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Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT04397497
Other study ID # COMBAT-19
Secondary ID
Status Not yet recruiting
Phase Phase 2
First received
Last updated
Start date May 22, 2020
Est. completion date November 22, 2020

Study information

Verified date May 2020
Source Ospedale San Raffaele
Contact Lorenzo Dagna, MD
Phone +390226434683
Email dagna.lorenzo@unisr.it
Is FDA regulated No
Health authority
Study type Interventional

Clinical 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. 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.


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.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 50
Est. completion date November 22, 2020
Est. primary completion date September 22, 2020
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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 Design


Intervention

Drug:
Mavrilimumab
human monoclonal antibody targeting GM-CSF receptor-alpha
Placebo
matching volume of diluent

Locations

Country Name City State
Italy IRCCS Istituto Ortopedico Galeazzi Milano
Italy IRCCS Ospedale San Raffaele Milano
Italy IRCCS Policlinico San Donato San Donato MI

Sponsors (1)

Lead Sponsor Collaborator
Ospedale San Raffaele

Country where clinical trial is conducted

Italy, 

Outcome

Type Measure Description Time frame Safety issue
Other 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
Other Changes in serum IL-6 (exploratory biomarker) Median changes in serum IL-6 By day 84
Other Changes in serum IL-1RA (exploratory biomarker) Median changes in serum IL-1 receptor antagonist By day 84
Other Changes in serum TNF-alpha (exploratory biomarker) Median changes in serum TNF-alpha By day 84
Other Changes in CBC + differential (exploratory biomarker) Median variations in haemoglobin and leucocyte counts By day 84
Other Level of anti-SARS-CoV2 antibodies (exploratory biomarker) Median titres od anti-SARS-CoV2 antibodies By day 84
Other Virus eradication (exploratory biomarker) Proportion of patients with a positive swab for SARS-CoV2 by PCR By day 84
Other Anti-drug antibodies (exploratory biomarker) Proportion of patients who developed anti-drug antibodies By day 84
Primary 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 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
Secondary 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
Secondary 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
Secondary 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
Secondary Reduction in case fatality COVID-19-related death Within day 28 of intervention
Secondary 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
Secondary 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
Secondary Median changes in the National Early Warning Score 2 (NEWS2) Median changes of NEWS2 score from baseline At day 7, 14, and 28
Secondary 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
Secondary 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
Secondary 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
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