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

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Community-acquired Pneumonia
• Intervention / Treatment: Drug: AON-D21; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Antonio Perez, MD; Phone Number: +49-30-959 982-140; Email: perez@aptarion.com
• Study Contact Backup: Name: Axel Vater, PhD; Phone Number: +49-30-959 982-140; Email: vater@aptarion.com

Study Locations

• Belgium
  • Brussels, Belgium
    • Recruiting
    • Cliniques Universitaires Saint-Luc
    • Contact: Xavier Wittebole, Prof.
  • Ottignies, Belgium
    • Recruiting
    • Clinique Saint Pierre
    • Contact: Nicolas De Schryver, Dr.
• France
  • Argenteuil, France
    • Recruiting
    • Centre Hospitalier Argenteuil
    • Contact: Gaetan Plantefeve, Dr.
  • La Roche-sur-Yon, France
    • Recruiting
    • Centre Hospitalier Départemental Vendée
    • Contact: Jean-Claude Lacherade, Dr.
  • Limoges, France
    • Recruiting
    • CHU Dupuytren
    • Contact: Bruno Francois, Dr.
  • Melun, France
    • Recruiting
    • Centre Hospitalier de Melun
    • Contact: Mehran Monchi, Dr.
  • Nantes, France
    • Recruiting
    • Hotel Dieu - CHU Nantes
    • Contact: Gauthier Blonz, Dr.
  • Strasbourg, France
    • Recruiting
    • Nouvel Hôpital Civil
    • Contact: Ferhat Meziani, Prof.
  • Trévenans, France
    • Recruiting
    • Hopital Nord Franche Comte
    • Contact: Julio Badie, Dr.
• Germany
  • Berlin, Germany
    • Recruiting
    • Charité - Universitätsmedizin Berlin
    • Contact: Martin Witzenrath, Prof.
• United Kingdom
  • Cardiff, United Kingdom
    • Recruiting
    • University Hospital of Wales
    • Contact: Matt Wise, Prof.
  • Liverpool, United Kingdom
    • Recruiting
    • Liverpool University Hospitals NHS Foundation Trust
    • Contact: Ingeborg Welters, Prof.
  • London, United Kingdom
    • Recruiting
    • University College London
    • Contact: David Brealey, Dr.
  • Reading, United Kingdom
    • Recruiting
    • Royal Berkshire Foundation Trust
    • Contact: Matthew Frise, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AON-D21 plus Standard of Care; 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; AON-D21 is a Pegylated L-configured aptamer that binds and thereby neutralizes the complement component C5a from activating both C5a receptors.
Placebo Comparator: Placebo plus Standard of Care; 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; Sterile liquid formulation of 5% glucose solution in matched glass vials with a 1.5 mL fill volume.

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Aptarion Biotech AG
• Investigators: Principal Investigator: Martin Witzenrath, MD, Critical Care Medicine. Charité Universitätsmedizin Berlin

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2024
• Primary Completion (Estimated): May 30, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: July 17, 2023
• First Submitted That Met QC Criteria: July 25, 2023
• First Posted (Actual): July 27, 2023

Study Record Updates

• Last Update Posted (Actual): April 29, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Pneumonia; Severe; Viral; Bacterial; Community-acquired
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia
• Other Study ID Numbers: S-D21-C300

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No