Acute Lung Injury, Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Respiratory Distress Syndrome, Adult Respiratory Distress Syndrome
Conditions
Keywords
ARDS, IC14
Brief summary
Hospitalized patients with ARDS will be randomized to intravenous treatment with a monoclonal antibody against CD14, called IC14, or placebo. They will be followed for 28 days. The primary outcome is the day 4 oxygenation index assessed as a continuous measure.
Detailed description
This is a phase 2, randomized, double-blind, placebo-controlled, safety and efficacy study of anti-CD14 treatment with a recombinant chimeric monoclonal antibody (IC14) in hospitalized patients with Acute Respiratory Distress Syndrome (ARDS). CD14 is a key mediator in recognition of molecular markers of tissue damage (damage-associated molecular patterns, DAMPs) and infection (pathogen-associated molecular patterns, PAMPS). The primary objective of the study is to determine the efficacy of IC14 in patients hospitalized with ARDS for reducing the severity of lung injury as measured by the day 4 Oxygenation Index (OI) assessed as a continuous measure (mean airway pressure x fraction of inspired oxygen \[FiO2\] x 100/partial pressure of oxygen \[PaO2\]). OI captures severity of hypoxemia and concurrent intensity of ventilatory support. Secondary objectives include determining whether IC14 reduces the systemic and alveolar inflammatory response, and improves indices of oxygenation and illness severity. Exploratory endpoints include determining the effect of CD14 blockade on duration of mechanical ventilation and mortality in patients hospitalized with ARDS. Pharmacokinetic \[PK\]/Pharmacodynamic \[PD\] endpoints include determining day 4 IC14 levels in bronchoalveolar fluid (BALF) vs. serum, and determining the feasibility of measuring blood presepsin levels, a CD14-pathway specific biomarker for rapid assessment.
Interventions
BIOLOGICALAtibuclimab
monoclonal antibody against human CD14
OTHERPlacebo
Sterile normal saline for injection
Sponsors
Implicit Bioscience
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Identical-appearing placebo prepared by research pharmacist
Intervention model description
Patients hospitalized with ARDS will be randomized to treatment with anti-CD14 monoclonal antibody, IC14, or placebo and evaluated for impact of treatment on severity of lung injury as measured by day 4 oxygenation index. Secondary objectives include determination of systemic and alveolar inflammatory responses; indices of oxygenation and illness severity; safety; and IC14 levels in bronchoalveolar lavage fluid and serum. Exploratory objectives include determining the effect of treatment on duration of mechanical ventilation, mortality, and feasibility of measuring presepsin, a CD14 pathway-specific biomarker at baseline using rapid testing
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients may be included in the study only if they meet all the following criteria: 1. Adult patients (18+) on mechanical ventilations with acute respiratory distress syndrome (ARDS) by Berlin Criteria (≤48 hours) 1. P:F ratio \< 300 2. Positive end-expiratory pressure (PEEP) ≥5 cm H2O 3. Bilateral opacities on chest x-ray or chest computerized tomography (CT)-- not fully explained by effusions, lobar/lung collapse, or nodules 4. Respiratory failure not fully explained by cardiac failure or fluid overload 5. Within 1 week of known clinical insult or new or worsening respiratory symptoms i. Common Risk Factors for ARDS: Pneumonia, aspiration, inhalation injury, pulmonary contusion, pulmonary vasculitis, drowning, non-pulmonary sepsis, major trauma, pancreatitis, severe burns, non-cardiogenic shock, drug overdose, multiple transfusions 2. Patient or Legal authorized representative able to understand and give written informed consent
Exclusion criteria
