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| Name | Class |
|---|---|
| Walter Reed National Military Medical Center | FED |
| Lviv National Medical University | OTHER |
| Womack Army Medical Center | FED |
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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:
Secondary Objectives:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A =Stellate ganglion block (SGB) with bupivacaine (LA) plus placebo ketamine (midazolam) | Active Comparator | Stellate ganglion block with the local anesthetic (LA) bupivacaine and placebo (1-7 mg midazolam + normal saline) ketamine. The stellate ganglion block will be performed with approximately 8 mL bupivacaine using ultrasound or fluoroscopic guidance. The placebo ketamine will consist of an initial 1-4 mg bolus of midazolam followed by boluses or an infusion (in normal saline) of midazolam up to 7 mg, over 30-60 minutes. |
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| Group B = Sham SGB plus ketamine infusion | Active Comparator | Sham SGB will be 1-2 mL of saline given subcutaneously using ultrasound or fluoroscopic guidance. The ketamine will consist of Prior to the sham Stellate Ganglion Block procedure, the study drug ketamine or normal saline will be administered by one of the study team physicians. 100 ml bag will be administered by bolus/infusion or intermittent boluses up to 0.3 mg/kg). The ketamine infusion will start before the sham block where patients will be given 1-4 mg of midazolam + up to 0.3 mg/kg of ketamine, as bolus doses. Over the next 30-60 minutes patients will receive between 0.5-1 mg/kg total dose of ketamine, + additional midazolam as needed. |
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| Group C = Stellate ganglion block (SGB) with bupivacaine LA plus ketamine infusion | Experimental | These patients will receive both SGB with bupivacaine + ketamine as described above. |
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| Group D = Sham SGB plus placebo ketamine (midazolam) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Group A active comparator | Procedure | Group A placebo comparator. Stellate Ganglion Block plus placebo (.9 normal saline) infusion |
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| Measure | Description | Time Frame |
|---|---|---|
| Headache Impact Test (HIT-6) | 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. | 4 weeks |
| PTSD Checklist (PCL-5) | 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. | 4 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Central Sensitization Inventory (CSI) | 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 | 1 week after procedure |
| Measure | Description | Time Frame |
|---|---|---|
| Quantitative sensory testing | 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 | 4 weeks after procedure |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jordan Wood, BS | Contact | 312-695-0915 | jordan.wood1@northwestern.edu |
| Name | Affiliation | Role |
|---|---|---|
| Steven Cohen, MD | Northwestern University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Anesthesiology Pain Medicine Center | Recruiting | Chicago | Illinois | 60611 | United States |
Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial
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Participant and outcomes assessor will be blinded to the study group received.
These patients will receive the sham SGB + placebo ketamine as described above. |
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| Group B active comparator | Drug | Active Comparator: Group B = Sham Stellate Ganglion Block plus ketamine infusion |
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| Group C Experimental | Combination Product | Group C experimental Stellate Ganglion Block plus ketamine infusion |
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| Group D Placebo Comparator | Other | Group D Placebo Comparator: Sham Stellate Ganglion Block plus placebo normal saline |
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| Central Sensitization Inventory (CSI) | 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 | 2 weeks after procedure |
| Central Sensitization Inventory (CSI) | 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 weeks after procedure |
| Central Sensitization Inventory (CSI) | 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 | 8 weeks after procedure |
| Central Sensitization Inventory (CSI) | 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 | 12 weeks after procedure |
| Headache intensity | Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable). NRS scale) | 1 week after procedure |
| Headache intensity | Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable). NRS scale) | 2 weeks after procedure |
| Headache intensity | Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable). NRS scale) | 4 weeks after procedure |
| Headache intensity | Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable). NRS scale) | 8 weeks after procedure |
| Headache intensity | Average and worst headache scores (0-10 numerical rating scale (NRS), overall pain (0=no pain, 10=worst pain imaginable). NRS scale) | 12 weeks after procedure |
| Headache frequency | Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache) | 1 week after procedure |
| Headache frequency | Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache) | 2 weeks after procedure |
| Headache frequency | Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache) | 4 weeks after procedure |
| Headache frequency | Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache) | 8 weeks after procedure |
