PTSD
Conditions
Keywords
PTSD, TBI, Riluzole, Rilutek, augmentation, supplement, double blinded, clinical trial, placebo, RCT, Randomized Control Trial
Brief summary
The purpose of this study is to determine whether Riluzole is effective in the augmentation treatment of post-traumatic stress disorder (PTSD) that is experienced by Active Duty military service members and Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) veterans who have not had symptom reduction after one or more kinds of medications or therapies.
Detailed description
Riluzole is a glutamatergic modulator that inhibits glutamate release and enhances AMPA trafficking and clearance of excessive synaptic glutamate resulting in neuroprotective properties. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis (ALS) and has been found to have antidepressant and anxiolytic properties in animals and in humans (Zarate et al., 2004). Posttraumatic stress disorder (PTSD) is a chronic and seriously debilitating anxiety disorder that develops following exposure to severe trauma, such as combat exposure. Structural magnetic resonance imaging has been used to measure the volume of crucial structures implicated in the pathophysiology of PTSD, with several morphometric studies confirming smaller hippocampal volume in PTSD patients. Current pharmacological treatment for PTSD, and particularly combat-related PTSD, is suboptimal. Drugs that alter neuronal survival pathways through reduction of glutamate activity may play a role in reversing the loss of neuronal integrity and possible focal atrophy in regions of the brain implicated in the pathophysiology of PTSD, potentially improving the symptoms of PTSD, as well as TBI. This study will evaluate the efficacy of acute riluzole treatment in active duty and Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), and Operation New Dawn (OND) veterans with PTSD, with or without mild TBI (mTBI), who are sub-optimally responsive to other medication treatments. A total of 158 active duty and OIF, OEF and OND veterans, aged 18 to 65 will be enrolled from WRNMMC and the Syracuse VA Medical Center to participate in this 8-week randomized, double- blind, placebo-controlled, parallel study. Patients who are suboptimal responders to their current psychotropic drugs will continue these at stable dosage for at least 2 weeks prior to randomization during the screening period. We hypothesize that those subjects with PTSD, with or without mTBI, who are only partially responsive to initial therapy and are subsequently randomized to augmentation therapy with Riluzole (100-200mg/day) will have a superior response rate compared to those subjects randomized to placebo.
Interventions
DRUGRiluzole
DRUGPlacebo (for Riluzole)
Sponsors
U.S. Army Medical Research and Development Command
Uniformed Services University of the Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Active-duty service member or an Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), or Operation New Dawn (OND) veteran. * Clinical diagnosis of PTSD and have not achieved remission with an adequate trial of medication treatment (8 weeks) as indicated by self-report at referral and confirmed by baseline CAPS score of greater than or = to 40 after informed consent is obtained.
Exclusion criteria
1. Female subjects of childbearing capacity who test positively for ß-HCG, or are either self-reporting as pregnant, planning to become pregnant, or nursing. 2. Presence of psychotic features. 3. Unable to provide informed consent or comply with study procedures. 4. Previous treatment with riluzole. 5. Serious, unstable illnesses including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, hematologic disease, or HIV. This includes individuals with a history of COPD by diagnosis as well as persons taking inhalers for Asthma or Reactive Airway Disease. 6. Clinically significant abnormal levels (3x ULN or greater) of serum transaminases (ALT/SGPT; AST/SGOT), current or past blood dyscrasia. 7. Subjects with uncorrected hypothyroidism or hyperthyroidism. 8. DSM-IV alcohol or substance abuse or dependence within 90 days of the screening visit. 9. Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 week, or any change in fluoxetine dosing within 8 weeks prior to visit 2. Use of antidepressant and sedative/hypnotic drugs at stable dose is permitted. 