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NCT Number: NCT06608277

Ketamine, SGB and Combination Treatment for TBI-associated Headache or PTSD

Post-Traumatic Stress Disorder (PTSD) and traumatic brain injury (TBI) with associated headache are amongst the most common injuries sustained by our deployed forces in Iraq and Afghanistan, as well as in more recent conflicts in Eastern Europe and the Middle East. This study aims to determine whether a procedural intervention (stellate ganglion block (SGB)) or medication (ketamine), alone or in combination, can alleviate PTSD and TBI-associated headache. Determining efficacious treatments in a randomized, double-blind, placebo-controlled, multicenter study trial may improve quality of life in those with TBI and PTSD, and identifying factors associated with treatment outcome (personalized medicine) may enhance selection, thereby improving the risk: benefit and cost-effectiveness ratios.

Primary Objectives:

1. To determine the efficacy of SGB and ketamine infusion as stand-alone treatments for TBI-related headache; 2. To determine the efficacy of SGB and ketamine infusion as stand-alone treatments for PTSD; 3. To determine the comparative effectiveness of SGB and ketamine infusion, and the effect of combination treatment on TBI-related headache and PTSD; 4. Exploratory Aim 1: To determine the effects of SGB, ketamine infusion, and the combination on structural and functional MRI, biomarker levels and pain thresholds and tolerance; 5. Exploratory Aim 2: To identify factors associated with treatment responders overall and for individual treatment groups.

Secondary Objectives:

1. Exploratory Aim 1: To determine the effects of SGB, ketamine infusion, and the combination on structural and functional MRI, biomarker levels and pain thresholds and tolerance (Biomedical levels and MRI not included at Northwestern University Site). 2. Exploratory Aim 2: To identify factors associated with treatment responders overall and for individual treatment groups.

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Key information

Conditions

Posttraumatic Headache Brain Diseases Central Nervous System Diseases Headache Disorders Headache Disorders, Secondary Mental Disorders Nervous System Diseases Post-Traumatic Headache Posttraumatic Stress Disorder Stress Disorders, Post-Traumatic Stress Disorders, Traumatic Trauma and Stressor Related Disorders

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Anesthesiology Pain Medicine Center, Chicago, Illinois, United States

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About this study

This is a multicenter randomized, double-blind (subject, evaluator) placebo-controlled parallel-group clinical trial where 175 eligible subjects will be randomized into 1 of 4 groups (described below) using a 2:2:2:1 ratio. The purpose of the trial is to test the efficacy and comparative effectiveness of SGB and ketamine infusion on PTSD and post-traumatic headache. There are no reliably effective treatments for either PTSD or TBI-associated headaches, with preliminary and/or conflicting results suggesting efficacy for both SGB and ketamine for both conditions.

The first three groups will receive at least one intervention, with a smaller number receiving sham SGB/ placebo ketamine, which is necessary to determine efficacy and serve as a comparator. Several patient-reported outcomes, including quality of life measures, will be collected at baseline and the primary endpoint at 4 weeks. There will also be patient-reported outcome measures recorded at 1 and 2 weeks. Those with a positive categorical response (described under data collection) at 4 weeks will be followed further at 8 and 12 weeks. Those with negative outcomes will exit the study and be followed as an observational cohort where they will be eligible for non-study measures as determined by the treating providers. This may include other novel treatments such as using higher doses of ketamine, left-sided sympathetic blocks, sympathetic blocks with botulinum toxin and liposomal bupivacaine, and the use of neuromodulation.

For all patients who continue to experience a positive categorical outcome, unblinding will occur at 12 weeks, and they will be followed at 6 months as part of an observational cohort whereby the same outcome measures will be recorded. Those who exit the study and are unblinded at early time points (i.e., 4, 8 or 12 weeks in those with a 12-week negative outcome) will be followed as an observational cohort if they received one of the study treatments, including a variation (e.g., a higher dose of ketamine, a left-sided cervical sympathetic blocks). These time points will be the same as in the clinical trial portion of the study (1,2,4,8 and 12 weeks), and 6 months. For those in either the clinical trial extension or observational cohort who continue to experience a positive outcome at 6 months, we will again follow them at 12 months.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Adults 18 years or older
  • Stable doses of medications for > 2 weeks for TBI and/or PTSD
  • For TBI-associated headache with or without PTSD: HIT-6 score of >/=53. For PTSD with or without TBI-associated headache: PCL-5 score >/=33 OR. For those with TBI and PTSD, and a HIT-6 score < 53 and PCL-5 score of <33, individuals with a HIT-6 score of 50-52 and a PCL-5 score of 31 or 32 will be included.
  • Duration of chronic TBI or PTSD > 3 months

Exclusion criteria

  • Ketamine infusion or SGB within the past 6 months
  • Serious medical or psychiatric conditions other than TBI or PTSD that could affect cognition (e.g., dementia, Parkinson's Disease)
  • Elevated intracranial pressure
  • For TBI, prior history of headache that can explain the headache intensity (i.e., headache not attributable to TBI)
  • Active psychosis or poorly controlled non-injury or PTSD-related psychiatric condition (e.g., bipolar disorder)
  • Poorly controlled medical conditions that could be exacerbated by treatment (e.g., unstable angina)
  • Pregnancy (women of childbearing age who can become pregnant will have to take a pregnancy test)
  • Non-fluency in English (poor generalizability to military and veteran populations, instruments not validated for use or translated in many languages)

Treatment and study plan

Group A active comparator

Procedure

Group A placebo comparator. Stellate Ganglion Block plus placebo (.9 normal saline) infusion

Other names: Group A

Group B active comparator

Drug

Active Comparator: Group B = Sham Stellate Ganglion Block plus ketamine infusion

Other names: Group B

Group C Experimental

Combination Product

Group C experimental Stellate Ganglion Block plus ketamine infusion

Other names: Group C

Group D Placebo Comparator

Other

Group D Placebo Comparator: Sham Stellate Ganglion Block plus placebo normal saline

Other names: Group D

Primary outcomes

  1. Headache Impact Test (HIT-6)

    Time frame: 4 weeks

    Headache Impact Test (HIT-6) is a 6-item instrument that measures the impact of headaches, scored from 36-78 with higher scores indicating greater disability impact of headaches in a 1-month period that has been validated for a variety of headache conditions, including tension-type headache and migraine.

  2. PTSD Checklist (PCL-5)

    Time frame: 4 weeks

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

Secondary outcomes

  1. Central Sensitization Inventory (CSI)

    Time frame: 1 week after procedure

    A 25-item survey which measures central sensitization, scored from 0-100 with higher scores indicating greater sensitization sensitization. It is a self-reported tool that consists of statements related to current health symptoms rated on a 5-point Likert scale, with a score of 40 being the cut off value for central sensitization

  2. Central Sensitization Inventory (CSI)

    Time frame: 2 weeks after procedure

    A 25-item survey which measures central sensitization (amplified nervous system response to sensory stimuli), scored from 0-100 with higher scores indicating greater sensitization sensitization. It is a self-reported tool that consists of statements related to current health symptoms rated on a 5-point Likert scale, with a score of 40 being the cut off value for central sensitization

  3. Central Sensitization Inventory (CSI)

    Time frame: 4 weeks after procedure

    A 25-item survey which measures central sensitization, scored from 0-100 with higher scores indicating greater sensitization sensitization. It is a self-reported tool that consists of statements related to current health symptoms rated on a 5-point Likert scale, with a score of 40 being the cut off value for central sensitization

  4. Central Sensitization Inventory (CSI)

    Time frame: 8 weeks after procedure

    A 25-item survey which measures central sensitization, scored from 0-100 with higher scores indicating greater sensitization sensitization. It is a self-reported tool that consists of statements related to current health symptoms rated on a 5-point Likert scale, with a score of 40 being the cut off value for central sensitization

  5. Central Sensitization Inventory (CSI)

    Time frame: 12 weeks after procedure

    A 25-item survey which measures central sensitization, scored from 0-100 with higher scores indicating greater sensitization sensitization. It is a self-reported tool that consists of statements related to current health symptoms rated on a 5-point Likert scale, with a score of 40 being the cut off value for central sensitization

  6. Headache intensity

    Time frame: 1 week after procedure

    Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable).

    NRS scale)

  7. Headache intensity

    Time frame: 2 weeks after procedure

    Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable).

    NRS scale)

  8. Headache intensity

    Time frame: 4 weeks after procedure

    Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable).

    NRS scale)

  9. Headache intensity

    Time frame: 8 weeks after procedure

    Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable).

    NRS scale)

  10. Headache intensity

    Time frame: 12 weeks after procedure

    Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable).

    NRS scale)

  11. Headache frequency

    Time frame: 1 week after procedure

    Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache)

  12. Headache frequency

    Time frame: 2 weeks after procedure

    Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache)

  13. Headache frequency

    Time frame: 4 weeks after procedure

    Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache)

  14. Headache frequency

    Time frame: 8 weeks after procedure

    Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache)

  15. Headache frequency

    Time frame: 12 weeks after procedure

    Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache)

  16. Analgesic or psychotropic medication reduction

    Time frame: 1 week after procedure

    An analgesic or psychotropic medication reduction identified as a > 20% reduction in opioid, barbiturate or benzodiazepine, or cessation of nonopioid analgesic, or > 50% reduction in non-benzodiazepine sedation or psychotropic medication (e.g., antidepressant or antipsychotic).

  17. Analgesic or psychotropic medication reduction

    Time frame: 2 weeks after procedure

    An analgesic or psychotropic medication reduction identified as a > 20% reduction in opioid, barbiturate or benzodiazepine, or cessation of nonopioid analgesic, or > 50% reduction in non-benzodiazepine sedation or psychotropic medication (e.g., antidepressant or antipsychotic).

  18. Analgesic or psychotropic medication reduction

    Time frame: 4 weeks after procedure

    An analgesic or psychotropic medication reduction identified as a > 20% reduction in opioid, barbiturate or benzodiazepine, or cessation of nonopioid analgesic, or > 50% reduction in non-benzodiazepine sedation or psychotropic medication (e.g., antidepressant or antipsychotic).

  19. Analgesic or psychotropic medication reduction

    Time frame: 8 weeks after procedure

    An analgesic or psychotropic medication reduction identified as a > 20% reduction in opioid, barbiturate or benzodiazepine, or cessation of nonopioid analgesic, or > 50% reduction in non-benzodiazepine sedation or psychotropic medication (e.g., antidepressant or antipsychotic).

  20. Analgesic or psychotropic medication reduction

    Time frame: 12 weeks after procedure

    An analgesic or psychotropic medication reduction identified as a > 20% reduction in opioid, barbiturate or benzodiazepine, or cessation of nonopioid analgesic, or > 50% reduction in non-benzodiazepine sedation or psychotropic medication (e.g., antidepressant or antipsychotic).

  21. Headache Impact Test (HIT-6)

    Time frame: 1 week

    Headache Impact Test (HIT-6) is a 6-item instrument that measures the impact of headaches, scored from 36-78 with higher scores indicating greater disability impact of headaches in a 1-month period that has been validated for a variety of headache conditions, including tension-type headache and migraine.

  22. Headache Impact Test (HIT-6)

    Time frame: 2 weeks

    Headache Impact Test (HIT-6) is a 6-item instrument that measures the impact of headaches, scored from 36-78 with higher scores indicating greater disability impact of headaches in a 1-month period that has been validated for a variety of headache conditions, including tension-type headache and migraine.

  23. Headache Impact Test (HIT-6)

    Time frame: 8 weeks

    Headache Impact Test (HIT-6) is a 6-item instrument that measures the impact of headaches, scored from 36-78 with higher scores indicating greater disability impact of headaches in a 1-month period that has been validated for a variety of headache conditions, including tension-type headache and migraine.

  24. Headache Impact Test (HIT-6)

    Time frame: 12 weeks

    Headache Impact Test (HIT-6) is a 6-item instrument that measures the impact of headaches, scored from 36-78 with higher scores indicating greater disability impact of headaches in a 1-month period that has been validated for a variety of headache conditions, including tension-type headache and migraine.

  25. Quality of Life after Brain Injury scale (QoLIBRI)

    Time frame: 1 week

    37-item scale with questions ranging from 1 (not at all) to 5 (very true), with a score ranging from 0-100 (higher numbers indicate better quality of life) calculated from the mean score minus 1, multiplied by 4.

  26. Quality of Life after Brain Injury scale (QoLIBRI)

    Time frame: 2 weeks

    37-item scale with questions ranging from 1 (not at all) to 5 (very true), with a score ranging from 0-100 (higher numbers indicate better quality of life) calculated from the mean score minus 1, multiplied by 4.

  27. Quality of Life after Brain Injury scale (QoLIBRI)

    Time frame: 4 weeks

    37-item scale with questions ranging from 1 (not at all) to 5 (very true), with a score ranging from 0-100 (higher numbers indicate better quality of life) calculated from the mean score minus 1, multiplied by 4.

  28. Quality of Life after Brain Injury scale (QoLIBRI)

    Time frame: 8 weeks

    37-item scale with questions ranging from 1 (not at all) to 5 (very true), with a score ranging from 0-100 (higher numbers indicate better quality of life) calculated from the mean score minus 1, multiplied by 4.

  29. Quality of Life after Brain Injury scale (QoLIBRI)

    Time frame: 12 weeks

    37-item scale with questions ranging from 1 (not at all) to 5 (very true), with a score ranging from 0-100 (higher numbers indicate better quality of life) calculated from the mean score minus 1, multiplied by 4.

  30. Hospital Anxiety and Depression Scale (HADS)

    Time frame: 1 week

    14-item instrument with questions assessing anxiety and depression (7 each) scored from 0-3. For each subscale (anxiety and depression), scores range from 0-21, with higher scores indicating greater pathology.

  31. Hospital Anxiety and Depression Scale (HADS)

    Time frame: 2 weeks after procedure

    Hospital anxiety and depression scale, a 14 question survey scored survey. The anxiety is scored 0 (low) to 21 (high). The depression is scored 0 (low) to 21 (high).

  32. Hospital Anxiety and Depression Scale (HADS)

    Time frame: 4 weeks

    14-item instrument with questions assessing anxiety and depression (7 each) scored from 0-3. For each subscale (anxiety and depression), scores range from 0-21, with higher scores indicating greater pathology.

  33. Hospital Anxiety and Depression Scale (HADS)

    Time frame: 8 weeks

    14-item instrument with questions assessing anxiety and depression (7 each) scored from 0-3. For each subscale (anxiety and depression), scores range from 0-21, with higher scores indicating greater pathology.

  34. Hospital Anxiety and Depression Scale (HADS)

    Time frame: 12 weeks

    14-item instrument with questions assessing anxiety and depression (7 each) scored from 0-3. For each subscale (anxiety and depression), scores range from 0-21, with higher scores indicating greater pathology.

  35. Patient Global Impression of Change Scale

    Time frame: 1 week

    7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better)

  36. Patient Global Impression of Change Scale

    Time frame: 2 weeks

    7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better)

  37. Patient Global Impression of Change Scale

    Time frame: 4 weeks

    7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better)

  38. Patient Global Impression of Change Scale

    Time frame: 8 weeks

    7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better)

  39. Patient Global Impression of Change Scale

    Time frame: 12 weeks

    7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better)

  40. Positive categorical outcome

    Time frame: 1 week

    Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5.

