Dose Escalation Study of Apomorphine Hydrochloride Hemihydrate and Psilocybin in Comatose Patients with Acute Brain Injury

The primary objective of this study is to conduct a **dose escalation** investigation to determine the safety of administering **apomorphine** and **psilocybin** in unresponsive intensive care unit (ICU) patients with acute brain injury. This is clinically relevant as it aims to explore potential therapeutic interventions for patients in a **coma** or other disorders of consciousness resulting from acute traumatic and non-traumatic brain injuries, which currently have limited treatment options.

Secondary objectives include the investigation of somatic and neuropsychiatric adverse events associated with the treatment. This is crucial for understanding the broader safety profile and potential side effects of the therapeutic agents being studied.

The clinical trial involves a study population comprising both **male** and **female** participants aged 18 years and older. The participants are clinically unresponsive patients admitted to the ICU with either traumatic or non-traumatic brain injury, or a systemic medical or surgical condition causing a non-medically induced coma. The unconsciousness in these patients is expected by attending physicians to last for three or more days. The trial focuses on individuals with **coma and other disorders of consciousness** due to acute traumatic and non-traumatic brain injury. The sponsor has not provided information regarding the total number of participants. The trial population includes a vulnerable group, and the selection criteria ensure that only those meeting specific medical conditions are included. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the safety and efficacy of **apomorphine hydrochloride hemihydrate** and **psilocybin** in patients with coma and other disorders of consciousness due to acute traumatic and non-traumatic brain injury. This study is structured as a randomized, double-blind, controlled trial with a dose-finding phase followed by a larger randomized phase. The trial is expected to commence on January 1, 2024, and conclude by December 31, 2028. The trial will be conducted in two phases: an initial dose-finding phase involving 12 patients, followed by a larger randomized trial involving 384 patients, with a 1:1:1 allocation ratio.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (≥18 years) and the expectation of unconsciousness lasting three or more days. The primary endpoint is the time to awakening within 30 days, with secondary endpoints including pupillary function, neurovascular coupling, clinical outcomes at day 90, days alive outside the ICU, and the incidence of serious adverse reactions and events. The study will involve regular follow-up visits to monitor these endpoints, with assessments at days 1, 7, and 90, and an end-of-study visit to evaluate overall outcomes.

The expected duration of participant involvement is up to 90 days, with conditions for early termination including withdrawal of consent, significant adverse events, or clinical judgment by the attending physician. The trial will utilize **sodium chloride** as a placebo control, with the investigational products administered via intravenous, subcutaneous, or oral routes as appropriate. The study aims to establish the safety profile of the investigational drugs and their potential to enhance recovery in comatose patients.

The clinical trial involves the administration of three distinct treatments. The first treatment is **Natriumklorid Fresenius Kabi 9 mg/ml**, a **solution for infusion** containing **sodium chloride** as the active substance. This product is manufactured by Fresenius Kabi Norge AS and is administered intravenously. The maximum daily dose is 10 mg, with a total dose not exceeding 2 mg over a treatment period of one day. This solution serves as a standard-of-care therapy and is not the primary focus of the trial.

The second treatment is **Apomorfin PharmSwed 5 mg/ml**, a **solution for infusion** containing **apomorphine hydrochloride hemihydrate**. This product is produced by Evolan Pharma AB and is administered subcutaneously. The maximum daily and total dose is 2 mg, with a treatment period limited to one day. Apomorphine is being tested for its potential therapeutic effects in the study, specifically in unresponsive ICU patients with acute brain injury.

The third treatment involves **PEX010 Psilocybin Capsules**, each containing 25 mg of **dry extract from Psilocybe cubensis**. This product is provided by Rigshospitalet and is administered orally. The maximum daily and total dose is 25 mg, with a treatment period of one day. Psilocybin is being evaluated for its safety and potential efficacy in the same patient population as apomorphine. Compliance with dosing schedules is monitored throughout the trial to ensure adherence to the protocol.

Efficacy in the clinical trial titled "Boosting recovery through excitation of arousal and awareness in comatose patients: Dose finding study (BREA2KTHROUGH DOSEFINDER)" will be assessed using both primary and secondary endpoints. The primary endpoint is the **time to awakening** within 30 days, which will be evaluated to determine overall safety. Secondary endpoints include assessments of **pupillary function** using pupillometry, which will measure spontaneous pupillary function and responses during a mental arithmetic paradigm. Additionally, **neurovascular coupling** will be evaluated using NIRS-EEG to assess spontaneous cortical activity and activation during a tongue motor imagery paradigm at days 1 and 7. Clinical outcomes will be measured at day 90 using the Glasgow Outcome Scale-Extended (GOS-E). Other secondary endpoints include the number of days patients are alive outside the ICU, as well as the occurrence of serious adverse reactions (SARs) and serious adverse events, both somatic and neuropsychiatric.