Ketamine and SGB for Traumatic Brain Injury

Recruiting at 2 trial locations

Overseen By Paul Fitzgerald, RN,BSN,MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Disqualifiers: Dementia, Parkinson's, Bipolar, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 4 weeks

175 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that your medication doses have been stable for more than two weeks for TBI and/or PTSD.

What evidence supports the effectiveness of the drug ketamine for treating traumatic brain injury?

Research shows that ketamine, a drug that blocks certain brain receptors, can improve neurological outcomes after head trauma in rats by reducing brain damage and improving recovery. Additionally, in a case report, combining ketamine with a nerve block treatment helped reduce symptoms of PTSD and cognitive issues in a patient with traumatic brain injury. ^{1 2 3 4 5}

Is ketamine safe for use in humans?

Ketamine has been used safely in humans for various conditions, including depression and PTSD, with some studies showing it can be effective and well-tolerated. However, it can have side effects, such as psycho-mimetic effects (hallucinations or altered perceptions), which are important to consider. ^{2 6 7 8 9}

How is the treatment using ketamine and stellate ganglion block different for traumatic brain injury?

This treatment is unique because it combines ketamine, which can enhance brain plasticity and improve memory, with stellate ganglion block, which can improve cognitive function and reduce stress-related symptoms. This combination may offer a synergistic effect, providing both immediate and long-term benefits for symptoms related to traumatic brain injury and associated conditions like PTSD. ^{1 2 5 10 11}

Research Team

Steven Cohen, MD

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for individuals with PTSD and TBI-related headaches, common in military personnel from recent conflicts. Participants should have these conditions to qualify but the full inclusion and exclusion criteria are not provided here.

Inclusion Criteria

I am 18 years old or older.

My medication doses for TBI or PTSD have been stable for more than 2 weeks.

I have severe headaches or PTSD with specific test scores.

Exclusion Criteria

I do not have conditions like dementia or Parkinson's affecting my thinking.

I do not have active psychosis or unmanaged mental health conditions like bipolar disorder.

I do not have any health conditions that could worsen with treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either stellate ganglion block (SGB), ketamine infusion, or a combination treatment for PTSD and TBI-associated headaches

4 weeks

Weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at 8 and 12 weeks

8 weeks

Follow-up visits at 8 and 12 weeks

Observational Cohort

Participants with negative outcomes exit the study and are followed as an observational cohort, eligible for non-study measures

Ongoing

Treatment Details

Interventions

• Group C Experimental
• Ketamine
• Stellate Ganglion Block (SGB)

Trial Overview The study tests if a nerve block procedure (SGB) or ketamine medication, alone or combined, can relieve PTSD and headache symptoms from TBI. It's a randomized, double-blind, placebo-controlled trial across multiple centers.

Participant Groups

Group I: Group C = Stellate ganglion block (SGB) with bupivacaine LA plus ketamine infusion Experimental Treatment 1 Intervention

These patients will receive both SGB with bupivacaine + ketamine as described above.

Group II: Group A =Stellate ganglion block (SGB) with bupivacaine (LA) plus placebo ketamine (midazolam) Active Control 1 Intervention

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.

Group III: Group B = Sham SGB plus ketamine infusion Active Control 1 Intervention

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.

Group IV: Group D = Sham SGB plus placebo ketamine (midazolam) Placebo Group 1 Intervention

These patients will receive the sham SGB + placebo ketamine as described above.

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Walter Reed National Military Medical Center

Collaborator

Trials

149

Recruited

33,800+

Lviv National Medical University

Collaborator

Trials

9

Recruited

1,300+

Findings from Research

In a study using rat models of traumatic brain injury caused by maxillofacial impact, ketamine treatment significantly improved recovery time, with treated rats recovering about 2 days faster than the control group.

The results suggest that ketamine may be an effective intervention for enhancing recovery following traumatic brain injuries, indicating its potential therapeutic role in similar human injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Animal experiment of the ketamine effects on traumatic brain injury resulting from impact maxillofacial injury]. Zhang, C., Li, H., Liao, W., et al.[2013]

Ketamine can be safely used in patients with neurological impairments when administered under controlled conditions, as it does not increase intracranial pressure and may improve cerebral perfusion.

In addition to its safety profile, ketamine shows neuroprotective effects in laboratory settings, suggesting potential benefits for brain injury recovery, although caution is needed due to possible neurotoxic effects at high doses in certain animal studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Revising a dogma: ketamine for patients with neurological injury? Himmelseher, S., Durieux, ME.[2022]

Ketamine is a promising medication for managing sedation and pain in patients with traumatic brain injury (TBI), as it does not increase intracranial pressure and may even lower it.

Its favorable safety profile makes ketamine a reliable option for use in prehospital settings during the acute phase of TBI, although careful consideration of its benefits and potential drawbacks is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine in acute phase of severe traumatic brain injury "an old drug for new uses?" Godoy, DA., Badenes, R., Pelosi, P., et al.[2021]

Subcutaneous (SC) administration of racemic ketamine and esketamine has shown rapid and robust antidepressant effects in both unipolar and bipolar patients, with response and remission rates ranging from 50% to 100% after single or multiple doses.

The studies indicated that SC ketamine is generally well-tolerated, with only transitory side effects, making it a promising and cost-effective treatment option for depression, especially in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. Cavenaghi, VB., da Costa, LP., Lacerda, ALT., et al.[2021]

Grapefruit juice significantly increases the plasma levels of oral S-ketamine, with a 3-fold increase in the area under the plasma concentration-time curve and a 2.1-fold increase in peak plasma concentration, indicating a strong interaction that could affect dosing.

Due to the increased plasma concentrations, it is recommended that dose reductions of S-ketamine be considered when taken with grapefruit juice to avoid potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-ketamine concentrations are greatly increased by grapefruit juice. Peltoniemi, MA., Saari, TI., Hagelberg, NM., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

[Animal experiment of the ketamine effects on traumatic brain injury resulting from impact maxillofacial injury]. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy of combined subanesthetic ketamine infusion and cervical sympathetic blockade as a symptomatic treatment of PTSD/TBI in a special forces patient with a 1-year follow-up: A case report. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Ketamine decreases cerebral infarct volume and improves neurological outcome following experimental head trauma in rats. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Revising a dogma: ketamine for patients with neurological injury? [2022]

5. England pubmed.ncbi.nlm.nih.gov

Ketamine in acute phase of severe traumatic brain injury "an old drug for new uses?" [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

S-ketamine concentrations are greatly increased by grapefruit juice. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. [2016]

9. Germany pubmed.ncbi.nlm.nih.gov

Ketamine. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Ketogenic Diet as a potential treatment for traumatic brain injury in mice. [2022]

11. England pubmed.ncbi.nlm.nih.gov

The ketone ester, 3-hydroxybutyl-3-hydroxybutyrate, attenuates neurobehavioral deficits and improves neuropathology following controlled cortical impact in male rats. [2022]