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IRCT20221101056357N2 IRCT 2026-05-12 Mazandaran University of Medical Sciences Comparative Effectiveness of Atomoxetine and Amantadine in the Level of consciousness of Patients with Traumatic Brain Injury: A Randomized Controlled Trial Comparative Effectiveness of Atomoxetine and Amantadine in the Level of consciousness of Patients with Traumatic Brain Injury: A Randomized Controlled Trial 2026-05-17 anticipated 306 Complete https://irct.ir/trial/89545 interventional Randomization: Randomized, Blinding: Triple blinded, Placebo: Used, Assignment: Parallel, Purpose: Treatment, Randomization description: 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, Blinding description: . 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. 3 Assessing the level of consciousness. Intervention 1: Intervention group: Atomoxetine, manufactured in Iran by Tehran Darou Pharmaceutical Company, will be given 20 mg twice daily (7 am and 12 pm) during the first week (1st week BD mg 20). After 7 days, 40 mg will be given twice daily for the next 11 weeks (weeks 2 to 12, BD mg 40). Intervention 2: Intervention group: Amantadine, manufactured in Iran, Tehran Darou Pharmaceutical Company Patients will receive 100 mg twice daily during weeks one and two. If tolerated, this will be increased to 150 mg BD during week three. This will be increased to 200 mg BD during weeks four to twelve, if tolerated and DRS responsive. If a participant cannot tolerate the full dose, they may remain at 100 or 150 mg daily, depending on their response and tolerance, as individual dose adjustment is part of the protocol. Intervention 3: Control group:Placebo mg 20, product of Iran, Tehran Pharmaceutical Company, will receive the drug twice a day (7 am and 12 pm) during the first week (first week BD mg 20). After 7 days, they will receive mg 40 twice a day for the next 11 weeks (weeks 2 to 12, BD mg 40). Undecided - It is not yet known if there will be a plan to make this available Justification or reason for indecision in sharing IPD is No further information available.
public Sajad Najafi
Neurosurgery Department, Imam Khomeini Hospital, Amir Mazandarani Blvd.
Sari Iran (Islamic Republic of) 48166-33131 +98 11 3336 1630 drsajjad_najafi@yahoo.com Mazandaran University of Medical Sciences scientific Sajad Najafi
Neurosurgery Department, Imam Khomeini Hospital, Amir Mazandarani Blvd.
Sari Iran (Islamic Republic of) 48166-33131 +98 11 3336 1630 drsajjad_najafi@yahoo.com Mazandaran University of Medical Sciences Iran (Islamic Republic of) Age 18 to 65 years Documented history of moderate to severe traumatic brain injury (TBI) (GCS ≤ 12 or evidence of intracranial injury on CT or MRI imaging) Recovery time from injury: 1 to 12 months Persistent functional disability (DRS ≥ 6 from baseline) Ability to give informed consent Medical stability in patients undergoing treatment and evaluation outside the hospital 18 years 65 years Both History of previous neurological conditions unrelated to TBI (such as epilepsy, stroke, dementia) Recent or current (within the past three months) substance abuse according to DSM-5 criteria Use of contraindicated medications such as monoamine oxidase inhibitors (MAOIs), stimulants or norepinephrine reuptake inhibitors (e.g., methylphenidate, bupropion), and use of medications that interact with atomoxetine or amantadine Having severe neuropsychiatric disorders (such as severe psychosis, severe major depression, or suicidal thoughts requiring immediate treatment) Known prior allergy to atomoxetine or amantadine Having uncontrolled cardiovascular disease (such as significant arrhythmia, recent MI, or severe hypertension) Having severe liver or kidney disorders Pregnancy or breastfeeding S06.0X0 Concussion without loss of consciousness Treatment - Drugs Treatment - Drugs Placebo Intervention group: Atomoxetine, manufactured in Iran by Tehran Darou Pharmaceutical Company, will be given 20 mg twice daily (7 am and 12 pm) during the first week (1st week BD mg 20). After 7 days, 40 mg will be given twice daily for the next 11 weeks (weeks 2 to 12, BD mg 40). Intervention group: Amantadine, manufactured in Iran, Tehran Darou Pharmaceutical Company Patients will receive 100 mg twice daily during weeks one and two. If tolerated, this will be increased to 150 mg BD during week three. This will be increased to 200 mg BD during weeks four to twelve, if tolerated and DRS responsive. If a participant cannot tolerate the full dose, they may remain at 100 or 150 mg daily, depending on their response and tolerance, as individual dose adjustment is part of the protocol. Control group:Placebo mg 20, product of Iran, Tehran Pharmaceutical Company, will receive the drug twice a day (7 am and 12 pm) during the first week (first week BD mg 20). After 7 days, they will receive mg 40 twice a day for the next 11 weeks (weeks 2 to 12, BD mg 40). Functional status. Timepoint: At weeks 0, 4, 8, and 12. Method of measurement: Disability Rating Scale. Cognitive function assessment. Timepoint: At weeks 0, 4, 8, and 12. Method of measurement: Using the Stroop Color-Word Test and MoCA. Behavioral assessments. Timepoint: Every two weeks. Method of measurement: Using ASRS and WCFS. Safety assessments including vital signs. Timepoint: In week 2. Method of measurement: ECG. Mazandaran University of Medical Sciences Approved 2025-08-16 Ethics Committee in Organizational Research, Imam (RA) Teaching and Medical Hospital, Sari Amir Mazandarani Blvd Sari Mazandaran Iran (Islamic Republic of)