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TTI-0102 for Veterans With TBI

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04262895
Recruitment Status : Not yet recruiting
First Posted : February 10, 2020
Last Update Posted : February 10, 2020
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Mild to Moderate TBI Posttraumatic Stress Disorder Drug: TTI-0102 Drug: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Doses of drug and placebo will be prepared in identical sachets, with group assignment known only to the research pharmacist.
Primary Purpose: Treatment
Official Title: TTI-0102, a Cysteamine Precursor for Mild to Moderate TBI: Dosing and Feasibility Study
Estimated Study Start Date : July 1, 2020
Estimated Primary Completion Date : December 30, 2021
Estimated Study Completion Date : December 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Cysteamine

Arm Intervention/treatment
Experimental: TTI-0102 2 mg/day
TTI-0102 2 mg/day
Drug: TTI-0102
TTI-0102 is a cysteamine precursor.

Experimental: TTI-0102 4 mg/day
TTI-0102 4 mg/day
Drug: TTI-0102
TTI-0102 is a cysteamine precursor.

Placebo Comparator: Placebo
Placebo
Drug: Placebo
Placebo




Primary Outcome Measures :
  1. Objective cognition [ Time Frame: Change from 0 to 12 weeks ]
    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)


Secondary Outcome Measures :
  1. Subjective cognition [ Time Frame: Change from 0 to 12 weeks ]
    Mean z-score of subjective cognitive measures (Neuro-QOL Applied Cognition Executive Function, Neuro-QOL Applied Cognition General Concerns)

  2. Neuropsychiatric symptoms [ Time Frame: Change from 0 to 12 weeks ]
    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)

  3. high-sensitive C-reactive protein [ Time Frame: Change from 0 to 12 weeks ]
    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.

  4. interleukin-6 [ Time Frame: change from 0 to 12 weeks ]
    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.

  5. brain-derived neurotrophic factor [ Time Frame: change from 0 to 12 weeks ]
    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.

  6. kynurenine metabolism [ Time Frame: change from 0 to 12 weeks ]
    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.

  7. sphingolipid metabolism [ Time Frame: change from 0 to 12 weeks ]
    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.

  8. purine metabolism [ Time Frame: change from 0 to 12 weeks ]
    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.

  9. eicosanoid metabolism [ Time Frame: change from 0 to 12 weeks ]
    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.

  10. sulfur amino acid metabolism [ Time Frame: change from 0 to 12 weeks ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04262895


Contacts
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Contact: Elizabeth W Twamley, PhD (858) 552-8585 ext 3848 Elizabeth.Twamley@va.gov
Contact: Amber V Keller, BA (858) 642-3878 amber.keller@va.gov

Locations
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United States, California
VA San Diego Healthcare System, San Diego, CA
San Diego, California, United States, 92161
Contact: Gerhard H Schulteis, PhD    858-642-3657    gerhard.schulteis@va.gov   
Contact: Coralyn Ana    (858) 552-8585 ext 5980    Coralyn.Ana@va.gov   
Principal Investigator: Elizabeth W. Twamley, PhD         
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Elizabeth W. Twamley, PhD VA San Diego Healthcare System, San Diego, CA

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT04262895    
Other Study ID Numbers: N3323-P
I21RX003323-01 ( Other Grant/Funding Number: VA RR&D )
First Posted: February 10, 2020    Key Record Dates
Last Update Posted: February 10, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: A de-identified, anonymized dataset will be created and shared upon request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Following study completion, indefinitely.
Access Criteria: Upon request.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by VA Office of Research and Development:
cognition
neurobehavioral symptoms
psychiatric symptoms
Additional relevant MeSH terms:
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Stress Disorders, Post-Traumatic
Stress Disorders, Traumatic
Trauma and Stressor Related Disorders
Mental Disorders
Cysteamine
Cystine Depleting Agents
Molecular Mechanisms of Pharmacological Action