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

Official 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

Overview

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.

Detailed description

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.

Interventions

• Procedure Group A active comparator
  Group A placebo comparator. Stellate Ganglion Block plus placebo (.9 normal saline) infusion
• Drug Group B active comparator
  Active Comparator: Group B = Sham Stellate Ganglion Block plus ketamine infusion
• Combination product Group C Experimental
  Group C experimental Stellate Ganglion Block plus ketamine infusion
• Other Group D Placebo Comparator
  Group D Placebo Comparator: Sham Stellate Ganglion Block plus placebo normal saline

Primary outcome measures

• Headache Impact Test (HIT-6) [Time frame: 4 weeks]
• PTSD Checklist (PCL-5) [Time frame: 4 weeks]

Secondary outcome measures (12)

• Central Sensitization Inventory (CSI) [Time frame: 1 week after procedure]
• Central Sensitization Inventory (CSI) [Time frame: 2 weeks after procedure]
• Central Sensitization Inventory (CSI) [Time frame: 4 weeks after procedure]
• Central Sensitization Inventory (CSI) [Time frame: 8 weeks after procedure]
• Central Sensitization Inventory (CSI) [Time frame: 12 weeks after procedure]
• Headache intensity [Time frame: 1 week after procedure]
• Headache intensity [Time frame: 2 weeks after procedure]
• Headache intensity [Time frame: 4 weeks after procedure]
• Headache intensity [Time frame: 8 weeks after procedure]
• Headache intensity [Time frame: 12 weeks after procedure]
• Headache frequency [Time frame: 1 week after procedure]
• Headache frequency [Time frame: 2 weeks after procedure]

Eligibility criteria

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 3 centers

• Anesthesiology Pain Medicine Center — Chicago
• Walter Reed National Military Medical Center — Bethesda
• Womack Army Medical Center — Fort Bragg

Identifiers

NCT: NCT06608277 · STU00221519

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