Traumatic Brain Injury
Conditions
Keywords
cognition, seizures, electroencephalography, transcranial magnetic stimulation, huperzine, chinese club moss
Brief summary
We will explore the use of Huperzine A in patients who have sustained a moderate to severe Traumatic Brain Injury. We aim to determine whether Huperzine A, as compared with placebo, would have an effect on memory function after TBI. Additionally, we aim to determine whether use of Huperzine A in these patients can change brain activity (as indexed by EEG and Transcranial Magnetic Stimulation - TMS), and reduce prevalence/frequency of post-traumatic seizures. We also aim to evaluate the safety of Huperzine A in this population as compared with placebo.
Interventions
DRUGHuperzine A
Huperzine A will be administered for 12 weeks as outlined in the Arm Description
DRUGPlacebo
Placebo Arm (blinded randomization) for Huperzine A Intervention
Sponsors
Spaulding Rehabilitation Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males and females aged 18 to 65 * Moderate or severe TBI, based on admission Emergency Room GCS 3-12 * All subjects will be greater than 2 weeks, but no more than 1 year, after the qualifying TBI, and will be symptomatic at enrollment (i.e. all subjects will exhibit evidence of ongoing posttraumatic amnesia via the Galveston Orientation Amnesia test (GOAT), or score at least 1.5 SD below the mean for completion time on Part B of the Trail Making Test. * Agreement to undergo no changes in concomitant medications (including dietary supplements) or therapeutic interventions during the first 12 weeks of the study (that is, the 12 weeks of dosing with study drug), except where medically indicated. Stable concomitant drug regimen (greater than two weeks pre-enrollment without changes) * Normal swallowing * English-speaking (since not all of the outcome metrics are normed outside of the English language) * Patient can be on seizure medication.
Exclusion criteria
* Patients taking acetylcholinesterase inhibitors and other cholinergic and anticholinergic drugs (e.g., tacrine, physostigmine, velnacrine, donepezil, rivastigmine, metrifonate) and CYP1A inducing drugs. * Evidence of more than 1 seizure in the past 4 weeks prior to enrollment: Patients may not be enrolled if there is evidence of more than one seizure (clinical or electrographic, but not including epileptiform or other irritative discharges) during the 4 weeks prior to enrollment. * Premorbid history of epilepsy with seizure frequency \>1 per month: Patients with a history of idiopathic epilepsy may not be enrolled if their seizure frequency was \> 1 per month in the 3 months prior to injury. If pre-injury seizure frequency was \< 1 per month but there is documented evidence that post-injury seizure frequency is \> 1 per month or there is documented evidence of an increase in the severity or duration of a single seizure relative to the premorbid history, the patient must be excluded. * Evidence of premorbid major CNS disorder, developmental disorder, psychiatric disorder or substance abuse: Prior to sustaining TBI, patient was diagnosed and/or treated for a major neurologic condition, pervasive developmental disorder (e.g., mental retardation, autism), psychiatric disorder or substance abuse that continued to produce functional disability up to the time of injury. * Individuals with disorders of consciousness, as defined at the time of screening of having vegetative and/or minimally conscious state, will not be enrolled. However, these patients may be followed until they: * Meet eligibility criteria * Are more than 12 weeks post injury * Are discharged * Pregnancy, as determined by urine hCG testing before randomization * Breast feeding females * Significant hematologic, renal or hepatic dysfunction \[Hepatic/renal dysfunction is generally identified as lab results \> two times the upper limits of normal (ULN), and hematologic dysfunction is determined by clinically significant abnormal lab results\], on baseline laboratory examination. * Slow heart rate (bradycardia) or other heart conditions related to rate * History of peptic ulcer disease * History of asthma or emphysema * History of GI/urinary tract blockages (i.e. ileus, IBS) * History of glaucoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks. | Measure of learning and memory function. Three indices of the CVLT-II were calculated. The full name, abbreviated name, and the minimum and maximum possible scores of each index are indicated below: 1. California Verbal Learning Test- 2nd Edition- Total Learning \[CVLT-II-TL\] (Minimum score=0; Maximum score= 80) 2. California Verbal Learning Test- 2nd Edition- Short delay free recall \[CVLT-II-SDFR\] (Minimum score=0; Maximum score=16) 3. California Verbal Learning Test- 2nd Edition- Long delay free recall \[CVLT-II-LDFR\] (Minimum score=0; Maximum score=16) High scores are indicative of greater memory and learning for each index (i.e. better outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amplitude of Event Related Potentials (ERPs) P50 and P300 | Baseline, 12 Weeks | Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit. P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks. |
| Latency of Event Related Potentials (ERPs) P50 and P300 | Baseline, 12 weeks | Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit and P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks. |
| Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window | Baseline and weekly for 12 weeks. | To determine whether Huperzine A changes the prevalence of post-traumatic seizure after moderate and severe TBI as compared to placebo at 12 weeks post-enrollment (immediate seizures prevalence). |
| Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Baseline and weekly for 12 weeks. | To evaluate the safety and tolerability of Huperzine A in this patient population as compared to placebo the frequency of self-reported side effects during the 12-week treatment window were grouped categorically by system (behavioral, cardiac-respiratory, dermatological,gastrointestinal, genitourinary/neurological, hematological, musculoskeletal, neurological). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Huperzine A Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description | 7 |
| Placebo Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention | 7 |
| Total | 14 |
Baseline characteristics
| Characteristic | Huperzine A | Total | Placebo |
