Evaluation of AON-D21 Efficacy and Safety in Severe Community-Acquired Pneumonia: A Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2023-505985-28-01
Protocol: S-D21-C300
Sponsor: Aptarion Biotech AG

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Diseases & Conditions

Pneumonia

Objectives

The primary objective of this clinical trial is to assess the **safety** and tolerability of AON-D21 in patients with severe **Community-Acquired Pneumonia** (CAP) admitted to an Intensive Care Unit or a similar unit. Evaluating the safety profile of AON-D21 is crucial for determining its potential as a therapeutic option for this patient population, ensuring that the treatment does not pose undue risk and is well-tolerated by patients with severe CAP.

Secondary objectives include:

Exploring the efficacy of AON-D21 in patients with severe CAP admitted to an Intensive Care Unit or similar unit, which is essential for understanding the therapeutic benefits of the treatment in improving patient outcomes.
Characterizing the pharmacokinetics of AON-D21, which involves studying how the drug is absorbed, distributed, metabolized, and excreted in the body, providing insights into the optimal dosing regimen.
Characterizing the pharmacodynamics of AON-D21, which focuses on the drug's biological effects and mechanisms of action, contributing to a comprehensive understanding of its therapeutic potential.

Participants

The clinical trial involves a total of **30 participants** diagnosed with **Severe Community-Acquired Pneumonia**. The study population includes both male and female subjects, aged between 18 and 85 years, who are admitted to an Intensive Care Unit or a similar unit. Participants are required to have a body mass index ranging from 17.5 kg/m² to 40 kg/m². The selection process for the trial population is based on specific inclusion criteria, including the need for respiratory support and elevated C-reactive protein levels. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraception guidelines if of childbearing potential. The trial also includes a vulnerable population, ensuring comprehensive monitoring and care. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the safety and efficacy of AON-D21 in patients with **severe community-acquired pneumonia**. The trial will involve the administration of AON-D21, a mixed RNA/DNA aptamer, as a **solution for infusion** via **intravenous use**. The study will be conducted over an estimated period from January 2024 to June 2026, with participant involvement expected to last up to 60 days. The trial will include a screening phase, treatment phase, and follow-up visits, with the primary endpoint being the frequency, severity, and relatedness of treatment-emergent adverse events until Day 28.

Participants will undergo an initial **screening visit** to confirm eligibility based on criteria such as age, body mass index, and the requirement for respiratory support. Following successful screening, participants will be **randomized** to receive either AON-D21 or a placebo (5% glucose solution for infusion). The treatment phase will last up to 10 days, with a maximum daily dose of 0.4 mg/kg and a total dose not exceeding 4.0 mg/kg. During this phase, participants will be closely monitored for adverse events and changes in respiratory support requirements.

Follow-up visits will occur at specified intervals to assess secondary endpoints, including the time to no longer requiring respiratory or organ support, improvement in respiratory function, and overall mortality rates up to Day 60. The end-of-study visit will conclude the participant's involvement, with data collection focusing on long-term outcomes and pharmacokinetic parameters in a subset of participants. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or the occurrence of serious adverse events deemed related to the study drug.

Treatment

The clinical trial involves the administration of **AON-D21**, an experimental medication formulated as a **solution for infusion**. AON-D21 is a mixed RNA/DNA aptamer developed by Aptarion Biotech AG. The medication is administered intravenously, with a maximum daily dose of 0.4 mg/kg and a total maximum dose of 4.0 mg/kg over a treatment period of up to 10 days. The dosing schedule is designed to ensure optimal safety and efficacy in patients with severe community-acquired pneumonia. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes a placebo control, which is a 5% glucose solution for infusion. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the experimental medication, via intravenous infusion, to provide a consistent comparison between the treatment and control groups. The use of a placebo is critical in assessing the true efficacy and safety profile of AON-D21 in the study population.

Efficacy

The efficacy of AON-D21 in patients with severe **Community-Acquired Pneumonia** will be assessed through a series of predefined endpoints. Primary efficacy will be evaluated by monitoring the frequency, severity, and relatedness of serious and non-serious treatment-emergent adverse events until Day 28. Secondary efficacy endpoints include the time to no longer requiring respiratory support, time to no longer requiring any organ support, and time to improvement in respiratory support within 28 days. Additional secondary endpoints involve the mean change in the S/F ratio from Day 1 to Day 7, organ support-free days, invasive mechanical ventilation or extracorporeal membrane oxygenation-free days, and respiratory support-free days until Day 28. All-cause mortality will be assessed up to Days 28 and 60.

