Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI (RIVET)

This study is currently recruiting participants.
Verified October 2013 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01670526
First received: August 1, 2012
Last updated: October 9, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Traumatic Brain Injury
Cognitive Impairment
Drug: Rivastigmine Transdermal Patch
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Impairment will be defined by memory impairments indexed by the Hopkins Verbal Learning Test-Revised (HVLT-R) total Trials 1-3 [ Time Frame: week 12 ] [ Designated as safety issue: No ]
    Efficacy will be determined by comparing the proportion of patients in each treatment group who are classified as responders at week 12. Treatment response is defined as a minimum 5-word improvement across alternate test forms from baseline to 12-weeks as measured on the HVLT-R total learning for Trials 1-3


Secondary Outcome Measures:
  • To compare the effects of rivastigmine transdermal patch with placebo using performance-based measures of functional capacity, cognitive functioning, mood, quality of life, and safety measures [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • To assess longer-term efficacy and safety of rivastigmine transdermal patch of double-blind treatment period [ Time Frame: additional 14 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 256
Study Start Date: January 2013
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rivastigmine
Rivastigmine transdermal patch
Drug: Rivastigmine Transdermal Patch
Cholinesterase Inhibitor
Placebo Comparator: Placebo
Placebo

Detailed Description:

Traumatic brain injury (TBI) represents one of the most significant health risks related to military duty; rapidly becoming the "signature injury" of the Iraq and Afghanistan conflicts. TBI patients often experience multiple cognitive problems, with disturbances in memory, attention, and executive functions among the most common. Disturbances in memory as well as attention are particularly problematic, as disruption of these relatively basic cognitive functions may exacerbate or cause additional disturbances in executive function, communication and other more complex cognitive domains. These cognitive deficits, especially when memory is affected, significantly impact day-to-day functioning and are the source of lingering disability and distress to the affected individuals. However, despite advances made in TBI care, treatment of cognitive deficits in TBI lag behind, forcing clinicians to provide treatment without the guidance of evidence-based scientific data. This proposal aims to begin the process of providing clinicians with evidence-based guidelines for pharmacological management of Veterans with TBI suffering from persistent cognitive deficits following their injuries. This aim will be accomplished by conducting a clinical trial in Veterans suffering from moderate to severe posttraumatic memory impairment following TBI. Specifically, this proposal will evaluate the efficacy and safety of rivastigmine transdermal patch, an intermediate-acting cholinesterase inhibitor, in this population.

We hypothesize that rivastigmine transdermal patch will be more effective than, and equally safe as, placebo in the treatment of moderate to severe posttraumatic memory impairment in Veterans with TBI when tested in a randomized, multi-site, parallel design, placebo-controlled trial, at a 12-week endpoint. The exploratory hypothesis states that compared to placebo, rivastigmine patch will be more effective and equally safe in the treatment of patients who will continue in a randomized, placebo-controlled phase for a total of 26 weeks. To test these hypotheses we will evaluate the effect and the safety of rivastigmine 9.5 mg/24 hours (10cm2) transdermal patch in 256 Veterans who meet or exceed the criteria for closed, non-penetrating, mild TBI and who present at baseline with moderate to severe memory impairment. Memory impairment will be defined as a Total Recall index (Trials 1-3) of the Hopkins Verbal Learning Test-Revised (HVLT-R) that is at least 25% lower than the intelligence-adjusted expected score, as assessed by the WAIS-IV Information and Vocabulary subtests. The study consists of a screening period, one-week single-blind, placebo run-in phase, and a 12-week double-blind acute treatment phase (Phase I). Subjects will be randomized 1:1 to rivastigmine transdermal patch 9.5mg/24 hours (10cm2) or matching placebo. During Phase I, there will be an initial 4-week titration period followed by an 8-week continuation phase. Following the 12-week acute treatment phase, randomized patients will continue in the double-blind phase (Phase II) for additional 14 weeks or until study treatment period ends. Efficacy will be determined by comparing the proportion of patients in each treatment group who are classified as responders at week 12. Secondary measure of functional capacity assessing the impact of memory improvement on real-world functioning, other measures of cognitive domains affected in TBI, namely attention, working and episodic memory and executive functions, as well as measures of mood and quality of life will be examined. Study findings will contribute to the body of evidence needed to establish standards of care for Veterans with posttraumatic memory impairment and other cognitive deficits.

  Eligibility

Ages Eligible for Study:   19 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be a male or a female of any race
  • Be outpatient Veterans residing in the community
  • Be 19-65 years old at the time of inclusion
  • 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 ICD 9 CM 10 diagnosis code 854.0 as determined by TBI diagnostic assessment
    • Meet or exceed the modified 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 DSM-IV-TR criteria 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

Exclusion Criteria:

  • Have a medical condition that can interfere with the diagnostic process and the assessment of clinical and mental status, or possibly endanger their health
  • Have a current diagnosis of any primary neurodegenerative disorder, including Huntington's disease, Parkinson's disease, or DSM-IV-TR dementia (other than Dementia Due to Head Trauma)
  • Have suicidal ideations or have been judged to be a significant suicide risk
  • 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
  • Have demonstrated suboptimal effort on cognitive testing
  • Have demonstrated a lack of tolerability to rivastigmine treatment in the past or severe reactions to other cholinesterase inhibitors
  • Be taking medications that significantly affect cognitive functioning in TBI population and/or may enhance the beneficial/adverse/toxic effect of rivastigmine or vice versa
  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01670526

Contacts
Contact: Rebekah Hardin, MHA (843) 740-1592 ext 37 hardinr@musc.edu

Locations
United States, California
VA San Diego Healthcare System, San Diego, CA Recruiting
San Diego, California, United States, 92161
Contact: Kathleen Gaa, BS    858-642-3764    kathleen.gaa@va.gov   
United States, Florida
Miami VA Healthcare System, Miami, FL Recruiting
Miami, Florida, United States, 33125
Contact: Pedja Stevanovic, PhD    305-575-7000    Pedja.Stevanovic@va.gov   
United States, Nebraska
Lincoln Community-Based Outpatient Clinic, Lincoln, NE Recruiting
Lincoln, Nebraska, United States, 68510
Contact: Ahsan Naseem, MD    402-486-7923    ahsan.naseem@va.gov   
United States, South Carolina
Ralph H Johnson VA Medical Center, Charleston Recruiting
Charleston, South Carolina, United States, 29401-5799
Contact: Deborah Agbor-Tabi    843-789-7147    Deborah.AgborTabi@va.gov   
Principal Investigator: Olga Brawman-Mintzer, MD         
United States, Utah
VA Salt Lake City Health Care System, Salt Lake City, UT Recruiting
Salt Lake City, Utah, United States, 84148
Contact: Holly Cannon    801-582-1565 ext 2733    holly.cannon@va.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Olga Brawman-Mintzer, MD Ralph H Johnson VA Medical Center, Charleston
  More Information

Additional Information:
No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01670526     History of Changes
Other Study ID Numbers: CLIN-003-10S, CCTA#0001
Study First Received: August 1, 2012
Last Updated: October 9, 2013
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
Traumatic Brain Injury
Cognitive Impairment
Rivastigmine
Pharmacologic Actions
TBI
Memory
Cholinesterase Inhibitors
Cognition
Head Trauma

Additional relevant MeSH terms:
Brain Injuries
Cognition Disorders
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Cholinesterase Inhibitors
Rivastigmine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014