|---|---|---|---|
| Admission status Inpatient | 1 Participants | 5 Participants | 4 Participants |
| Admission status Outpatient | 6 Participants | 9 Participants | 3 Participants |
| Age, Continuous | 37.00 years STANDARD_DEVIATION 16.21 | 37.79 years STANDARD_DEVIATION 15.78 | 38.57 years STANDARD_DEVIATION 16.6 |
| Days post-injury | 155.40 days STANDARD_DEVIATION 130.27 | 197.08 days STANDARD_DEVIATION 124.17 | 226.86 days STANDARD_DEVIATION 120.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 7 participants | 14 participants | 7 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 |
| other Total, other adverse events | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 2 / 7 | 1 / 6 |
Outcome results
Primary
California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory
Measure of learning and memory function. Three indices of the CVLT-II were calculated. The full name, abbreviated name, and the minimum and maximum possible scores of each index are indicated below: 1. California Verbal Learning Test- 2nd Edition- Total Learning \[CVLT-II-TL\] (Minimum score=0; Maximum score= 80) 2. California Verbal Learning Test- 2nd Edition- Short delay free recall \[CVLT-II-SDFR\] (Minimum score=0; Maximum score=16) 3. California Verbal Learning Test- 2nd Edition- Long delay free recall \[CVLT-II-LDFR\] (Minimum score=0; Maximum score=16) High scores are indicative of greater memory and learning for each index (i.e. better outcome).
Time frame: Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Baseline | 5.00 score on a scale | Standard Deviation 4.8 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Baseline | 28.57 score on a scale | Standard Deviation 12.35 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 6 | 31.43 score on a scale | Standard Deviation 11.37 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 12 | 38.29 score on a scale | Standard Deviation 14.2 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 24 | 33.29 score on a scale | Standard Deviation 14.29 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 52 | 37.43 score on a scale | Standard Deviation 11.3 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Baseline | 3.86 score on a scale | Standard Deviation 4.38 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 6 | 4.14 score on a scale | Standard Deviation 3.53 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 12 | 6.29 score on a scale | Standard Deviation 4.99 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 24 | 4.86 score on a scale | Standard Deviation 4.45 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 52 | 5.43 score on a scale | Standard Deviation 3.36 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 6 | 4.43 score on a scale | Standard Deviation 4.39 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 12 | 6.00 score on a scale | Standard Deviation 4.76 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 24 | 4.29 score on a scale | Standard Deviation 4.46 |
| Huperzine A | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 52 | 6.14 score on a scale | Standard Deviation 4.67 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 6 | 8.33 score on a scale | Standard Deviation 4.08 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 12 | 10.40 score on a scale | Standard Deviation 5.46 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Baseline | 34.40 score on a scale | Standard Deviation 18.73 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 24 | 8.40 score on a scale | Standard Deviation 4.67 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 6 | 45.00 score on a scale | Standard Deviation 17.65 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 24 | 10.00 score on a scale | Standard Deviation 4.24 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 12 | 49.60 score on a scale | Standard Deviation 18.27 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 12 | 10.00 score on a scale | Standard Deviation 5.96 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 24 | 44.60 score on a scale | Standard Deviation 14.12 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 52 | 9.80 score on a scale | Standard Deviation 5.5 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-TL - Week 52 | 49.40 score on a scale | Standard Deviation 15 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Baseline | 7.00 score on a scale | Standard Deviation 5.7 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Baseline | 5.80 score on a scale | Standard Deviation 4.66 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-LDFR - Week 52 | 10.00 score on a scale | Standard Deviation 4.74 |
| Placebo | California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory | CVLT-II-SDFR - Week 6 | 7.83 score on a scale | Standard Deviation 4.12 |
Comparison: Regression analysis was run incorporating group, CVLT-II-total learning score at baseline and week 12, and covariates (Beck Depression Index \[BDI\], time post-injury, British Columbia Postconcussion Symptom Inventory \[BC-PSI\]). Regression analyses were repeated, permuting data observations for each outcome. The BDI and BC-PSI are covariates in the regression model and not pre-specified Primary and Secondary Outcome Measures.p-value: 0.38Regression, Linear
Comparison: Regression analysis was run incorporating group (Huperzine A, placebo), baseline CVLT-II-short delay free recall (SDFR) score, outcome (CVLT-II-SDFR at week 12) and covariates (Beck Depression Index, time post-injury, British Columbia Postconcussion Symptom Inventory). Regression analyses were repeated, permuting data observations for each outcome i.e. we permuted the labels (Huperzine A or placebo) among the data observations and re-ran the regression.p-value: 0.38Regression, Linear
Comparison: Regression analysis was run incorporating group (Huperzine A, placebo), baseline CVLT-II-long delay free recall (LDFR) score, outcome (CVLT-II-LDFR at week 12) and covariates (Beck Depression Index, time post-injury, British Columbia Postconcussion Symptom Inventory). Regression analyses were repeated, permuting data observations for each outcome i.e. we permuted the labels (Huperzine A or placebo) among the data observations and re-ran the regression.p-value: 0.42Regression, Linear
Secondary
Amplitude of Event Related Potentials (ERPs) P50 and P300
Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit. P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.
