Evaluation of Amantadine Hemisulfate for Neuroenhancement in Patients with Unresponsive Wakefulness Syndrome in Intensive and Intermediate Care Settings

The primary objective of this study is to evaluate the efficacy of **Amantadine** in enhancing the level of vigilance and responsiveness in patients diagnosed with unresponsive wakefulness syndrome. This is assessed using clinical scores, with a primary focus on the **Glasgow Coma Scale (GCS)**. The primary outcome measure is the level of vigilance as determined by the GCS after 120 hours (± 4 hours) of treatment. This is clinically relevant as it aims to improve patient outcomes by potentially increasing consciousness levels in a critical care setting.

The secondary objective is to assess the improvement of vigilance using alternative scales such as the Richmond Agitation-Sedation Scale (RASS), Full Outline of UnResponsiveness (FOUR) Score Coma Scale, Intensive Care Delirium Screening Checklist (ICDSC), National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Glasgow Outcome Scale – Extended (GOS-E), Coma Recovery Scale revised (CRSR), and Montreal Cognitive Assessment (MoCA) after 90 days. Additionally, the study will evaluate EEG results, survival rates, and clinical improvement as reported in therapists' questionnaires. These secondary measures provide a comprehensive assessment of the patient's neurological and cognitive recovery, which is crucial for understanding the broader impact of the treatment.

The clinical trial involves participants diagnosed with **unresponsive wakefulness syndrome**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults. The trial population was selected based on specific criteria, including reduced consciousness lasting at least 72 hours, defined by a Glasgow Coma Scale (GCS) score of less than 8, and not otherwise explained. Participants are required to have inconspicuous EEG and ECG results. The trial includes a vulnerable population, as it involves individuals with reduced consciousness. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **amantadine hemisulfate** in patients with unresponsive wakefulness syndrome not otherwise explained. This study is a prospective, randomized, double-blind, controlled trial conducted over a period of approximately two years, with an estimated end date of March 20, 2025. The trial involves the administration of Amantadin-ratiopharm® 200 mg solution for infusion, with a maximum daily dose of 200 mg and a total dose not exceeding 1000 mg over a treatment period of five days. The primary objective is to assess the improvement in the level of vigilance and responsiveness, primarily measured by the Glasgow Coma Scale (GCS) after five days of treatment. Secondary endpoints include improvements in alternative scales such as the Richmond Agitation-Sedation Scale (RASS) and the Full Outline of UnResponsiveness (FOUR) Score Coma Scale, among others, evaluated after 90 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as reduced consciousness lasting at least 72 hours and inconspicuous EEG and ECG results. Informed consent must be obtained from the patient or their legal representative if the patient is unable to provide consent due to reduced consciousness. The study includes follow-up visits to monitor the patient's response to treatment and assess any adverse events. The end-of-study visit will occur after the completion of the treatment period and the final assessment of the primary and secondary endpoints. The expected length of participant involvement is approximately 90 days, with conditions for early termination including withdrawal of consent or the occurrence of significant adverse events. The trial is conducted in compliance with ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Amantadine hemisulfate**, marketed under the name Amantadin-ratiopharm® 200 mg Infusionslösung. This experimental medication is provided in the form of a **solution for infusion**. The active substance, **amantadine hemisulfate**, is of chemical origin. The medication is administered via infusion, with a maximum daily dose of 200 mg and a total maximum dose of 1000 mg over a treatment period of 5 days. The primary objective of the trial is to evaluate the efficacy of Amantadine in enhancing vigilance and responsiveness in patients, as measured by the Glasgow Coma Scale (GCS) after 120 hours of treatment.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The trial is designed to focus solely on the effects of the experimental medication, Amantadin-ratiopharm® 200 mg Infusionslösung. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy in the clinical trial titled "AmaNtadine for NeuroenhancEment in acutE patients Study - A prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES)" will be assessed primarily through the **Glasgow Coma Scale (GCS)**. The main objective is to demonstrate that Amantadine is efficacious in increasing the level of vigilance/responsiveness. The primary endpoint is defined as an improvement of at least 3 points on the GCS after 5 days of treatment, assessed at study visit 6.

Secondary endpoints include the improvement of vigilance measured via alternative scales such as the Richmond Agitation-Sedation Scale (RASS), Full Outline of UnResponsiveness (FOUR) Score Coma Scale, Intensive Care Delirium Screening Checklist (ICDSC), National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Glasgow Outcome Scale – Extended (GOS-E), Coma Recovery Scale revised (CRSR), and Montreal Cognitive Assessment (MoCA) after 90 days. Additional assessments will include EEG results, survival, and clinical improvement.