| Headache frequency | Days per week with scores greater or equal to 2, and 7/10 (2= mild headache, 7=severe headache) | 12 weeks after procedure |
| Analgesic or psychotropic medication reduction | 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). | 1 week after procedure |
| Analgesic or psychotropic medication reduction | 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). | 2 weeks after procedure |
| Analgesic or psychotropic medication reduction | 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). | 4 weeks after procedure |
| Analgesic or psychotropic medication reduction | 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). | 8 weeks after procedure |
| Analgesic or psychotropic medication reduction | 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). | 12 weeks after procedure |
| Headache Impact Test (HIT-6) | 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. | 1 week |
| Headache Impact Test (HIT-6) | 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 weeks |
| Headache Impact Test (HIT-6) | 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. | 8 weeks |
| Headache Impact Test (HIT-6) | 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. | 12 weeks |
| Quality of Life after Brain Injury scale (QoLIBRI) | 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. | 1 week |
| Quality of Life after Brain Injury scale (QoLIBRI) | 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. | 2 weeks |
| Quality of Life after Brain Injury scale (QoLIBRI) | 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. | 4 weeks |
| Quality of Life after Brain Injury scale (QoLIBRI) | 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. | 8 weeks |
| Quality of Life after Brain Injury scale (QoLIBRI) | 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. | 12 weeks |
| Hospital Anxiety and Depression Scale (HADS) | 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. | 1 week |
| Hospital Anxiety and Depression Scale (HADS) | 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). | 2 weeks after procedure |
| Hospital Anxiety and Depression Scale (HADS) | 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. | 4 weeks |
| Hospital Anxiety and Depression Scale (HADS) | 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. | 8 weeks |
| Hospital Anxiety and Depression Scale (HADS) | 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. | 12 weeks |
| Patient Global Impression of Change Scale | 7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better) | 1 week |
| Patient Global Impression of Change Scale | 7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better) | 2 weeks |
| Patient Global Impression of Change Scale | 7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better) | 4 weeks |
| Patient Global Impression of Change Scale | 7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better) | 8 weeks |
| Patient Global Impression of Change Scale | 7-item Likert scale with scores ranging from 0 (worse or no change) to 7 (a great deal better) | 12 weeks |
| Positive categorical outcome | Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5. | 1 week |
| Positive categorical outcome | Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5. | 2 weeks |
| Positive categorical outcome | Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5. | 4 weeks |
| Positive categorical outcome | Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5. | 8 weeks |
| Positive categorical outcome | Positive is >/= 4 on the PGIC scale and >/= 6-point reduction in HIT-6 and/or a >/= 10-point reduction in PCL-5. | 12 weeks |
| Sheehan Suicidality Tracking Scale (S-STS) | 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. | 4 weeks after procedure |
| International Trauma Questionnaire | 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. | 4 weeks |
| International Trauma Questionnaire | 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. | 12 weeks |
| PCL-5 | 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. | 1 week |
| PCL-5 | 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. | 2 weeks |
| PCL-5 | 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. | 8 weeks |
| PCL-5 | 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. | 12 weeks |
| PTSD Checklist (PCL-5) | 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. | 1 week |
| PTSD Checklist (PCL-5) | 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. | 2 weeks |
| PTSD Checklist (PCL-5) | 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. | 8 weeks |
| PTSD Checklist (PCL-5) | 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. | 12 weeks |
| Serum biomarkers |
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. |
| 4 weeks after procedure |
| Structural MRI Imaging | Volumetric changes in gray and white matter, in different regions. This test is optional. | 4 weeks after procedure |
| Functional MRI | 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. | 4 weeks after procedure |
| Walter Reed National Military Medical Center | Recruiting | Bethesda | Maryland | 20889 | United States |
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| Womack Army Medical Center | Not yet recruiting | Fort Bragg | North Carolina | 28310 | United States |
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| ID | Term |
|---|---|
| D051298 | Post-Traumatic Headache |
| D013313 | Stress Disorders, Post-Traumatic |
| ID | Term |
|---|---|
| D051271 | Headache Disorders, Secondary |
| D020773 | Headache Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D040921 | Stress Disorders, Traumatic |
| D000068099 | Trauma and Stressor Related Disorders |
| D001523 | Mental Disorders |
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