Memantine for Neuroprotection and Cognitive Enhancement Following Traumatic Brain Injury

The purpose of this study is to determine if memantine can improve cognitive and neuropsychiatric outcomes after severe traumatic brain injury.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Memantine; Drug: Placebo

Detailed Description

This is a pilot/feasibility study of memantine in severe traumatic brain injury (TBI) persons, employing a randomized, double-blind, placebo-controlled, design. Outcome evaluations will occur after 24 weeks of treatment (on medication) and 4 weeks after treatment discontinuation.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Facilities

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18-65 years old of age at time of enrollment
• Severe traumatic brain injury (TBI)
• Feeding access (e.g., orogastric (OG), nasogastric (NG), or percutaneous endoscopic gastrostomy (PEG) tube) permitting delivery of memantine or placebo
• Availability of legally-authorized representative (LAR) to provide consent and participate in some study activities (e.g., monitoring for side effects, providing information about the patient)

Exclusion Criteria:

• Pre-existing history of serious neurological disorder
• Pre-existing history of serious psychiatric disorder (e.g., schizophrenia)
• Anticipated poor prognosis, based on the presence of bilaterally fixed and dilated pupils, severe hemodynamic instability, severe elevations in intracranial pressure refractory to interventions, or other factors leading to a determination of a probable non-survivable injury
• Primarily penetrating mechanism of injury (e.g., gunshot wound to the head)
• Isolated epidural hematoma with anticipated good prognosis
• Low probability of participant being compliant or being able to finish study procedures (e.g., present for outcome rating) in the judgment of the investigator
• Not English speaking (due to inability to complete outcome measure)
• Medical contraindications to memantine: Severe hepatic impairment (defined as albumin > 15gm/dL, Alk Phos > 375 U/L, ALT > 150 U/L, AST > 120 U/L or bilirubin > 3mg/dL). Moderate-to-Severe renal impairment (defined as creatinine clearance < 60)
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Memantine; 24 weeks of memantine with accelerated titration, beginning within 48 hours of injury.	Drug: Memantine; Day 1 to 3: 10 mg bid memantine. Day 3 to 21: 20 mg bid memantine. Day 21 to 168: 10 mg bid memantine.; Other Names: Namenda
Placebo Comparator: Placebo; 24 weeks of placebo matched to memantine formulation, beginning within 48 hours of injury.	Drug: Placebo; Day 1 to 3: 10 mg bid placebo. Day 3 to 21: 20 mg bid placebo. Day 21 to 168: 10 mg bid placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
California Verbal Learning Test - Second Edition (CVLT-II) - Long Delay Free Recall	Neuropsychological test used to assess an individual's verbal memory abilities. The California Verbal Learning Test-Second Edition (CVLT-II) Long Delay Free Recall measures total word list items recalled after a 20-minute delay. The raw score is converted to a Z-score (Mean=0; SD=1) which was used for statistical analysis. Higher scores reflect worse performance (i.e., more recall errors) on this variable.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CVLT-II Trials 1-5 Free Recall Total	Neuropsychological test used to assess an individual's verbal memory abilities. California Verbal Learning Test-Second Edition (CVLT-II) Trials 1-5 Free Recall Total measures the sum of all word list items correctly recalled on learning trials 1 through 5. This raw score is converted to a T-score (Mean=50; SD=10) which was used for statistical analysis. The total A1-5T score reflects accurate recall over the five learning trials of the first list, and is most often used as a summary index of learning on the CVLT-II, with higher scores reflecting better performance.	Week 24
Brief Visuospatial Memory Test - Revised (BVMT-R) Delayed Recall	Brief Visuospatial Memory Test-Revised (BVMT-R) Delayed Recall measures the correctly recalled designs (i.e., standard scoring of accuracy and location as described in the manual) after a 25 minute delay. The delayed recall raw score ranges from 0 to 12 with 12 being the highest and best possible score. The raw score is converted to a T-score (Mean=50; SD=10) which was used for statistical analysis.	Week 24
BVMT-R Learning	Brief Visuospatial Memory Test-Revised (BVMT-R) Learning measures the correctly recalled designs (i.e., standard scoring of accuracy and location as described in the manual) over 3 learning trials. The Learning raw score is the sum of the higher number of correctly recalled designs on either Trial 2 or Trial 3 minus the number of correctly recalled designs on Trial 1. A higher score is a better score. The raw score was converted to a T-score (Mean=50; SD=10) for analysis.	Week 24
Trail Making Part B	Neuropsychological test of visual attention and executive functioning. The trail making tests are thought to reflect a variety of cognitive processes including attention, visual search and scanning, sequencing and shifting, psychomotor speed, abstraction, flexibility, ability to execute and modify a plan of action, and ability to maintain two trains of thought simultaneously. In Trails B, the participant is instructed to draw lines to connect numbers and letters in an alternating numeric and alphabetic sequence as rapidly as possible. Lower scores are better scores and the range of scores can be from 0 to no limit for Trail Making Test part B. This is a timed test and the number of seconds to complete the task is recorded. The unit of measure in seconds is converted to a scaled score (mean =10, SD = 3) using the Heaton et al. norms with lower scores indicating better performance.	Week 24
Stroop Interference	Stroop Interference Test is a neuropsychological test to assess a person's executive function. Specifically, the test is thought to reflect selective attention, cognitive flexibility and processing speed. The raw score for this measure is the number of items correctly identified within 45 seconds. The raw score was converted to a T-score (mean=50; SD=10) for analysis. Higher scores reflect better performance and less interference on reading ability.	Week 24
Behavior Rating Inventory of Executive Function (BRIEF) Inhibit	The Behavior Rating Inventory of Executive Function (BRIEF) Inhibit subscale is a rating scale completed by the participant and independently by an observer that assesses the ability to control impulses (inhibitory control) and to stop engaging in a behavior. The frequency of behaviors indicated by items is rated on a 3-point scale (never, sometimes, often). The raw score for the Inhibit subscale is the sum of ratings for the 8 items included in this measure. This sum was converted to a T-score (mean=50; SD=10) for analysis. Higher scores suggest a higher level of dysfunction in a specific domain of executive functions.	Week 24
Traumatic Brain Injury Quality of Life Anger (TBI QOL Anger)	The TBI-QOL Anger item bank includes 38 hierarchically ordered items designed to measure the full continuum of anger in a way which is both sensitive and appropriate for TBI. The TBI-QOL Anger item bank can be administered as a computer-adaptive test (CAT), allowing precise measurement of self-reported anger using only 4-8 adaptively selected items. Using CAT technology, an individual participant's responses to the TBIQoL Anger scale generated a T-score (Mean=50; SD=10) with a range of 0 (lowest anger) to 100 (greatest anger).	Week 24

Collaborators and Investigators

• Sponsor: Indiana University

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: September 11, 2014
• First Submitted That Met QC Criteria: September 11, 2014
• First Posted (Estimate): September 15, 2014

Study Record Updates

• Last Update Posted (Actual): August 30, 2017
• Last Update Submitted That Met QC Criteria: August 28, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Memory; Traumatic Brain Injury; Memantine
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Memantine
• Other Study ID Numbers: A70-4-0791023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO