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

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.

Study Overview

• Status: Unknown
• Conditions: Covid-19; Acute Respiratory Failure; ARDS, Human; Sars-CoV2; Viral Pneumonia
• Intervention / Treatment: Drug: Mavrilimumab; Drug: Placebo

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 Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lorenzo Dagna, MD; Phone Number: +390226434683; Email: dagna.lorenzo@unisr.it
• Study Contact Backup: Name: Giacomo De Luca, MD; Phone Number: +390226434683; Email: deluca.giacomo@hsr.it

Study Locations

• Italy
  • Milano, Italy, 20132
    • IRCCS Ospedale San Raffaele
    • Contact: Giacomo De Luca, MD
  • Milano, Italy, 20161
    • IRCCS Istituto Ortopedico Galeazzi
  • MI
    • San Donato, MI, Italy, 20097
      • IRCCS Policlinico San Donato

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	within day 14 of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	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	Within day 28 of intervention
Reduction in case fatality	COVID-19-related death	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)	Within day 14 of intervention
Change in biochemical markers	Change of the following serological markers over follow-up (C-reactive protein; Ferritin; D-Dimer)	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	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)	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.	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	By day 84

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical efficacy of mavrilimumab compared to the control arm by clinical severity	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	Within day 28 of intervention
Changes in serum IL-6 (exploratory biomarker)	Median changes in serum IL-6	By day 84
Changes in serum IL-1RA (exploratory biomarker)	Median changes in serum IL-1 receptor antagonist	By day 84
Changes in serum TNF-alpha (exploratory biomarker)	Median changes in serum TNF-alpha	By day 84
Changes in CBC + differential (exploratory biomarker)	Median variations in haemoglobin and leucocyte counts	By day 84
Level of anti-SARS-CoV2 antibodies (exploratory biomarker)	Median titres od anti-SARS-CoV2 antibodies	By day 84
Virus eradication (exploratory biomarker)	Proportion of patients with a positive swab for SARS-CoV2 by PCR	By day 84
Anti-drug antibodies (exploratory biomarker)	Proportion of patients who developed anti-drug antibodies	By day 84

Collaborators and Investigators

• Sponsor: Ospedale San Raffaele
• Investigators: Principal Investigator: Lorenzo Dagna, MD, Ospedale San Raffaele

Study record dates

Study Major Dates

• Study Start (Anticipated): May 22, 2020
• Primary Completion (Anticipated): September 22, 2020
• Study Completion (Anticipated): November 22, 2020

Study Registration Dates

• First Submitted: May 20, 2020
• First Submitted That Met QC Criteria: May 20, 2020
• First Posted (Actual): May 21, 2020

Study Record Updates

• Last Update Posted (Actual): May 26, 2020
• Last Update Submitted That Met QC Criteria: May 21, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: covid-19; SARS-CoV2; GM-CSF; Acute respiratory failure; viral pneumonia; mavrilimumab; GM-CSF receptor alpha
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; COVID-19; Inflammation; Respiratory Insufficiency; Pneumonia; Pneumonia, Viral; Respiratory Distress Syndrome; Antirheumatic Agents; Mavrilimumab
• Other Study ID Numbers: COMBAT-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• 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