Time frame: Baseline, 12 Weeks
Population: Of the 12 participants who completed the 12-week treatment period, P50 and P500 amplitude data could be analyzed for 4 participants. Data for the other 8 participants could not be analyzed as the data were compromised by movement artifact during recording.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Huperzine A | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P300 Amplitude - Baseline | 13.57 mV |
| Huperzine A | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P300 Amplitude - Week 12 | 12.69 mV |
| Huperzine A | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P50 Amplitude - Baseline | 7.89 mV |
| Huperzine A | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P50 Amplitude - Week 12 | 5.89 mV |
| Placebo | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P50 Amplitude - Week 12 | NA mV |
| Placebo | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P300 Amplitude - Baseline | 9.96 mV |
| Placebo | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P50 Amplitude - Baseline | NA mV |
| Placebo | Amplitude of Event Related Potentials (ERPs) P50 and P300 | P300 Amplitude - Week 12 | 9.69 mV |
Secondary
Latency of Event Related Potentials (ERPs) P50 and P300
Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit and P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.
Time frame: Baseline, 12 weeks
Population: Of the 12 participants who completed the 12-week treatment period, P50 and P500 latency data could be analyzed for 3 participants. Data for the other 9 participants could not be analyzed as the data were compromised by movement artifact during recording.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Huperzine A | Latency of Event Related Potentials (ERPs) P50 and P300 | P300 Latency - Baseline | 309 ms |
| Huperzine A | Latency of Event Related Potentials (ERPs) P50 and P300 | P300 Latency - Week 12 | 311 ms |
| Huperzine A | Latency of Event Related Potentials (ERPs) P50 and P300 | P50 Latency - Baseline | 50 ms |
| Huperzine A | Latency of Event Related Potentials (ERPs) P50 and P300 | P50 Latency - Week 12 | 49 ms |
Secondary
Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window
To determine whether Huperzine A changes the prevalence of post-traumatic seizure after moderate and severe TBI as compared to placebo at 12 weeks post-enrollment (immediate seizures prevalence).
Time frame: Baseline and weekly for 12 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Huperzine A | Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window | 2 Participants |
| Placebo | Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window | 1 Participants |
p-value: 0.48Chi-squared test and permutation test
Secondary
Number of Participants With Self-reported Side Effects During 12-week Treatment Window
To evaluate the safety and tolerability of Huperzine A in this patient population as compared to placebo the frequency of self-reported side effects during the 12-week treatment window were grouped categorically by system (behavioral, cardiac-respiratory, dermatological,gastrointestinal, genitourinary/neurological, hematological, musculoskeletal, neurological).
Time frame: Baseline and weekly for 12 weeks.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Neurological side effects | 7 Participants |
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Behavioral side effects | 5 Participants |
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Cardiac-respiratory side effects | 6 Participants |
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Dematological side effects | 2 Participants |
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Gastrointestinal side effects | 3 Participants |
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Genitourinary/neurological side effects | 1 Participants |
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Hematological side effects | 6 Participants |
| Huperzine A | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Musculoskeletal side effects | 3 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Musculoskeletal side effects | 2 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Neurological side effects | 5 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Gastrointestinal side effects | 1 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Behavioral side effects | 4 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Hematological side effects | 6 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Cardiac-respiratory side effects | 4 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Genitourinary/neurological side effects | 1 Participants |
| Placebo | Number of Participants With Self-reported Side Effects During 12-week Treatment Window | Dematological side effects | 0 Participants |
Comparison: Behavioral side effects statistical analysisp-value: 0.44Chi-squared test and permutation test
Comparison: Cardiac-respiratory side effects statistical analysisp-value: 0.81Chi-squared test and permutation test
Comparison: Dermatological side effects statistical analysisp-value: 0.81Chi-squared test and permutation test
Comparison: Gastrointestinal side effects statistical analysisp-value: 0.73Chi-squared test and permutation test
Comparison: Genitourinary/neurological side effects statistical analysisp-value: 0.54Chi-squared test and permutation test
Comparison: Hematological side effects statistical analysisp-value: 0.27Chi-squared test and permutation test
Comparison: Musculoskeletal side effects statistical analysisp-value: 0.41Chi-squared test and permutation test
Comparison: Neurological side effects statistical analysisp-value: 1Chi-squared test and permutation test