Pharmacokinetic parameters such as the area under the concentration-time curve (AUC), maximum concentration (Cmax), average drug concentration (Cav), trough concentrations (Ctrough), time of maximum concentration (tmax), terminal half-life (t1/2), accumulation ratios, clearance (CL), and volume of distribution (Vz) of AON-D21 in plasma will be determined from a subset of at least 20 participants. Additionally, C5a inhibitory activity will be measured in a subset of at least 100 participants. These assessments will provide comprehensive data on the efficacy of AON-D21 in the target patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

At Screening, Randomisation and prior to administration of first dose; community-acquired pneumonia according to local guidelines. Community-acquired pneumonia may be confirmed or suspected to be of bacterial or viral origin.
At Screening, Randomisation and prior to administration of first dose; admitted to an Intensive Care Unit (or similar unit) defined as any hospital facility with intensive and specialised medical and nursing care, with capacity for monitoring, and physiological organ support to sustain life during a period of life-threatening organ system insufficiency.
At Screening, Randomisation and prior to administration of first dose: requiring respiratory support by High-Flow Oxygen ≥ 30 L/min with FiO2 ≥ 30% or Non-Invasive Mechanical Ventilation or Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation.
At Screening, C-reactive protein ≥ 50 mg/L. C-reactive protein measurement must be repeated and confirmed to be ≥ 50 mg/L if randomisation is not done within 24 h of Screening sample collection (local laboratory testing).
PaO2/FiO2 ratio ≤ 150 mmHg (≤ 20 kPa), with PaO2 from arterial blood (or arterialised capillary blood from a vasodilated ear lobe).
Treatment initiation no more than 48 h after initiation of respiratory support (High-Flow Oxygen ≥ 30 L/min with FiO2 ≥ 30%, Non-Invasive Mechanical Ventilation, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation).
Written informed consent obtained from patient or legally designated representative or authorisation from an independent physician*, as per local guidelines. * In emergency situations, when prior consent of the participant or their legally designated representative is not possible, enrolment of the participant may be authorised by an independent physician (NON-EU Countries) or a treating physician independent of the research team (EU Countries), as per local guidelines. The participant or the participant’s legally designated representative should be informed about the trial as soon as possible, and consent should be requested.
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.

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Exclusion Criteria

Refractory septic shock at Screening, Randomisation or prior to administration of the first dose of study drug. Participants can be enrolled if they are no longer refractory. The presence of refractory septic shock shall be determined by the investigator. As a guidance, septic shock may be judged as refractory if treatment with ≥ 0.5 mcg/kg/min norepinephrine or equivalent (cumulative) for at least 2 h to maintain or attempt to maintain systolic blood pressure (SBP) >90 mmHg (or mean arterial pressure (MAP) >70 mmHg) after adequate fluid resuscitation is required.
Receiving chronic immunosuppressive therapy in clinically relevant doses (> 15 mg/day prednisolone or equivalent as maintenance treatment for > 14 days).
Known immunodeficiency disease/condition (iatrogenic or congenital), including human immunodeficiency virus infection (type 1 or 2) with CD4+ counts < 200 cells/µL, asplenia, or recurrent severe infections.
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 blood test (local laboratory).
Current or recent participation in an investigational trial (within 30 days of screening, or 5 half-lives of the respective investigational compound, whichever is longer).
Systemic treatment with any complement inhibitor, e.g., eculizumab or avacopan.
Known complement deficiency.
Known or suspected hypersensitivity to AON-D21 or any components of the formulation used (e.g., Polyethylene Glycol, mannitol or Ethylenediaminetetraacetic Acid) or a history of clinically relevant allergy requiring continuous treatment, or of anaphylaxis.
Unlikely to remain at the investigational site beyond 96 hours.
Not expected to survive 72 h, at Screening, Randomisation or prior to administration of first dose.
Hospital-acquired or ventilator-associated pneumonia or known or suspected pneumonia due to aspiration or other physical injury or trauma or tuberculosis.
Known fibrotic lung disease, bronchiectasis with ≥ 3 exacerbations requiring antibiotic treatment during the last year or any other known severe chronic respiratory disease (e.g., chronic obstructive pulmonary disease or cystic fibrosis) requiring home oxygen/non-invasive ventilation or with known forced expiratory volume in the first second < 30% of predicted.
Factors other than a pathogen suspected or confirmed to be causative for the respiratory insufficiency, e.g., clinically suspected pulmonary thromboembolism, cardiac insufficiency, including decompensated heart failure (≥ Class 3, New York Heart Association classification).
Active malignant disease with chemotherapy or immunomodulating cancer therapy within 30 days of screening or intended within the next 30 days or active primary lung cancer or another malignancy metastatic to the lungs or end-stage cancer.
Hepatocellular injury defined by an alanine aminotransferase or aspartate aminotransferase value ≥ 3 times the upper limit of normal (local laboratory). Known acute or chronic liver disease with Child-Pugh C.
Any medical disease (acute, subacute, intermittent, or chronic) or condition that, in the opinion of the investigator(s), compromises the participant’s safety or compromises the interpretation of the results.
Vasopressors, intubation, renal replacement therapy or cardiopulmonary resuscitation procedures are precluded on the basis of a patient order, next-of-kin communication or per staff decision. Clarification: The exclusion only applies when the precluded therapies or procedures result in a limitation in Standard of Care treatment escalation.
Applicable in France only. Persons under court protection, persons not affiliated to a social security system, protected adults (Art. L. 1121-6, Art. L. 1121-8, Art. L. 1121-8-1).