An individual fulfilling any of the following criteria should be excluded from enrollment in the study: 1. Significant pre-existing organ dysfunction prior to hospitalization 1. Lung: Currently receiving home oxygen therapy as documented in medical record 2. Heart: Pre-existing congestive heart failure defined as an ejection fraction \<20% as documented in the medical record 3. Renal: End-stage renal disease requiring renal replacement therapy or estimated glomerular filtration rate (eGFR) \<30 mL/min. 4. Liver: Severe chronic liver disease defined as Child-Pugh Class C or hepatic transaminases \>5 times upper limit of normal 5. Hematologic: Baseline platelet count \<50,000/mm3 2. Presence of co-existing infection, including, but not limited to: 1. HIV infection not virally suppressed and with pre-hospitalization CD4 counts ≤ 500 cell/mm3 2. Active tuberculosis or a history of inadequately treated tuberculosis 3. Active hepatitis B or hepatitis C viral infection 3. Current treatment, or treatment within 30 days or five half-lives (whichever is longer) with etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab (Cimzia®), golimumab (Simponi®), anakinra (Kineret®), rilonacept (Arcalyst®), tocilizumab (Actemra®), sarilumab (Kevzara®), siltuximab (Sylvant®), or other potent immunosuppressant or immunomodulatory drugs or treatments 4. Receiving comfort measures only 5. Requiring \>2 vasopressors 6. Pregnant 7. Prisoners 8. History of hypersensitivity or idiosyncratic reaction to IC14 9. Women who are currently breastfeeding 10. Bronchoscopy safety exclusions 1. P:F \<100 on 100% FiO2 2. Mean pulmonary artery pressure \> 55 mmHg 3. Marked cardiovascular instability (Mean arterial pressure \<55 mmHg with vasopressor support) 4. Intracranial pressure ≥20 mmHg 5. Acute ischemic heart disease (unstable angina or ST-elevation myocardial infarction or Type 1 non-ST-elevation myocardial infarction) 6. Supported on extracorporeal membrane oxygenation 7. Endotracheal tube \<6.5 mm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Day 4 Oxygenation Index | Day 1 through Day 4 | (mean airway pressure x fraction of inspired oxygen \[FiO2\] x100)/ partial pressure of oxygen \[PaO2\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biomarkers of injury and inflammation measured in bronchoalveolar lavage fluid | Day 4 | Interleukin(IL)-6 |
| Biomarkers of injury and inflammation measured in plasma | Day 4 | Interleukin(IL)-6 |
| Oxygenation index | Days 7 and 14 | (mean airway pressure x FiO2 x100)/PaO2 |
| Oxygen saturation index | Days 4, 7, and 14 | (mean airway pressure x FiO2 x100)/peripheral oxygen saturation \[SpO2\] |
| P:F ratio | Days 4, 7, and 14 | Ratio of partial pressure of arterial oxygen (P) to fraction of inspired oxygen (F) |
| S:F ratio | Days 4, 7, and 14 | Ratio of the arterial oxygen saturation (S) to fraction of inspired oxygen (F) |
| Sequential Organ Failure Assessment (SOFA) Score (range 0 [best] to 24 [worst]) | Days 4, 7, and 14 | Disease severity scale |
| Time to blood presepsin level | Days 0-4 | Time from study consent to measurement completion of blood presepsin level via the PATHFASTTM instrument |
| Cumulative incidence of run failures | Days 0-1 | Defined as not completing presepsin measurement between consent and infusion of study drug |
| Cumulative incidence of protocol-specified exempt serious events | Days 1-28 | protocol-specified exempt serious events |
| Cumulative incidence of grade 3 and 4 clinical and laboratory adverse events | Days 1-28 | Common Toxicity Criteria for Adverse Events version 5.0 |
| Cumulative incidence of serious adverse events | Days 1-28 | Serious adverse events standard definition |
| Cumulative incidence of adverse events of special interest | Days 1-28 | Adverse events of special interest for test article and bronchoalveolar lavage |
Countries
United States
Contacts
CONTACTLinzee Mabrey, MD, MSc
PRINCIPAL_INVESTIGATORLinzee Mabrey, MD, MsC
Unversity of Washington
Outcome results
None listed