10. Documented history of hypersensitivity or intolerance to riluzole. 11. Subjects with a current or past history of other axis I disorders including schizophrenia, schizoaffective disorder, bipolar disorder or dementia. However, those with a co-morbid history of other Axis I disorder like major depression, dysthymia or other anxiety disorders will be included; the justification for this is that approximately 70% of subjects with PTSD have co-morbid depression and or alcohol abuse, and restricting the sample to PTSD patients without depression will not accurately reflect the scope of this disorder. 12. Patients who are currently at high risk for homicide or suicide, as indicated by an affirmative answer to the question: In the last three months, have you attempted to kill yourself, made specific plans to kill yourself, or had the intention to kill yourself? 13. Current or planned litigation regarding the traumatic event. 14. Patients who recently started trauma focused cognitive behavioral psychotherapy (Patient's underlying educational or supportive individual or group therapy will be included). 15. Patient's actively enrolled in an evidence based psychotherapy treatment (e.g., Cognitive Processing Therapy or Prolonged Exposure Therapy) will be excluded until that therapy has concluded, but may be re-approached at that time if patient self-report or clinician referral suggests persistent PTSD symptoms upon conclusion of that treatment. 16. Subjects with an artificial cardiac pacemaker or metallic implants within their body will be enrolled at WRNMMC for the placebo-control clinical trial portion of the study only. These individuals, due to their pre-existing medical condition, are medically ineligible to participate in the 1H MRS imaging portion of the study. Further, the Magnetic Resonance (MRI) Screening Form is use at WRNMMC will be used for participant screening prior to any imaging procedures. 17. Use of benzodiazepines.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinician Administered PTSD Scale (CAPS) Score | Week 1 and 8 | CAPS is a 30-item structured interview that can be used to make current (past month) diagnoses of PTSD, make lifetime diagnoses of PTSD, and assess PTSD symptoms over the past week. A summed score of 17 items: Minimum Score: 0 (no symptoms) Maximum Score: 136 (very severe symptoms) Subscales: Subscale B (re-experiencing): items 1-5, a score of 0-40. Subscale C (avoidance): items 6-12, a score of 0-56. Subscale D (hyperarousal): items 13-17, a score of 0-40. CAPS scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PTSD Check List Specific (PCL-S) | Week 1 and 8 | A 17-item self-report measure used to assess PTSD symptoms related to a specific traumatic event. Scoring: A sum of all 17 items. Minimum: 17 (no symptoms) Maximum: 85 (very severe symptoms) PCL-S scores were measured at every study visit. For outcome analyses, differences between pre-treatment and post-treatment scores were used. |
| Montgomery-Åsberg Depression Rating Scale (MADRS) Score | Week 1 and 8 | A ten-item diagnostic questionnaire to measure the severity of depressive episodes. Scoring: A sum of all 10 items. Minimum: 0 (no symptoms) Maximum: 60 (very severe symptoms) MADRS scores were measured at every study visit. For outcome analyses, differences between pre-treatment and post-treatment scores were used. |
| Hamilton Anxiety Rating Scale (HAM-A) | Week 1 and 8 | A 14-item clinician-administered assessment measuring anxiety symptoms. Scoring: A sum of all 14 items. Minimum: 0 (no symptoms) Maximum: 56 (very severe symptoms) HAM-A scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used. |
| Clinician Administered PTSD Subscale D (CAPS-D) | Week 1 and 8 | Subscale D (items 13-17 on the CAPS-IV) measures Hyperarousal symptoms of PTSD Scoring: A sum of items 13-17. Minimum: 0 (no symptoms) Maximum: 40 (very severe symptoms) CAPS-D scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used. |
| PTSD Checklist - D (PCL-D) | Week 1 and week 8 | The subscale D (items 13-17 on the PCL) measures hyperarousal symptoms of PTSD. Scoring: A sum of items 13 to 17. Minimum: 5 (no symptoms) Maximum: 25 (very severe symptoms) PCL-D scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used. |
