Mavrilimumab in Severe COVID-19 Pneumonia and Hyper-inflammation (COMBAT-19) (COMBAT-19)

• ClinicalTrials.gov Identifier: NCT04397497
• Recruitment Status: Not yet recruiting
• First Posted: May 21, 2020
• Last Update Posted: May 26, 2020
• Sponsor: Ospedale San Raffaele
• Information provided by (Responsible Party): Lorenzo Dagna, Ospedale San Raffaele

Study Description

Brief 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. 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.

Condition or disease	Intervention/treatment	Phase
Covid-19; Acute Respiratory Failure; ARDS, Human; Sars-CoV2; Viral Pneumonia	Drug: Mavrilimumab; Drug: Placebo	Phase 2

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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Estimated Study Start Date: May 22, 2020
• Estimated Primary Completion Date: September 22, 2020
• Estimated Study Completion Date: November 22, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Mavrilimumab; Single dose of IV Mavrilimumab	Drug: Mavrilimumab; human monoclonal antibody targeting GM-CSF receptor-alpha; Other Names: KPL-301; CAM-3001
Placebo Comparator: Placebo; Single dose of matching IV placebo	Drug: Placebo; matching volume of diluent

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. Proportion of responders (using the WHO 7-point ordinal scale) [ Time Frame: Day 7, 14, and 28 ]
   Response is defined as a 7-point ordinal scale of 3 or less, i.e. no supplemental oxygen
2. Time to response (using the WHO 7-point ordinal scale) [ Time Frame: Within day 28 of intervention ]
   Time from date of randomization to the date with a 7-point ordinal scale of 3 or less, i.e. no supplemental oxygen
3. Proportion of improving patients (using the WHO 7-point ordinal scale) [ Time Frame: At day 7, 14, and 28 ]
   Proportion of patients with at least two-point improvement in clinical status
4. Time to resolution of fever [ Time Frame: Within day 28 of intervention ]
   Time to resolution of fever (for at least 48 hours) in absence of antipyretics, or discharge, whichever is sooner
5. Reduction in case fatality [ Time Frame: Within day 28 of intervention ]
   COVID-19-related death
6. Proportion of patient requiring mechanical ventilation/deaths [ Time Frame: Within day 14 of intervention ]
   Proportion of hospitalized patients who died or required mechanical ventilation (WHO Categories 6 or 7)
7. Change in biochemical markers [ Time Frame: Within day 28 of intervention or discharge -whatever comes first ]
   Change of the following serological markers over follow-up (C-reactive protein; Ferritin; D-Dimer)
8. Median changes in the National Early Warning Score 2 (NEWS2) [ Time Frame: At day 7, 14, and 28 ]
   Median changes of NEWS2 score from baseline
9. 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 ]
   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)
10. Variations in radiological findings [ Time Frame: Within day 28 of intervention or discharge -whatever comes first ]
    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.
11. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: By day 84 ]
    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

Other Outcome Measures:

1. Clinical efficacy of mavrilimumab compared to the control arm by clinical severity [ Time Frame: Within day 28 of intervention ]

   To evaluate the primary and secondary endpoints in different subgroups of patients:

   • mild respiratory failure: PaO2/FiO2 ≤ 300 and > 200 mmHg;
   • moderate respiratory failure: PaO2/FiO2 ≤ 200 and > 100 mmHg
2. Changes in serum IL-6 (exploratory biomarker) [ Time Frame: By day 84 ]
   Median changes in serum IL-6
3. Changes in serum IL-1RA (exploratory biomarker) [ Time Frame: By day 84 ]
   Median changes in serum IL-1 receptor antagonist
4. Changes in serum TNF-alpha (exploratory biomarker) [ Time Frame: By day 84 ]
   Median changes in serum TNF-alpha
5. Changes in CBC + differential (exploratory biomarker) [ Time Frame: By day 84 ]
   Median variations in haemoglobin and leucocyte counts
6. Level of anti-SARS-CoV2 antibodies (exploratory biomarker) [ Time Frame: By day 84 ]
   Median titres od anti-SARS-CoV2 antibodies
7. Virus eradication (exploratory biomarker) [ Time Frame: By day 84 ]
   Proportion of patients with a positive swab for SARS-CoV2 by PCR
8. Anti-drug antibodies (exploratory biomarker) [ Time Frame: By day 84 ]
   Proportion of patients who developed anti-drug antibodies

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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:

  1. fever > 38.0 °C;
  2. increased levels of C-reactive Protein (CRP) ≥ 10x UNL mg/L (≥ 60 mg/l);
  3. increased levels of ferritin ≥ 2.5x UNL ( ≥ 1000 μg/L)

Exclusion Criteria:

• 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
• 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:

  1. 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;
  2. Cell-depleting agents (e.g., anti CD20) without evidence of recovery of B cells to baseline level;
  3. Anakinra within 1 week of baseline; canakinumab within 8 weeks of baseline; abatacept within 8 weeks of baseline.
  4. 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;
  5. Alkylating agents including cyclophosphamide (CYC) within 6 months of baseline;
  6. 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

Contacts and Locations

Contacts

Contact: Lorenzo Dagna, MD; +390226434683; dagna.lorenzo@unisr.it

Contact: Giacomo De Luca, MD; +390226434683; deluca.giacomo@hsr.it

Locations

Italy

IRCCS Policlinico San Donato

San Donato, MI, Italy, 20097

IRCCS Ospedale San Raffaele

Milano, Italy, 20132

Contact: Giacomo De Luca, MD

IRCCS Istituto Ortopedico Galeazzi

Milano, Italy, 20161

Sponsors and Collaborators

Ospedale San Raffaele

Investigators

• Principal Investigator: Lorenzo Dagna, MD; Ospedale San Raffaele

More Information

• Responsible Party: Lorenzo Dagna, Head, Unit of Immunology Rheumatology Allergy and Rare Diseases (UnIRAR), Ospedale San Raffaele
• ClinicalTrials.gov Identifier: NCT04397497
• Other Study ID Numbers: COMBAT-19
• First Posted: May 21, 2020
• Last Update Posted: May 26, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

• 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 Lorenzo Dagna, Ospedale San Raffaele:

covid-19; Acute respiratory failure; mavrilimumab; GM-CSF; GM-CSF receptor alpha; SARS-CoV2; viral pneumonia

Additional relevant MeSH terms:

Pneumonia, Viral; Pneumonia; Respiratory Insufficiency; Respiratory Distress Syndrome, Adult; Inflammation; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Respiration Disorders; Virus Diseases; Mavrilimumab; Antirheumatic Agents