Safety and Efficacy of AON-D21 in Severe Community-Acquired Pneumonia.

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Exploratory, Multi-Centre, Interventional, Prospective, Randomised, Double-Blind, Placebo-Controlled Clinical Trial to Assess the Safety and Efficacy of AON-D21 in Patients With Severe Community-Acquired Pneumonia.

Conditions
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Community-acquired Pneumonia

Intervention / Treatment
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* Drug: AON-D21
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 ≤ 300 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center, interventional, randomized, double-blind, placebo-controlled study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AON-D21 plus Standard of Care<br>Sterile liquid formulation of AON-D21 in 4% mannitol + 0.05% EDTA in glass vials. It will be administered intravenously, for up to 10 days plus Standard of Care therapy for severe community-acquired pneumonia as per local guidelines. | Drug: AON-D21<br>* AON-D21 is a Pegylated L-configured aptamer that binds and thereby neutralizes the complement component C5a from activating both C5a receptors.<br>|
| Placebo Comparator: Placebo plus Standard of Care<br>Sterile liquid formulation of 5% glucose solution in matched glass vials with a 1.5 mL fill volume. It will be administered intravenously, for up to 10 days plus Standard of Care therapy for severe community-acquired pneumonia as per local guidelines. | Drug: Placebo<br>* Sterile liquid formulation of 5% glucose solution in matched glass vials with a 1.5 mL fill volume.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events. | 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. | 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy-no longer requiring respiratory support. | 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. | 28 days. | 
| Efficacy-no longer requiring any organ support. | Comparing AON-D21 vs placebo on time no longer requiring any organ support within 28 days. | 28 days. | 
| Efficacy-time to improvement. | Comparing AON-D21 vs placebo on time to improvement (defined as a de-escalation in respiratory support) within 28 days. | 28 days. | 
| Efficacy-mean change in SaO2/FiO2 ratio. | Comparing AON-D21 vs placebo on mean change in SaO2/FiO2 ratio from Day 1 (Baseline) to Day 7. | 7 days. | 
| Efficacy-organ support-free days. | Comparing AON-D21 vs placebo on organ support-free days until Day 28. | 28 days. | 
| Efficacy-invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO)-free days. | Comparing AON-D21 vs placebo on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO)-free days until Day 28. | 28 days. | 
| Efficacy-respiratory support-free days. | Comparing AON-D21 vs placebo on respiratory support-free days until Day 28. | 28 days. | 
| Efficacy-all-cause mortality. | Comparing AON-D21 vs placebo on all-cause mortality up to Day 28. | 28 days. | 
| Efficacy-all-cause mortality. | Comparing AON-D21 vs placebo on all-cause mortality up to Day 60. | 60 days. | 
| AUC of AON-D21. | Area under the concentration-time curve (AUC) over the dosing interval at steady state (AUC0-tau). | 10 days. | 
| Cmax of AON-D21. | Maximum concentration at steady state (Cmax) | 10 days. | 
| Cav of AON-D21. | Average drug concentration at steady state (Cav). | 10 days. | 
| Ctrough of AON-D21. | Trough concentrations (Ctrough). | 10 days. | 
| Tmax of AON-D21. | Time of maximum concentration at steady state (Tmax). | 10 days. | 
| Half-life of AON-D21. | Terminal half-life at steady state (t1/2). | 12 days. | 
| Accumulation of AON-D21. | Accumulation ratio for Cmax. | 10 days. | 
| Clearance of AON-D21. | Clearance (CL). | 12 days. | 
| Volume of distribution of AON-D21. | Volume of distribution (Vz). | 12 days. | 
| C5a inhibition with AON-D21. | To determine the C5a inhibition capacity of AON-D21 by measuring active C5a in blood using a cell-based assay. | 12 days. | 
| Procalcitonin's measurement. | Evolution of procalcitonin over time. | 12 days. | 
| Ferritin's measurement. | Evolution of ferritin over time. | 12 days. | 
| IL-6's measurement. | Evolution of IL-6 over time. | 12 days. | 
| C5a's measurement | Evolution of C5a over time. | 12 days. | 
| sC5b-9's measurement. | Evolution of sC5b-9 over time. | 12 days. | 
| Neutrophil elastase's measurement. | Evolution of neutrophil elastase over time. | 12 days. | 
| D-dimer's measurement. | Evolution of D-dimer over time. | 12 days. | 
| Pro-Adrenomedullin's measurement. | Evolution of Pro-Adrenomedullin over time. | 12 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pneumonia, Community-acquired, Severe, Bacterial, Viral