  41. Positive categorical outcome

    Time frame: 2 weeks

    Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5.

  42. Positive categorical outcome

    Time frame: 4 weeks

    Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5.

  43. Positive categorical outcome

    Time frame: 8 weeks

    Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5.

  44. Positive categorical outcome

    Time frame: 12 weeks

    Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5.

  45. Sheehan Suicidality Tracking Scale (S-STS)

    Time frame: 4 weeks after procedure

    The S-STS is a short scale designed to assess and monitor suicidality over time and is very sensitive to changes in treatment. The survey has 8 questions with each scored from none (0) to extremely (4).

    outcomes.

  46. International Trauma Questionnaire

    Time frame: 4 weeks

    18-question survey that measures the impact PTSD has on an individual, and helps phenotype PTSD (i.e., into complex PTSD or non-complex). Each question is scored from 0-4 (range 0-72), with higher scores indicating greater disease burden.

  47. International Trauma Questionnaire

    Time frame: 12 weeks

    18-question survey that measures the impact PTSD has on an individual, and helps phenotype PTSD (i.e., into complex PTSD or non-complex). Each question is scored from 0-4 (range 0-72), with higher scores indicating greater disease burden.

  48. PCL-5

    Time frame: 1 week

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

  49. PCL-5

    Time frame: 2 weeks

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

  50. PCL-5

    Time frame: 8 weeks

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

  51. PCL-5

    Time frame: 12 weeks

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

  52. PTSD Checklist (PCL-5)

    Time frame: 1 week

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

  53. PTSD Checklist (PCL-5)

    Time frame: 2 weeks

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

  54. PTSD Checklist (PCL-5)

    Time frame: 8 weeks

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

  55. PTSD Checklist (PCL-5)

    Time frame: 12 weeks

    PTSD Checklist (PCL-5) is a psychometrically-validated 20-item instrument that measures the quality of life in people with posttraumatic stress disorder (PTSD_, scored from 0-80 with higher scores indicating greater disability assesses 20 DSM-5 symptoms of posttraumatic stress disorder.

Other outcomes

  1. Quantitative sensory testing

    Time frame: 4 weeks after procedure

    Quantitative sensory testing will include mechanical temporal summation, a measure of central sensitization, pressure pain thresholds, and the simultaneous presentation of 2 stimuli to assess intrinsic modulation, known as conditioned pain modulation. This test is optional

  2. Serum biomarkers

    Time frame: 4 weeks after procedure

    Markers of inflammation to include interleukins 1 and 6 (IL1 and 6), tumor necrosis factor-alpha (TNF), C-reactive protein (CRP), nerve growth factor (NGF), brain-derived neutrotrophic factor (BDNF), Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). This test is optional.

  3. Structural MRI Imaging

    Time frame: 4 weeks after procedure

    Volumetric changes in gray and white matter, in different regions. This test is optional.

  4. Functional MRI

    Time frame: 4 weeks after procedure

    Functional changes in pain and emotion processing centers (e.g., activation of brainstem, thalamus, hippocampus, insula, anterior cingulate, and somatosensory cortices) as well as changes in connectivity between regions. This test is optional.

Study contacts

Contact information is provided by the study sponsor or research team.

Jordan Wood, BS

CONTACT

[email protected]

312-695-0915

Sponsors and collaborators

Lead sponsor

Northwestern University

Other

Collaborators

  • Lviv National Medical University
  • Walter Reed National Military Medical Center
  • Womack Army Medical Center

Registry information

Official study title

Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial Comparing Ketamine, Stellate Ganglion Blocks and Combination Treatment to Sham Therapies for Traumatic Brain Injury-Associated Headaches and Post-Traumatic Stress Disorder

Important dates

Study start
2025
Primary completion
2027
Study completion
2028
First posted
Sep 23, 2024
Registry last updated
May 1, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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