported to be approximately 3.7%, which is nearly 4 times higher than that of influenza: there is an urgent need for effective treatment.
Accumulating evidence suggests that patients with severe acute COVID-19 pneumonia have a cytokine storm syndrome, or unbalanced hyper-inflammatory response resulting in markedly elevated cytokine and chemokine production.
GM-CSF is a cytokine with dual roles as a critical pulmonary hormone and proinflammatory properties that can exaggerate tissue inflammation. Recent preliminary uncontrolled clinical observations on 13 non-mechanically-ventilated patients in the promoter institution suggest that GM-CSF pathway blockade with mavrilimumab is an effective and well-tolerated treatment for COVID-19 pneumonia.
We will perform a prospective, phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of mavrilimumab in hospitalized patients with acute respiratory failure requiring oxygen supplementation in COVID- 19 pneumonia and a hyper-inflammatory status. The study will randomize non-mechanically-ventilated adult patients to mavrilimumab or placebo, in addition to standard of care per local practice, which may include but not limited to anti-viral treatment, hydroxychloroquine, low-dose corticosteroids (≤ 10 mg of prednisone or equivalent) and/or supportive care. The total trial duration will be 12 weeks after single mavrilimumab or placebo infusion. Safety will be closely monitored by a dedicated external data safety monitoring board (DSMB) at regular intervals during the study.
- Conditions
- Covid-19, Acute Respiratory Failure, ARDS, Human, Sars-CoV2, Viral Pneumonia
- Being tested
- Mavrilimumab, Placebo
- Keywords
- covid-19, Acute respiratory failure, mavrilimumab, GM-CSF, GM-CSF receptor alpha, SARS-CoV2, viral pneumonia
- Medical subject headings
- COVID-19, Respiratory Distress Syndrome, Pneumonia, Viral
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MavrilimumabDrug
Also called KPL-301, CAM-3001
human monoclonal antibody targeting GM-CSF receptor-alpha
PlaceboDrug
matching volume of diluent
| Study group | Role | What they receive |
|---|---|---|
| Mavrilimumab | Experimental | Single dose of IV Mavrilimumab Receives: Drug: Mavrilimumab |
| Placebo | Placebo comparator | Single dose of matching IV placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reduction in the dependency on oxygen supplementation
Time to the absence of need for oxygen supplementation (time to first period of 24 hrs with a SpO2 of 94%) within day 14 of treatment, stated as Kaplan- Mayer estimates of the proportion of patients on room air at day 14 and median time to room air attainment in each arm
Measured: within day 14 of treatment
Secondary outcomes (11)
Proportion of responders (using the WHO 7-point ordinal scale)
Response is defined as a 7-point ordinal scale of 3 or less, i.e. no supplemental oxygen
Measured: Day 7, 14, and 28
Time to response (using the WHO 7-point ordinal scale)
Time from date of randomization to the date with a 7-point ordinal scale of 3 or less, i.e. no supplemental oxygen
Measured: Within day 28 of intervention
Proportion of improving patients (using the WHO 7-point ordinal scale)
Proportion of patients with at least two-point improvement in clinical status
Measured: At day 7, 14, and 28
Time to resolution of fever
Time to resolution of fever (for at least 48 hours) in absence of antipyretics, or discharge, whichever is sooner
Measured: Within day 28 of intervention
Reduction in case fatality
COVID-19-related death
Measured: Within day 28 of intervention
Proportion of patient requiring mechanical ventilation/deaths
Proportion of hospitalized patients who died or required mechanical ventilation (WHO Categories 6 or 7)
Measured: Within day 14 of intervention
Change in biochemical markers
Change of the following serological markers over follow-up (C-reactive protein; Ferritin; D-Dimer)
Measured: Within day 28 of intervention or discharge -whatever comes first
Median changes in the National Early Warning Score 2 (NEWS2)
Median changes of NEWS2 score from baseline
Measured: At day 7, 14, and 28
Time to clinical improvement as evaluated with the National Early Warning Score 2 (NEWS2)
Time to clinical improvement (as defined as a NEWS2 score of 2 or less maintained for at least 24 hours or discharge, whichever comes first)
Measured: Within day 28 of intervention or discharge -whatever comes first
Variations in radiological findings
Variations from baseline to subsequent timepoints (when available) in terms of percentage of lung involvement, modifications in the normal parenchyma, ground glass opacities (GGO), crazy paving pattern,parenchymal consolidations, and evolution towards fibrosis.
Measured: Within day 28 of intervention or discharge -whatever comes first
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Number of patients with treatment- related side effects (as assessed by Common Terminology Criteria for Adverse Event (CTCAE) v.5.0), serious adverse events, adverse events of special interest, clinically significant changes in laboratory measurements and vital signs
Measured: By day 84
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2020
- Study start22 May 2020 (estimated)
- Primary completion22 Sep 2020 (estimated)
- Study completion22 Nov 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ospedale San Raffaele
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Lorenzo Dagna, Ospedale San Raffaele
- Investigators
- Lorenzo Dagna, MD, Principal investigator, Ospedale San Raffaele
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04397497
- Sponsor's protocol ID
- COMBAT-19
- Acronym
- COMBAT-19
- Status last verified
- May 2020
- First submitted
- 20 May 2020
- Last updated
- 26 May 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 26 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double Blind, Placebo-controlled Trial of Mavrilimumab for Acute Respiratory Failure Due to COVID-19 Pneumonia With Hyper-inflammation (the COMBAT-19 Trial)
- ClinicalTrials.gov ID
- NCT04397497
- Acronym / sponsor ID
- COMBAT-19 / COMBAT-19
- Conditions
- Covid-19, Acute Respiratory Failure, ARDS, Human, Sars-CoV2, Viral Pneumonia
- Keywords
- covid-19, Acute respiratory failure, mavrilimumab, GM-CSF, GM-CSF receptor alpha, SARS-CoV2, viral pneumonia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Ospedale San RaffaeleUniversity, hospital or other
- Study start
- 22 May 2020 (estimated)
- Primary completion
- 22 Sep 2020 (estimated)
- Study completion
- 22 Nov 2020 (estimated)
- First posted
- 21 May 2020 (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.
