Comparative Effectiveness of Atomoxetine and Amantadine in the Level of consciousness of Patients with Traumatic Brain Injury: A Randomized Controlled Trial

To evaluate and compare the effectiveness of atomoxetine and amantadine, versus placebo, in improving functional recovery during a 12-week intervention period in patients with moderate to severe traumatic brain injury.

A controlled, triple-blind, randomized, phase 3 clinical trial with parallel groups on 306 patients. The rand function of Excel software was used for randomization.

This trial will evaluate the effectiveness of atomoxetine, amantadine, and placebo in patients with TBI attending Imam Khomeini Hospital in Sari during a 12-week intervention period. The study will be conducted in a triple-blind manner: participants, clinical assessors, and data analysts will be unaware of treatment allocation. All capsules will be in identical packages. Drug packages will be coded by the pharmacy.

Inclusion criteria: Age 18 to 65 years Recorded history of moderate to severe TBI Time since injury: 1 to 12 months Persistent functional disability Ability to give informed consent Medically stable Exclusion criteria: History of previous neurological disease unrelated to TBI Recent or current substance abuse Use of medications with contraindications and use of medications that interact with atomoxetine or amantadine Severe neuropsychiatric disorders Known prior hypersensitivity to atomoxetine or amantadine Uncontrolled cardiovascular disease Severe hepatic or renal impairment Pregnancy or lactation

Intervention group 1: 20 mg atomoxetine twice daily (one week), then 40 mg twice daily (weeks 2 to 12) Intervention group 2: 100 mg amantadine twice daily (two weeks), 150 mg (week 3), 200 mg if tolerated (weeks 4 to 12) Control group: Placebo in capsule form and similar schedule

Functional status, cognitive function assessment, behavioral assessments, safety assessments including vital signs

This randomized, controlled trial will use a parallel group design with three arms: atomoxetine, amantadine, and placebo. Eligible participants will be randomly assigned in a 1:1:1 ratio using a computerized randomization sequence. Block randomization with varying block sizes (such as blocks of 6 or 9) will be used to maintain allocation concealment and ensure a balanced distribution of participants across the three study arms during the sampling period. The randomization sequence will be performed by an independent biostatistician who is not involved in the sampling or patient assessment. Allocation will be performed by the hospital pharmacy or a central randomization center, which will allocate participants based on the randomization list after enrollment is confirmed.

. The study will be triple-blind: participants, clinical assessors, and data analysts will all be unaware of treatment allocation. To ensure integrity of blinding, active treatments (amantadine and atomoxetine) and placebo will be encapsulated in identical gelatin capsules to mask differences in size, color, or flavor. All capsules will be packaged in identical packages. The dosing schedule will be standardized across groups to minimize the risk of blinding due to dietary differences. Drug packages will be coded by the pharmacy with unique identifiers related to the treatment group but without revealing the contents. Only the pharmacy will have the decryption key. The study team (including prescribing physicians, outcome assessors, and coordinators) will not have access to the randomization list or the decryption key until the trial is over and the database is locked. In the event of an emergency, the treating physician may request a participant's allocation to be determined through a secure process, but such cases will be recorded and reported to the trial supervisor and ethics board.