| Sheehan Disability Scale (SDS) Score | Week 1 and 8 | A 3-item self-report measure to assess functional impairment in work/school, social, and family life. Scoring: A sum of all 3 items. Minimum: 0 (no symptoms) Maximum: 30 (very severe symptoms) SDS scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used. |
Other
| Measure | Time frame | Description |
|---|---|---|
| NAA/Cr Ratio | Measured at study start (Week 0) for baseline and measured at study completion (Week 8) | The N-acetyl aspartate to creatine ratio (NAA/Cr) in the hippocampus and anterior cingulate, measured using magnetic resonance spectroscopy (1H MRS), will be evaluated for change after 8-week treatment with riluzole. |
Countries
United States
Participant flow
Recruitment details
Recruitment from WRNMMC = Walter Reed National Military Medical Center ; SVAMC = Syracuse Veterans Administration Medical Center
Participants by arm
| Arm | Count |
|---|---|
| Riluzole Weeks 1 and 2: Riluzole 50 mg tablet by mouth every 12 hours (100 mg/day) for 2-weeks
Weeks 3 to 8 (optional dose increase): 2 Riluzole 50 mg tablets by mouth every 12 hours (200 mg/day) for 6-weeks
Riluzole | 36 |
| Placebo Weeks 1 and 2: Placebo 50 mg tablet by mouth every 12 hours (100 mg/day) for 2-weeks
Weeks 3 to 8 (optional dose increase): 2 Placebo 50 mg tablets by mouth every 12 hours (200 mg/day) for 6-weeks
Placebo (for Riluzole) | 38 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Riluzole | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 37.4 years STANDARD_DEVIATION 8.9 | 38.1 years STANDARD_DEVIATION 8.2 | 37.8 years STANDARD_DEVIATION 8.5 |
| Clinician Administered PTSD Scale - IV | 70.6 units on a scale STANDARD_DEVIATION 19.8 | 62.4 units on a scale STANDARD_DEVIATION 16.9 | 66.4 units on a scale STANDARD_DEVIATION 18.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 3 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 33 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) White | 26 Participants | 25 Participants | 51 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Male | 31 Participants | 32 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 38 |
| other Total, other adverse events | 2 / 37 | 0 / 38 |
| serious Total, serious adverse events | 0 / 37 | 0 / 38 |
Outcome results
Primary
Clinician Administered PTSD Scale (CAPS) Score
CAPS is a 30-item structured interview that can be used to make current (past month) diagnoses of PTSD, make lifetime diagnoses of PTSD, and assess PTSD symptoms over the past week. A summed score of 17 items: Minimum Score: 0 (no symptoms) Maximum Score: 136 (very severe symptoms) Subscales: Subscale B (re-experiencing): items 1-5, a score of 0-40. Subscale C (avoidance): items 6-12, a score of 0-56. Subscale D (hyperarousal): items 13-17, a score of 0-40. CAPS scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used.
Time frame: Week 1 and 8
Population: One participant failed to meet minimum Clinician-Administered PTSD Scale IV (CAPS-IV) score for inclusion at phase 2 baseline and was excluded from intent-to treat (ITT) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | Clinician Administered PTSD Scale (CAPS) Score | -21.1 score on a scale | Standard Deviation 18.9 |
| Placebo | Clinician Administered PTSD Scale (CAPS) Score | -16.7 score on a scale | Standard Deviation 17.2 |
p-value: 0.442ANCOVA
Secondary
Clinician Administered PTSD Subscale D (CAPS-D)
Subscale D (items 13-17 on the CAPS-IV) measures Hyperarousal symptoms of PTSD Scoring: A sum of items 13-17. Minimum: 0 (no symptoms) Maximum: 40 (very severe symptoms) CAPS-D scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used.
Time frame: Week 1 and 8
Population: One participant failed to meet minimum Clinician-Administered PTSD Scale IV (CAPS-IV) score for inclusion at phase 2 baseline and was excluded from intent-to treat (ITT) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | Clinician Administered PTSD Subscale D (CAPS-D) | -6.8 score on a scale | Standard Deviation 8.2 |
| Placebo | Clinician Administered PTSD Subscale D (CAPS-D) | -3.7 score on a scale | Standard Deviation 7.3 |
p-value: 0.057ANCOVA
Secondary
Hamilton Anxiety Rating Scale (HAM-A)
A 14-item clinician-administered assessment measuring anxiety symptoms. Scoring: A sum of all 14 items. Minimum: 0 (no symptoms) Maximum: 56 (very severe symptoms) HAM-A scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used.
