Evaluation of Psilocybin and Apomorphine Hydrochloride Hemihydrate in Enhancing Consciousness in Comatose Patients with Acute Brain Injury

The primary objective of the BREA2KTHROUGH trial is to evaluate whether **psilocybin** and **apomorphine** can enhance clinical levels of consciousness in patients with coma and other disorders of consciousness resulting from acute traumatic and non-traumatic brain injury. This is assessed using the FOUR score and the SECONDs, which are established clinical measures of consciousness. Improving consciousness levels in such patients is clinically significant as it may lead to better recovery outcomes and quality of life.

The secondary objective is to determine if psilocybin and apomorphine can improve proxy biomarkers of consciousness, as measured by NIRS-EEG and pupillometry. These biomarkers provide additional insights into the physiological changes associated with consciousness, potentially offering a more comprehensive understanding of the treatment effects.

The clinical trial involves participants diagnosed with **coma and other disorders of consciousness** due to acute traumatic and non-traumatic brain injury. The study population includes both male and female subjects aged 18 years and older. Participants are clinically unresponsive patients admitted to the ICU with either a traumatic or non-traumatic brain injury or a systemic medical or surgical condition causing non-medically induced coma. The unconsciousness is expected by attending physicians to last for three or more days. The trial population is considered vulnerable due to their medical condition. The sponsor has not provided information regarding the total number of participants. The selection criteria focus on the clinical status of the patients, ensuring that only those meeting the specific medical conditions are included in the study.

The clinical trial is designed to evaluate the efficacy of **psilocybin** and **apomorphine** in improving consciousness levels in patients with **coma** and other disorders of consciousness due to acute traumatic and non-traumatic brain injury. This is a phase 2b, randomized, double-blind, controlled trial. The trial will commence on January 1, 2024, and is expected to conclude by December 31, 2028. Participants will be randomly assigned to receive either a single oral dose of psilocybin, psilocybin with apomorphine, or a placebo. The primary objective is to assess the improvement in consciousness levels within 3-6 hours post-administration, measured by the FOUR score and SECONDs.

The study will include several key visits: an initial screening visit, follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be confirmed based on criteria such as age (≥18 years), clinical unresponsiveness, and expected unconsciousness duration of ≥3 days. Follow-up visits will occur at days 1 and 7 to monitor pupillary function and neurovascular coupling, with a final assessment at day 90 to evaluate clinical outcomes using the GOS-E scale. The total duration of participant involvement is expected to be approximately 90 days.

Participants may be withdrawn from the study if they experience serious adverse reactions or events, or if they no longer meet the inclusion criteria. The trial will ensure rigorous monitoring to maintain participant safety and data integrity. The study aims to provide valuable insights into the potential therapeutic benefits of psilocybin and apomorphine in enhancing recovery in comatose patients.

The clinical trial involves the administration of **PEX010 Psilocybin Capsules**, which contain 25 mg of **psilocybin**. The active substance is a dry extract from **Psilocybe cubensis** with an extraction ratio of 15-25:1, using methanol as the solvent. The pharmaceutical form is capsules, and the route of administration is oral. The psilocybin capsules are not a pediatric formulation and are classified under the role of a test product in the trial. The product is manufactured by Rigshospitalet and is currently authorized with a status of 1.

Another experimental treatment in the trial is **Apomorfin PharmSwed 5 mg/ml**, a solution for infusion containing **apomorphine hydrochloride hemihydrate**. This product is administered subcutaneously. The solution is not a pediatric formulation and serves as a test product in the study. The manufacturer of this product is Evolan Pharma AB, and it holds an authorization status of 2. The product is identified with the ATC code N04BC07, which classifies it under apomorphine.

The trial also includes the use of **Natriumklorid Fresenius Kabi 9 mg/ml**, a solution for infusion containing **sodium chloride**. This product is administered intravenously and is used as a placebo in the study. It is not a pediatric formulation and is manufactured by Fresenius Kabi Norge AS. The product has an authorization status of 2 and is classified under the ATC code B05BB01, which pertains to electrolytes.

Efficacy in the clinical trial titled "Boosting recovery through excitation of arousal and awareness in comatose patients: The BREA2KTHROUGH trial" will be assessed using specific co-primary and secondary endpoints. The co-primary endpoints focus on the number of patients exhibiting improved consciousness within 3-6 hours following a single dose of oral **psilocybin** with or without **apomorphine** compared to placebo. This improvement is measured using a composite score of either the FOUR score ≥2 and/or SECONDs ≥1. The secondary endpoints include assessments of pupillary function through pupillometry, neurovascular coupling using NIRS-EEG, clinical outcomes at day 90 measured by the Glasgow Outcome Scale-Extended (GOS-E), days alive outside the ICU, and the occurrence of serious adverse reactions and events.

The efficacy parameters will be collected and analyzed at specified timepoints, including days 1 and 7 for neurovascular coupling and day 90 for clinical outcomes. The tools and instruments involved in these assessments include validated scales such as the FOUR score and SECONDs for consciousness levels, pupillometry for pupillary function, and NIRS-EEG for neurovascular coupling. The trial is designed as a phase 2b study, aiming to rigorously test the efficacy of the investigational drugs in improving clinical levels of consciousness in comatose patients.