Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI

NCT01670526 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CLIN-003-10SCCTA#0001
• Study Type: interventional
• Target: 94
• Locations: 1 country
• Sites: 8

Brief Summary

Difficulties with intellectual functioning, particularly memory functions, are common and source of long-term disability after Traumatic Brain Injury (TBI). However, there is very little information about pharmacologic (i.e., medication) treatments targeting these deficits. There are growing data showing brain abnormalities in acetylcholine, the chemical system that manages memory, in TBI. These findings provide the rationale for the use of cholinesterase inhibitors, medications that modulate this system, in TBI patients. As the prevalence of TBI among Veterans of recent military conflicts increases, becoming a "signature injury" of the Iraq and Afghanistan conflicts, it is of utmost importance to the Veterans Health Administration to collect scientific data on the efficacy of pharmacological treatments for intellectual difficulties in TBI patients. This study will evaluate the effects of the cholinesterase inhibitor rivastigmine transdermal patch in Veterans with TBI and posttraumatic memory problems. Results will provide much needed data that will help treat Veterans with TBI.

Conditions

Traumatic Brain Injury; Cognitive Impairment

Keywords

Traumatic Brain Injury; Cognitive Impairment; Rivastigmine; Pharmacologic Actions; TBI; Memory; Cholinesterase Inhibitors; Cognition; Head Trauma

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Demonstrated Improvement From Baseline on the Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall

  The primary efficacy measure was the Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall Index. HVLT-R was administered at screen, baseline, weeks 4, and 12. The HVLT is a measure that assesses verbal learning and memory. Alternate versions of the HVLT-R were administered at each of the different time points. The test consists of 12 words which are read to participants for three consecutive trials, each trial followed by free recall. The Total Recall score is the total number of words recalled over the three trials. The primary endpoint evaluation was to compare the proportion of patients who demonstrated improvement from baseline on the HVLT-R Total Recall of at least 5-word and at week 12 between the treatment and placebo group.

  week 12

Secondary Outcomes (3)

• Twelve-week Change in University of California San Diego Performance-based Skills Assessment - Brief (UPSA-B)

  12 weeks

• Twelve-week Change in The PTSD Symptom Checklist-Military Version (PCL-M)

  12 week

• Twelve-week Change in Beck Depression Inventory-II (BDI-II)

  12 week

Study Arms (2)

Rivastigmine

EXPERIMENTAL

Rivastigmine transdermal patch

Drug: Rivastigmine Transdermal Patch

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Rivastigmine Transdermal Patch

Interventions

Rivastigmine Transdermal Patch DRUG

Cholinesterase Inhibitor

Also known as: Cholinesterase Inhibitor

Placebo; Rivastigmine

Eligibility Criteria

• Age: 19 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be a male or a female of any race
• Be outpatient Veterans residing in the community
• Female patients of childbearing potential must have a negative pregnancy test at baseline and must practice an acceptable method of birth control during the trial
• Satisfy the following diagnostic criteria:
• A history of previous head trauma(s) at least 12 months prior to study enrollment as determined by TBI diagnostic assessment
• Closed head injury (non-penetrating) based on International Classification of Disease (ICD) 9 CM (Clinical Modification) 10 diagnosis code 854.0 as determined by TBI diagnostic assessment
• Meet or exceed the modified American Congress of Rehabilitation Medicines (ACRM) criteria for Mild TBI as determined by TBI diagnostic assessment
• Have a deficit in the area of verbal memory
• Have subjective memory impairment that was reported to be present from the time of injury or shortly thereafter to be associated with brain injury
• Satisfy the Diagnostic and Statistical Manual (DSM, 4th edition) for cognitive disorder not otherwise specified, dementia due to TBI, or amnestic disorder due to TBI
• Demonstrate willingness to accept randomization
• Provide written informed consent to participate in the study

You may not qualify if:

• Have a medical condition that can interfere with the diagnostic process and the assessment of clinical and mental status, or possibly endanger their health. Such conditions include, but are not limited to endocrinological, neurological (including epilepsy), cardiovascular (including clinically significant bradyarrhythmia, resting heart rate \<50 without a pacemaker or treating physician's approval), pulmonary, hematologic, hepatic, and renal conditions, and significant laboratory abnormalities as determined by Study Chair.
• Have a current diagnosis of any primary neurodegenerative disorder, including Huntington's disease, Parkinson's disease, or DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) dementia (other than Dementia Due to Head Trauma).
• Have suicidal ideations or have been judged to be a significant suicide risk per clinical judgment and the Columbia Suicide Severity Rating Scale (C-SSRS).
• Have a history of DSM-IV-TR substance (drug and/or alcohol) dependence disorder within the last 5 years or a history of a substance abuse disorder within the past 6 months.
• Have a DSM-IV-TR lifetime and current psychotic disorder (except lifetime depression with psychotic features), bipolar disorder, or pre-TBI onset attention-deficit/hyperactivity disorder.
• Have current PTSD symptoms that can bias or interfere with cognitive and clinical assessments as determined by study site PI.
• Have demonstrated suboptimal effort on cognitive testing as defined by:
• Test of Memory Malingering (TOMM) raw score below 45 on either Trial 2 or the Retention Trial, or
• Green's Medical Symptom Validity Test (MSVT) score of 85% on any one of the Immediate Recall, Delayed Recall, or Consistency indices.
• Have demonstrated a lack of tolerability to rivastigmine treatment in the past or severe reactions to other cholinesterase inhibitors as determined by the site investigator.
• Have been exposed to other cholinesterase inhibitors in the 30 days prior to randomization.
• Have a history of penetrating brain injury, cerebrovascular disease, cerebral neoplasm, major brain surgery, or multiple sclerosis.
• Have a significant visual or auditory deficit that may interfere with ability to complete study assessments.
• Have a limited ability to speak and read English.
• Be participating in another clinical trial with active intervention.

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (8)

VA San Diego Healthcare System, San Diego, CA

San Diego, California, 92161, United States

Location

Miami VA Healthcare System, Miami, FL

Miami, Florida, 33125, United States

Location

James A. Haley Veterans' Hospital, Tampa, FL

Tampa, Florida, 33612, United States

Location

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, 60141-5000, United States

Location

Lincoln Community-Based Outpatient Clinic, Lincoln, NE

Lincoln, Nebraska, 68510, United States

Location

Ralph H. Johnson VA Medical Center, Charleston, SC

Charleston, South Carolina, 29401-5799, United States

Location

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, 77030, United States

Location

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, 84148, United States

Location

Related Publications (2)

• Brody DL. Taking a Bite of the Elephant: A Well-Executed Clinical Trial Answers a Key Question About Rivastigmine Treatment for Memory Impairment after TBI. J Neurotrauma. 2021 Jul 15;38(14):1889. doi: 10.1089/neu.2021.29110.editorial. No abstract available.

  PMID: 34213962 DERIVED

• Brawman-Mintzer O, Tang XC, Bizien M, Harvey PD, Horner MD, Arciniegas DB, Raskind M, Johnson-Greene L, Martineau RJ, Hamner M, Rodriguez-Suarez M, Jorge RE, McGarity S, Wortzel HS, Wei Y, Sindowski T, Mintzer J, Kindy AZ, Donovan K, Reda D. Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial. J Neurotrauma. 2021 Jul 15;38(14):1943-1952. doi: 10.1089/neu.2020.7146. Epub 2021 Mar 8.

  PMID: 33514274 DERIVED

Related Links

• The War Related Illness and Injury Study Center offers services for combat veterans

MeSH Terms

Conditions

Brain Injuries, Traumatic; Cognitive Dysfunction; Craniocerebral Trauma

Interventions

Cholinesterase Inhibitors

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Wounds and Injuries; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs

Results Point of Contact

• Title: Tom Sindowski
• Organization: Hines CSPCC

tom.sindowski@va.gov

708-202-5858

Study Officials

• Olga Brawman-Mintzer, MD

  Ralph H. Johnson VA Medical Center, Charleston, SC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 1, 2012
• First Posted: August 22, 2012
• Study Start: December 1, 2012
• Primary Completion: June 1, 2016
• Study Completion: September 1, 2017
• Last Updated: February 27, 2018
• Results First Posted: July 25, 2017

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (8)