Time frame: Week 1 and 8
Population: One participant failed to meet minimum Clinician-Administered PTSD Scale IV (CAPS-IV) score for inclusion at phase 2 baseline and was excluded from intent-to treat (ITT) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | Hamilton Anxiety Rating Scale (HAM-A) | -7.8 score on a scale | Standard Deviation 7.4 |
| Placebo | Hamilton Anxiety Rating Scale (HAM-A) | -6.7 score on a scale | Standard Deviation 6.9 |
p-value: 0.913ANCOVA
Secondary
Montgomery-Åsberg Depression Rating Scale (MADRS) Score
A ten-item diagnostic questionnaire to measure the severity of depressive episodes. Scoring: A sum of all 10 items. Minimum: 0 (no symptoms) Maximum: 60 (very severe symptoms) MADRS scores were measured at every study visit. For outcome analyses, differences between pre-treatment and post-treatment scores were used.
Time frame: Week 1 and 8
Population: One participant failed to meet minimum Clinician-Administered PTSD Scale IV (CAPS-IV) score for inclusion at phase 2 baseline and was excluded from intent-to treat (ITT) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | Montgomery-Åsberg Depression Rating Scale (MADRS) Score | -7.9 score on a scale | Standard Deviation 7.6 |
| Placebo | Montgomery-Åsberg Depression Rating Scale (MADRS) Score | -8.2 score on a scale | Standard Deviation 9.6 |
p-value: 0.684ANCOVA
Secondary
PTSD Checklist - D (PCL-D)
The subscale D (items 13-17 on the PCL) measures hyperarousal symptoms of PTSD. Scoring: A sum of items 13 to 17. Minimum: 5 (no symptoms) Maximum: 25 (very severe symptoms) PCL-D scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used.
Time frame: Week 1 and week 8
Population: One participant failed to meet minimum Clinician-Administered PTSD Scale IV (CAPS-IV) score for inclusion at phase 2 baseline and was excluded from intent-to treat (ITT) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | PTSD Checklist - D (PCL-D) | -5.9 score on a scale | Standard Deviation 5.6 |
| Placebo | PTSD Checklist - D (PCL-D) | -3.4 score on a scale | Standard Deviation 4.9 |
p-value: 0.0496ANCOVA
Secondary
PTSD Check List Specific (PCL-S)
A 17-item self-report measure used to assess PTSD symptoms related to a specific traumatic event. Scoring: A sum of all 17 items. Minimum: 17 (no symptoms) Maximum: 85 (very severe symptoms) PCL-S scores were measured at every study visit. For outcome analyses, differences between pre-treatment and post-treatment scores were used.
Time frame: Week 1 and 8
Population: One participant failed to meet minimum Clinician-Administered PTSD Scale IV (CAPS-IV) score for inclusion at phase 2 baseline and was excluded from intent-to treat (ITT) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | PTSD Check List Specific (PCL-S) | -15.4 score on a scale | Standard Deviation 13.5 |
| Placebo | PTSD Check List Specific (PCL-S) | -14.5 score on a scale | Standard Deviation 11.4 |
p-value: 0.994ANCOVA
Secondary
Sheehan Disability Scale (SDS) Score
A 3-item self-report measure to assess functional impairment in work/school, social, and family life. Scoring: A sum of all 3 items. Minimum: 0 (no symptoms) Maximum: 30 (very severe symptoms) SDS scores were measured at baseline, mid-treatment, and post-treatment. For outcome analyses, differences between pre-treatment and post-treatment scores were used.
Time frame: Week 1 and 8
Population: One participant failed to meet minimum Clinician-Administered PTSD Scale IV (CAPS-IV) score for inclusion at phase 2 baseline and was excluded from intent-to treat (ITT) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | Sheehan Disability Scale (SDS) Score | -6.3 score on a scale | Standard Deviation 6.8 |
| Placebo | Sheehan Disability Scale (SDS) Score | -5.7 score on a scale | Standard Deviation 5.9 |
p-value: 0.746ANCOVA
Other Pre-specified
NAA/Cr Ratio
The N-acetyl aspartate to creatine ratio (NAA/Cr) in the hippocampus and anterior cingulate, measured using magnetic resonance spectroscopy (1H MRS), will be evaluated for change after 8-week treatment with riluzole.
Time frame: Measured at study start (Week 0) for baseline and measured at study completion (Week 8)