Clinical trial NCT04262895: TTI-0102 for Veterans With TBI
Official title: TTI-0102, a Cysteamine Precursor for Mild to Moderate TBI: Dosing and Feasibility Study
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Mild to Moderate TBI
Posttraumatic Stress Disorder
Keywords: cognition
neurobehavioral symptoms
psychiatric symptoms
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2020-02-10
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In Phase 1, the investigators will determine whether TTI-0102 2 mg/day or 4 mg/day is more tolerated and/or more effective compared with placebo in Veterans with mild to moderate TBI and PTSD. In Phase 2, the investigators will determine the feasibility and acceptability of trial procedures involving TTI-0102 (dose determined in Phase 1) vs placebo in Veteran participants receiving Compensatory Cognitive Training.
Primary purpose: TREATMENT

Brief summary: Traumatic brain injury (TBI) is a signature wound of the recent wars. How chronic TBI symptoms develop after a mild brain injury is not fully understood, but it is now thought that injury results in damage that reduces brain energy production, increases inflammation, and results in a leaky blood-brain barrier. Difficulties in daily function may persist in areas such as thinking (e.g., attention, learning, memory, planning, and problem-solving), pain (e.g., headache) and behavior (e.g., sleep, posttraumatic stress disorder, depression). No medications for TBI have been developed, so evidence-based cognitive rehabilitation interventions such as Compensatory Cognitive Training (CCT) are the mainstay of treatment. The investigators are proposing to study a medication, TTI-0102, that shows anti-inflammatory activity, as a potential adjunct treatment with CCT for Veterans with TBI-related symptoms. The investigators plan to first determine the best dose of TTI-0102 to use, and then to conduct a pilot study to test the feasibility and acceptability of combining TTI-0102 with CCT in Veterans with mild to moderate TBI and PTSD.

Detailed description: Approximately 12-23% of returning service members report a history of traumatic brain injury, mostly mild (mTBI). Post-concussive symptoms such as memory problems, irritability, and difficulty concentrating are common after TBI and may become chronic, interfering with successful return to duty or civilian reintegration, reducing quality of life, and increasing health care utilization for Veterans. In those whose TBI-related symptoms persist, there is accumulating evidence for increased morbidity (e.g., worse PTSD symptoms, chronic hypopituitarism, dementia), spurring efforts to improve diagnosis and intervention. Following a primary TBI injury, secondary injury and persistent symptoms may evolve through a complex cascade of events that culminate in inflammation, alterations in mitochondrial bioenergetics, and diminished blood brain barrier integrity, ultimately yielding a chronic disease state. To date, Veterans receiving strategy-based cognitive rehabilitation for TBI (CCT/CogSMART) have shown improvement in cognition and subjective neuropsychiatric symptoms. CCT is an evidence-based cognitive rehabilitation intervention emphasizing training in cognitive strategies to improve post-concussive symptoms, attention, learning/memory, and executive functioning. However, no pharmaceuticals have been developed for direct or adjunct-to CCT use to maximize treatment outcomes.

Given that inflammation has been observed in TBI, PTSD, and in co-occurring TBI/PTSD, it may be an important aspect of the TBI/PTSD disease state that could be manipulated to promote healing. The investigators are proposing to study TTI-0102, a cysteamine precursor that shows anti-inflammatory activity, as a potential adjunct to CCT for Veterans with TBI-related symptoms. TTI-0102 is a safe, easily administered, highly-water soluble compound that readily crosses the blood brain barrier. Compared with cysteamine, TTI-0102 degrades more slowly, dampening peak drug concentrations and sustaining drug plasma concentrations in a narrow therapeutic range. Developed to treat cystinosis, cysteamine is now believed to have potential for treatment of neurodegenerative disorders.

The goal of this proof of concept study is first, in Phase I (Year 1), to use symptom change (i.e., objective cognitive performance and subjective cognitive and neuropsychiatric symptoms) and biological profiles (i.e., metabolomics, inflammatory peptides \[interleukin-6 and C-reactive protein\], and brain-derived neurotrophic factor) to learn optimal dosing of TTI-0102 and to assess mechanism of action, and in Phase II (Year 2), to implement a feasibility trial in Veterans with a history of mild to moderate TBI and PTSD. In Phase I, 3 groups of 10 Veterans each will be randomly assigned to receive TTI-0102 2 grams/day, 4 grams/day, or placebo for 12 weeks. Baseline and post-treatment measures of objective cognition and subjective cognitive and neuropsychiatric symptoms will be administered, and plasma will be collected to measure the metabolomic, inflammatory, and protein biomarkers. In Phase II (Year 2), 12 different Veterans (6 per group) will be enrolled in a pilot randomized controlled trial (RCT) to assess the feasibility and acceptability of trial procedures. Participants in Phase II will be randomized to receive TTI-0102 (dose determined in Phase I) or placebo for 12 weeks as an adjunct to evidence-based CCT. The results of these double-blind, placebo-controlled trials will be used to plan a larger, fully-powered trial.

Eligibility criteria: Inclusion Criteria:

* Veteran receiving care at the VA San Diego Healthcare system
* age 18-65
* history of mild to moderate TBI (loss of consciousness \<24 hours; posttraumatic amnesia \<7 days)
* documented impairment (\>1 standard deviation below the mean) in at least one neuropsychological domain as determined by valid clinical neuropsychological testing using at least one performance validity test, i.e.:

  * attention
  * processing speed
  * working memory
  * learning, memory
  * executive functioning
  * DSM-5 diagnosis of PTSD based on the Clinician-Administered PTSD Scale

Exclusion Criteria:

* current alcohol and/or substance abuse or dependence
* high risk for homicide or suicide
* evidence of a significant uncontrolled/unstable medical illness or clinically significant surgery
* laboratory values that are significantly outside normal limits
* history of intolerance or hypersensitivity to cysteamine or penicillamine
* current participation in other intervention studies
* pregnant or intending to become pregnant in the next 3 months

Primary outcomes:
measure: Objective cognition
timeFrame: Change from 0 to 12 weeks
Secondary outcomes:
measure: Subjective cognition
timeFrame: Change from 0 to 12 weeks
measure: Neuropsychiatric symptoms
timeFrame: Change from 0 to 12 weeks
measure: high-sensitive C-reactive protein
timeFrame: Change from 0 to 12 weeks
measure: interleukin-6
timeFrame: change from 0 to 12 weeks
measure: brain-derived neurotrophic factor
timeFrame: change from 0 to 12 weeks
measure: kynurenine metabolism
timeFrame: change from 0 to 12 weeks
measure: sphingolipid metabolism
timeFrame: change from 0 to 12 weeks
measure: purine metabolism
timeFrame: change from 0 to 12 weeks
measure: eicosanoid metabolism
timeFrame: change from 0 to 12 weeks
measure: sulfur amino acid metabolism
timeFrame: change from 0 to 12 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego, CA
state: California
Study officials:
affiliation: VA San Diego Healthcare System, San Diego, CA
name: Elizabeth W. Twamley, PhD
role: PRINCIPAL_INVESTIGATOR
References: