Community-acquired Pneumonia
Conditions
Keywords
Pneumonia, Community-acquired, Severe, Bacterial, Viral
Brief summary
The goal of this clinical trial is to compare the safety and efficacy of AON-D21 versus placebo, both on top of standard of care, in patients with severe community acquired pneumonia admitted to ICU (or similar unit). The main questions to answer are: * The safety and tolerability of AON-D21 vs placebo. * The efficacy of AON-D21vs placebo. * The pharmacokinetics of AON-D21. * The pharmacodynamics of AON D21. * To identify biomarkers for patient stratification and analyses in future trials.
Detailed description
This clinical trial will enroll 100 participants, randomized 2:1 (AON-D21:placebo). Participants diagnosed with severe community-acquired pneumonia of bacterial or viral origin requiring admission to an intensive care unit or similar setting, will receive either AON-D21 or placebo intravenous infusions for up to 10 days. In addition, participants will receive standard of care as per local guidelines.
Interventions
DRUGAON-D21
AON-D21 is a Pegylated L-configured aptamer that binds and thereby neutralizes the complement component C5a from activating both C5a receptors.
DRUGPlacebo
Sterile liquid formulation of 5% glucose solution in matched glass vials with a 1.5 mL fill volume.
Sponsors
Aptarion Biotech AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo-controlled
Intervention model description
Multi-center, interventional, randomized, double-blind, placebo-controlled study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Community-acquired pneumonia, confirmed or suspected of bacterial or viral origin. * Admitted to an ICU (or similar unit). * Requiring respiratory support by HFO ≥ 30 L/min with FiO2 ≥ 30% or NIV or IMV or ECMO. * CRP ≥ 50 mg/L. * PaO2/FiO2 ratio ≤ 150 mmHg. * Treatment initiation no more than 48 h after initiation of respiratory support (HFO ≥ 30 L/min with FiO2 ≥ 30%, NIV, IMV or ECMO). * Written informed consent. * Age ≥ 18 years to ≤ 85 years. * Body mass index ≥ 17.5 kg/m² and ≤ 40 kg/m². * For female participants of childbearing potential, agreement to use dual methods of contraception until Day 60. * For male participants with female partners of childbearing potential, agreement to use barrier method of contraception until Day 60 and to refrain from donating sperm during the study and for 3 months after the last infusion.
Exclusion criteria
* Refractory septic shock. * Not expected to survive 72 hours. * Hospital-acquired or ventilator-associated pneumonia or known or suspected pneumonia due to aspiration or other physical injury or trauma or tuberculosis. * Known or suspected hypersensitivity to AON-D21 or any components of the formulation used (e.g., PEG, mannitol or EDTA) or a history of clinically relevant allergy requiring continuous treatment, or of anaphylaxis. * Known fibrotic lung disease, bronchiectasis or any other known severe chronic respiratory disease. * Active malignant disease. * Factors other than a pathogen suspected or confirmed to be causative for the respiratory insufficiency. * Hepatocellular injury defined by an ALT or AST value ≥ 3 times the ULN. Known acute or chronic liver disease with Child-Pugh C (See Appendix 13.6.2). * Any medical disease or condition that, in the opinion of the investigator(s), compromises the participant's safety or compromises the interpretation of the results. * Receiving chronic immunosuppressive therapy in relevant doses. * Known immunodeficiency disease/condition. * Nursing and pregnant women (defined as the state after conception until the termination of gestation, screened in all women of child-bearing potential with a chorionic gonadotrophin (hCG) blood test (local laboratory). * Current or recent participation in an investigational trial. * Systemic treatment with any complement inhibitor. * Known complement deficiency. * Unlikely to remain at the investigational site beyond 96 h.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events. | 28 days. | To evaluate the safety and tolerability of AON-D21 versus placebo, including the frequency, severity, and relatedness to study drug of serious and non-serious treatment-emergent adverse events (TEAEs) until Day 28. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy-no longer requiring respiratory support. | 28 days. | Comparing AON-D21 vs placebo on time to no longer requiring respiratory support (defined as high-flow oxygen (HFO) ≥ 30 L/min with FiO2 ≥ 30%), non-invasive mechanical ventilation (NIV), invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) within 28 days. |
| Efficacy-no longer requiring any organ support. | 28 days. | Comparing AON-D21 vs placebo on time no longer requiring any organ support within 28 days. |
| Efficacy-time to improvement. | 28 days. | Comparing AON-D21 vs placebo on time to improvement (defined as a de-escalation in respiratory support) within 28 days. |
| Efficacy-mean change in SaO2/FiO2 ratio. | 7 days. | Comparing AON-D21 vs placebo on mean change in SaO2/FiO2 ratio from Day 1 (Baseline) to Day 7. |
| Efficacy-organ support-free days. | 28 days. | Comparing AON-D21 vs placebo on organ support-free days until Day 28. |
| Efficacy-invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO)-free days. | 28 days. | Comparing AON-D21 vs placebo on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO)-free days until Day 28. |
| Efficacy-respiratory support-free days. | 28 days. | Comparing AON-D21 vs placebo on respiratory support-free days until Day 28. |
| Efficacy-all-cause mortality. | 28 days. | Comparing AON-D21 vs placebo on all-cause mortality up to Day 28. |
| AUC of AON-D21. | 10 days. | Area under the concentration-time curve (AUC) over the dosing interval at steady state (AUC0-tau). |
| Cmax of AON-D21. | 10 days. | Maximum concentration at steady state (Cmax) |
| Cav of AON-D21. | 10 days. | Average drug concentration at steady state (Cav). |
| Ctrough of AON-D21. | 10 days. | Trough concentrations (Ctrough). |
| Tmax of AON-D21. | 10 days. | Time of maximum concentration at steady state (Tmax). |
| Half-life of AON-D21. | 12 days. | Terminal half-life at steady state (t1/2). |
| Accumulation of AON-D21. | 10 days. | Accumulation ratio for Cmax. |
| Clearance of AON-D21. | 12 days. | Clearance (CL). |
| Volume of distribution of AON-D21. | 12 days. | Volume of distribution (Vz). |
| C5a inhibition with AON-D21. | 12 days. | To determine the C5a inhibition capacity of AON-D21 by measuring active C5a in blood using a cell-based assay. |
| Procalcitonin's measurement. | 12 days. | Evolution of procalcitonin over time. |
| Ferritin's measurement. | 12 days. | Evolution of ferritin over time. |
| IL-6's measurement. | 12 days. | Evolution of IL-6 over time. |
| C5a's measurement | 12 days. | Evolution of C5a over time. |
| sC5b-9's measurement. | 12 days. | Evolution of sC5b-9 over time. |
| Neutrophil elastase's measurement. | 12 days. | Evolution of neutrophil elastase over time. |
| D-dimer's measurement. | 12 days. | Evolution of D-dimer over time. |
| Pro-Adrenomedullin's measurement. | 12 days. | Evolution of Pro-Adrenomedullin over time. |
Countries
Belgium, France, Germany, Spain, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORMartin Witzenrath, MD
Critical Care Medicine. Charité Universitätsmedizin Berlin
Outcome results
None listed