Mild to Moderate TBI

Posttraumatic Stress Disorder

TTI-0102

Placebo

VA San Diego Healthcare System, San Diego, CA

TTI-0102 for Veterans With TBI

TTI-0102, a Cysteamine Precursor for Mild to Moderate TBI: Dosing and Feasibility Study

Mean z-score of objective cognitive measures (Wechsler Adult Intelligence Scale-4th Edition Digit Span, WAIS-IV Coding, Hopkins Verbal Learning Test-Revised, Brief Visuospatial Memory Test-Revised, Delis-Kaplan Executive Function System Trails, D-KEFS Color-Word Interference, D-KEFS Verbal Fluency)

Mean z-score of subjective cognitive measures (Neuro-QOL Applied Cognition Executive Function, Neuro-QOL Applied Cognition General Concerns)

Mean z-score of subjective neuropsychiatric symptom measures (Neurobehavioral Symptom Inventory Patient Health Questionnaire-9, General Anxiety Disorder-7, Insomnia Severity Index, PTSD Checklist for DSM-5, WHO Disability Assessment Schedule 2.0)

high-sensitive C-reactive protein Plasma high sensitivity C-reactive protein (hsCRP) will be measured using the Quantikine HS ELISA kit. The assay sensitivity is 10 pg/ml, the standard range is linear to 100 pg/ml, and intra- and inter-assay CVs are 4.1% and 6.5%, respectively.

interleukin-6 Plasma interleukin-6 (IL-6) will be measured using the Quantikine HS ELISA kit. The assay sensitivity is 0.70 pg/ml, the standard range is linear to 100 pg/ml, and intra- and inter-assay CVs are 2.6% and 4.5%, respectively.

brain-derived neurotrophic factor We will use the Quantikine direct ELISA that selectively detects plasma levels of free brain-derived neurotrophic factor (BNDF) without measuring BDNF bound to blood protein that occurs with ELISAs that detect total BDNF. Specificity of this BDNF immunoassay has been further confirmed by using Western blots to detect BDNF levels in plasma that were also measured with the Quantikine BDNF ELISA. We will use our previously established protocol to increase ELISA sensitivity to <4 pg/ml and maximize performance by blocking nonspecific binding on the 96-well plate and optimizing incubation times and other variables for the Quantikine free BDNF ELISA. The intra- and inter-assay CVs for the BDNF ELISA are 4.4% and 7.8%, respectively.

kynurenine metabolism Kynurenine metabolism will be assessed by broad-spectrum, targeted metabolomics using high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS). Paired samples from each participant will be analyzed comparing baseline and TTI-0102-associated changes.

sphingolipid metabolism Sphingolipid metabolism will be assessed by broad-spectrum, targeted metabolomics using high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS). Paired samples from each participant will be analyzed comparing baseline and TTI-0102-associated changes.

purine metabolism Purine metabolism will be assessed by broad-spectrum, targeted metabolomics using high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS). Paired samples from each participant will be analyzed comparing baseline and TTI-0102-associated changes.

eicosanoid metabolism Eicosanoid metabolism will be assessed by broad-spectrum, targeted metabolomics using high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS). Paired samples from each participant will be analyzed comparing baseline and TTI-0102-associated changes.

sulfur amino acid metabolism Sulfur amino acid metabolism will be assessed by broad-spectrum, targeted metabolomics using high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS). Paired samples from each participant will be analyzed comparing baseline and TTI-0102-associated changes.

A de-identified, anonymized dataset will be created and shared upon request.

VA Office of Research and Development

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.

Doses of drug and placebo will be prepared in identical sachets, with group assignment known only to the research pharmacist.

cystinosis/headache

TTI-0102 for Veterans With TBI

The Role of Susceptibility to Thrombosis in the Pseudotumor Cerebri of Nephropathic Cystinosis: A Case-Control Study

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