Efficacy and Safety of Anakinra in Patients with Post-Acute COVID-19 Syndrome: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** and **safety** of **anakinra** in patients with **Post-Acute COVID Syndrome (PACS)**. This is a proof-of-concept, phase II/III randomized clinical trial designed to assess improvements in the clinical and immunological state of patients over a period of 4 to 8 weeks. The evaluation will be based on a composite endpoint, referred to as the "Score of PACS progression reversal." This objective is clinically relevant as it aims to address persistent respiratory symptoms and immune system activation in patients post-acute COVID, potentially offering a therapeutic option for managing PACS.

The clinical trial focuses on evaluating the efficacy and safety of anakinra in patients with **Post-Acute COVID Syndrome (PACS)**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a history of confirmed COVID-19 infection within the last 90 days or more, with symptoms compatible with PACS lasting for more than two months. The trial includes individuals with impaired lung function tests and specific radiological findings. The trial population was selected based on these criteria, ensuring that participants have a parallel presence of conditions affecting lung function and radiological patterns. The sponsor has not provided information regarding the total number of participants. Participants are expected to use adequate contraception methods if applicable. The study includes a vulnerable population, and written informed consent is mandatory for participation.

The clinical trial is a **randomized**, double-blind, controlled study designed to evaluate the efficacy and safety of **anakinra** in patients with **Post-Acute COVID Syndrome (PACS)**. The trial is structured as a phase II/III study, with the primary objective of assessing improvements in clinical and immunological states over a period of 4 to 8 weeks. The trial employs a composite endpoint, the "Score of PACS progression reversal," to measure outcomes. Participants will be randomly assigned to receive either anakinra or a placebo, with the treatment administered via **intravenous (IV) or subcutaneous (SC)** routes.

The trial duration is estimated to conclude by June 19, 2025, with recruitment having commenced on June 19, 2023. Participants will be involved in the study for a maximum of 8 weeks, during which they will attend several study visits. The sequence of visits includes an initial screening visit to confirm eligibility based on criteria such as age, gender, history of confirmed COVID-19 infection, and symptoms compatible with PACS. Follow-up visits will occur at regular intervals to monitor the treatment's effects and any adverse events. The end-of-study visit will assess the primary and secondary endpoints, including changes in cytokine production, pulmonary artery pressure, and the 6-minute walk test results.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with study procedures, or withdraw consent. The study's design ensures that all data collected will contribute to understanding the potential benefits and risks of anakinra in treating PACS, with safety being a critical component of the evaluation. The trial's methodology and procedures are meticulously planned to maintain scientific rigor and ensure the reliability of the results.

The clinical trial involves the administration of **Anakinra**, marketed under the name Kineret, which is a **solution for injection** in a pre-filled syringe. The active substance, Anakinra, is a protein-based therapeutic agent. The pharmaceutical form is a solution for injection, and it is administered either intravenously (IV) or subcutaneously (SC). The dosage is 100 mg per 0.67 ml, with a maximum daily dose of 100 mg. The total maximum dose over the treatment period is 5600 mg. The treatment duration is set for a maximum of 8 weeks. The product is manufactured by Swedish Orphan Biovitrum AB (Publ) and is authorized for use in the European Union under the marketing authorization number EU/1/02/203/006.

The study also includes a **placebo** control, which is a solution for injection with no active substance, provided in a 0.67 ml syringe for clinical packaging. The placebo is designed to match the appearance and administration route of the active treatment to maintain the double-blind nature of the trial. The placebo is administered with the same frequency and route as the active treatment, either intravenously or subcutaneously, to ensure consistency in the study protocol.

The efficacy of anakinra in the treatment of patients with persistent respiratory symptoms post-acute COVID-19 syndrome (PACS) will be assessed in a double-blind, randomized clinical trial. The primary endpoint for evaluating efficacy is the "Score of PACS progression reversal," which is achieved when both Conditions A and B, as detailed in the study protocol, are met. Secondary endpoints include the frequency of the Score of PACS progression reversal between patients receiving 8 weeks of anakinra treatment compared to those receiving 4 weeks of anakinra followed by 4 weeks of placebo. Additional secondary endpoints involve changes in cytokine production capacity of stimulated peripheral blood mononuclear cells (PBMCs) at week 4, changes in each component of the primary outcome score at week 4, and at least a 10% decrease in pulmonary artery pressure at week 4 between the two treatment arms.

Further secondary endpoints include at least a 10% increase in left ventricular ejection fraction (if abnormal at baseline) at week 4, the number of meters walked during the 6-minute walk test at week 4, and the number of criteria of Condition A met. The safety of anakinra will also be evaluated. Efficacy parameters will be measured and collected at specified timepoints, including week 4 and the end of treatment. The trial aims to improve the clinical and immunological state of patients over a period of 4 to 8 weeks, with the primary focus on the composite endpoint of PACS progression reversal.