This study is a prospective, phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of mavrilimumab in hospitalized patients with acute respiratory failure requiring oxygen supplementation in COVID- 19 pneumonia and a hyper-inflammatory status. The study will randomize patients to mavrilimumab or placebo, in addition to standard of care per local practice. The total trial duration will be 12 weeks after single mavrilimumab or placebo dose.
Detailed description
To evaluate the efficacy and safety of mavrilimumab versus placebo in addition to best standard of care (SoC) in the treatment of COVID-19 pneumonia.
As of May 13, 2020, COVID-19 has been confirmed in more than 4.2 million people worldwide. Mortality rate has been reported to be approximately 3.7%, which is nearly 4 times higher than that of influenza: there is an urgent need for effective treatment.
Accumulating evidence suggests that patients with severe acute COVID-19 pneumonia have a cytokine storm syndrome, or unbalanced hyper-inflammatory response resulting in markedly elevated cytokine and chemokine production.
GM-CSF is a cytokine with dual roles as a critical pulmonary hormone and proinflammatory properties that can exaggerate tissue inflammation. Recent preliminary uncontrolled clinical observations on 13 non-mechanically-ventilated patients in the promoter institution suggest that GM-CSF pathway blockade with mavrilimumab is an effective and well-tolerated treatment for COVID-19 pneumonia.
We will perform a prospective, phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of mavrilimumab in hospitalized patients with acute respiratory failure requiring oxygen supplementation in COVID- 19 pneumonia and a hyper-inflammatory status. The study will randomize non-mechanically-ventilated adult patients to mavrilimumab or placebo, in addition to standard of care per local practice, which may include but not limited to anti-viral treatment, hydroxychloroquine, low-dose corticosteroids (≤ 10 mg of prednisone or equivalent) and/or supportive care. The total trial duration will be 12 weeks after single mavrilimumab or placebo infusion. Safety will be closely monitored by a dedicated external data safety monitoring board (DSMB) at regular intervals during the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Mavrilimumab | Experimental | Drug: MavrilimumabSingle dose of IV Mavrilimumab |
| Placebo | Placebo comparator | Drug: PlaceboSingle dose of matching IV placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Adults (≥ 18 years of age)
- Signed informed consent by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representative or according to local guidelines
- Patients clinically diagnosed with SARS-CoV-2 virus by PCR or by other approved diagnostic methodology
- Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray or CT scan with pulmonary infiltrates
- Patient requiring oxygen supplementation (i.e. with a SpO2 ≤ 92% while breathing room air) and having a PAO2/FIO2 ratio ≤ 300 mmHg
Key exclusion criteria (21 listed)
- Onset of COVID-19 pneumonia symptoms (i.e. dyspnea/respiratory insufficiency) >14 days
- On mechanical ventilation at the time of randomization
- A PaO2/FiO2 < 100 mmHg
- Uncontrolled systemic infection (other than COVID-19)
- Hypersensitivity to the active substance or to any of the excipients of the experimental drug
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 |
|---|---|---|
| MavrilimumabAlso: KPL-301, CAM-3001human monoclonal antibody targeting GM-CSF receptor-alpha | Drug | Mavrilimumab |
| Placebomatching volume of diluent | Drug | Placebo |
Primary outcome
Reduction in the dependency on oxygen supplementation
Time frame: within day 14 of treatment
Time to the absence of need for oxygen supplementation (time to first period of 24 hrs with a SpO2 of 94%) within day 14 of treatment, stated as Kaplan- Mayer estimates of the proportion of patients on room air at day 14 and median time to room air attainment in each arm
11 secondary outcomes
Proportion of responders (using the WHO 7-point ordinal scale)
Time frame: Day 7, 14, and 28
Time to response (using the WHO 7-point ordinal scale)
Time frame: Within day 28 of intervention
Proportion of improving patients (using the WHO 7-point ordinal scale)
Time frame: At day 7, 14, and 28
Time to resolution of fever
Time frame: Within day 28 of intervention
Reduction in case fatality
Time frame: Within day 28 of intervention
Proportion of patient requiring mechanical ventilation/deaths
Time frame: Within day 14 of intervention
Change in biochemical markers
Time frame: Within day 28 of intervention or discharge -whatever comes first
Median changes in the National Early Warning Score 2 (NEWS2)
Time frame: At day 7, 14, and 28
Time to clinical improvement as evaluated with the National Early Warning Score 2 (NEWS2)
Time frame: Within day 28 of intervention or discharge -whatever comes first
Variations in radiological findings
Time frame: Within day 28 of intervention or discharge -whatever comes first
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time frame: By day 84
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 May 2020.
- Individual participant dataSharing planned: Yes
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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.
Lorenzo Dagna, MD principal investigator
Ospedale San Raffaele
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Mavrilimumab in people with Covid-19 and Acute Respiratory Failure, run by Ospedale San Raffaele at 3 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 9 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: status not confirmed, as of the sponsor's last update on 26 May 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 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. Some participants in this study may receive a placebo. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Lorenzo Dagna, MD (+390226434683, dagna.lorenzo@unisr.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction in the dependency on oxygen supplementation (time frame: within day 14 of treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 26 May 2020.