Clinical trial NCT04397497: Mavrilimumab in Severe COVID-19 Pneumonia and Hyper-inflammation (COMBAT-19)
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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
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
Lead sponsor: Ospedale San Raffaele
Sponsor class: OTHER
First posted: 2020-05-21
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Reduction in the dependency on oxygen supplementation
timeFrame: within day 14 of treatment
Secondary outcomes:
measure: Proportion of responders (using the WHO 7-point ordinal scale)
timeFrame: Day 7, 14, and 28
measure: Time to response (using the WHO 7-point ordinal scale)
timeFrame: Within day 28 of intervention
measure: Proportion of improving patients (using the WHO 7-point ordinal scale)
timeFrame: At day 7, 14, and 28
measure: Time to resolution of fever
timeFrame: Within day 28 of intervention
measure: Reduction in case fatality
timeFrame: Within day 28 of intervention
measure: Proportion of patient requiring mechanical ventilation/deaths
timeFrame: Within day 14 of intervention
measure: Change in biochemical markers
timeFrame: Within day 28 of intervention or discharge -whatever comes first
measure: Median changes in the National Early Warning Score 2 (NEWS2)
timeFrame: At day 7, 14, and 28
measure: Time to clinical improvement as evaluated with the National Early Warning Score 2 (NEWS2)
timeFrame: Within day 28 of intervention or discharge -whatever comes first
measure: Variations in radiological findings
timeFrame: Within day 28 of intervention or discharge -whatever comes first
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: By day 84
Other outcomes:
measure: Clinical efficacy of mavrilimumab compared to the control arm by clinical severity
timeFrame: Within day 28 of intervention
measure: Changes in serum IL-6 (exploratory biomarker)
timeFrame: By day 84
measure: Changes in serum IL-1RA (exploratory biomarker)
timeFrame: By day 84
measure: Changes in serum TNF-alpha (exploratory biomarker)
timeFrame: By day 84
measure: Changes in CBC + differential (exploratory biomarker)
timeFrame: By day 84
measure: Level of anti-SARS-CoV2 antibodies (exploratory biomarker)
timeFrame: By day 84
measure: Virus eradication (exploratory biomarker)
timeFrame: By day 84
measure: Anti-drug antibodies (exploratory biomarker)
timeFrame: By day 84
Locations:
city: San Donato
country: Italy
facility: IRCCS Policlinico San Donato
state: MI
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Milano
country: Italy
facility: IRCCS Istituto Ortopedico Galeazzi
Study officials:
affiliation: Ospedale San Raffaele
name: Lorenzo Dagna, MD
role: PRINCIPAL_INVESTIGATOR
References: