Effect of Methylphenidate on the Time to Awakening in Patients with Coma Due to Acute Brain Injury: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective is to evaluate whether daily administration of methylphenidate facilitates earlier awakening in patients in coma resulting from acute brain injury. This study aims to determine the efficacy of this pharmacological intervention in promoting recovery of consciousness. 3, 5

The secondary objectives include:

• Investigation of whether covert consciousness, identified via pupillometry, near-infrared spectroscopy, or functional magnetic resonance imaging, serves as a predictor for drug response.
• Examination of changes in electroencephalography connectivity associated with the administration of the study drug and the emergence of consciousness.
• Assessment of the safety and feasibility of repeated methylphenidate administration within the intensive care unit setting.

The sponsor did not provide information regarding the total number of participants. The study population consists of adults, both male and female, who are admitted to the intensive care unit due to acute brain injury. Participants are characterized by unresponsiveness, as indicated by a FOUR score of 11 or less or a SECONDs score of 5 or less, without consistent command-following. Inclusion requires the patients to be hemodynamically stable. This population is classified as vulnerable.

This international, prospective, randomized, double-blind, placebo-controlled trial is a phase 4 study designed to evaluate the efficacy of methylphenidate in patients experiencing coma due to acute brain injury. The methodology involves comparing daily oral administration of 20 mg of methylphenidate hydrochloride against a placebo to determine if it facilitates earlier awakening. The primary endpoint is the time to awakening, defined by specific improvements in consciousness scores such as the FOUR score or SECONDs. Secondary endpoints include the proportion of patients achieving clinical arousal, ICU mortality, length of stay, and 3-month outcomes measured by the modified Rankin Scale, Cerebral Performance Category, and Glasgow Outcome Scale-Extended. The study period is estimated to occur between June 2026 and December 2028.

The experimental treatment consists of methylphenidate hydrochloride in a pharmaceutical form designated as PHF00131MIG. This medication is administered via the oral route at a dosage of 20 mg.

The control group receives a placebo manufactured by the hospital pharmacy of the Capital Region in Denmark. This product contains no active substance and is identical to the investigational medicinal product following preparation.

The primary efficacy endpoint is the time to awakening, which is defined as the first sustained improvement in consciousness. This is quantified using the Full Outline of UnResponsiveness (FOUR) score, specifically requiring an e-score of 4 or a total score of at least 12, or a Semiquantitative EEG in the Comatose (SECONDs) score of at least 6. This status must be confirmed via two consecutive examinations performed 1 hour apart. Coma resulting from acute brain injury is the target condition.

Secondary endpoints include the proportion of patients achieving clinical arousal, ICU mortality, and length of stay. Long-term outcomes at 3 months are evaluated using the modified Rankin Scale (mRS), the Cerebral Performance Category (CPC), and the Glasgow Outcome Scale-Extended (GOS-E).