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Insufficient accrual rate: 14 participants enrolled (target of 30).
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Huperzine A | Experimental | 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. |
|
| Placebo | Placebo Comparator | Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Huperzine A | Drug | Huperzine A will be administered for 12 weeks as outlined in the Arm Description |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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:
High scores are indicative of greater memory and learning for each index (i.e. better outcome). | Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
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:
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
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| Name | Affiliation | Role |
|---|---|---|
| Ross Zafonte, DO | Spaulding Rehabilitation Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Spaulding Rehabilitation Hospital | Charlestown | Massachusetts | 02129 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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:
High scores are indicative of greater memory and learning for each index (i.e. better outcome). | Posted | Mean | Standard Deviation | score on a scale | Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks. |
|
Telephone: Weekly from baseline to 12 weeks (active treatment phase). In-person follow-up visits: Baseline, 6, 12, 13, 24, and 52 weeks. Subjects were instructed to call the Study Coordinator if a serious adverse event occurred between scheduled telephone or in-person follow-ups.
Adverse events were collected and recorded using a standard adverse event form that included 35 possible adverse events. For 'Adverse Events', 'Serious Adverse Events', and 'Other (Not Including Serious) Adverse Events', results are reported for all participants who were 'at risk' i.e. received Huperzine A or placebo and completed at least one telephone or in-person follow-up visit (Huperzine A group: 7 participants; Placebo group: 6 participants).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure | Nervous system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anxiety | Psychiatric disorders | Systematic Assessment |
Enrollment - not able to enroll target N, therefore small number of subjects analyzed.
Neurophysiologic measures - difficulty collecting data from subjects for several reasons.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ross Zafonte, DO | Spaulding Rehabilitation Hospital | 617-952-5227 | rzafonte@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 11, 2019 | Jul 22, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000070642 | Brain Injuries, Traumatic |
| D012640 | Seizures |
| ID | Term |
|---|---|
| D001930 | Brain Injuries |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C050426 | huperzine A |
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| Placebo | Drug | Placebo Arm (blinded randomization) for Huperzine A Intervention |
|
| Baseline, 12 Weeks |
| 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. | Baseline, 12 weeks |
| 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). | Baseline and weekly for 12 weeks. |
| 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). | Baseline and weekly for 12 weeks. |
| BG001 |
| 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 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Admission status | Count of Participants | Participants |
|
| Days post-injury | Mean | Standard Deviation | days |
|
| OG001 | 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 |
|
|
|
| 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. | 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. | Posted | Median | Inter-Quartile Range | mV | Baseline, 12 Weeks |
|
|
|
| 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. | 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. | Posted | Median | Inter-Quartile Range | ms | Baseline, 12 weeks |
|
|
|
| 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). | Posted | Count of Participants | Participants | Baseline and weekly for 12 weeks. |
|
|
|
|
| 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). | Posted | Count of Participants | Participants | Baseline and weekly for 12 weeks. |
|
|
|
|
| 0 |
| 7 |
| 2 |
| 7 |
| 7 |
| 7 |
| EG001 | 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 | 0 | 6 | 1 | 6 | 6 | 6 |
| Irritability | Psychiatric disorders | Systematic Assessment |
|
| Depression | Psychiatric disorders | Systematic Assessment |
|
| Difficulty breathing | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Increased blood pressure | General disorders | Systematic Assessment |
|
| Decrease in heart rate | General disorders | Systematic Assessment |
|
| Skin rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Loss of appetite | Gastrointestinal disorders | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Increased saliva production | Gastrointestinal disorders | Systematic Assessment |
|
| Incontinence | Renal and urinary disorders | Systematic Assessment |
|
| Low white blood cell count | Blood and lymphatic system disorders | Systematic Assessment |
|
| Muscle cramps | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Muscle twitching | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Difficulty sleeping | General disorders | Systematic Assessment |
|
| Confusion | Nervous system disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Thinking abnormalities | Nervous system disorders | Systematic Assessment |
|
| Weakness | Nervous system disorders | Systematic Assessment |
|
| Slurred speech | Nervous system disorders | Systematic Assessment |
|
| Abnormal vision | Eye disorders | Systematic Assessment |
|
| Light sensitivity | Nervous system disorders | Systematic Assessment |
|
| Increased uncontrolled movement | Nervous system disorders | Systematic Assessment |
|
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| D006259 |
| Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| P50 Amplitude - Baseline |
|
| P50 Amplitude - Week 12 |
|
| Title | Measurements |
|---|---|
|
| P50 Latency - Week 12 |
|
| Dematological side effects |
|
| Gastrointestinal side effects |
|
| Genitourinary/neurological side effects |
|
| Hematological side effects |
|
| Musculoskeletal side effects |
|
| Neurological side effects |
|
Cardiac-respiratory side effects statistical analysis |
| Chi-squared test and permutation test |
| 0.81 |
A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of cardiac-respiratory side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects. |
| Superiority |
| Dermatological side effects statistical analysis | Chi-squared test and permutation test | 0.81 | A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of dermatological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of dermatological side effects. | Superiority |
| Gastrointestinal side effects statistical analysis | Chi-squared test and permutation test | 0.73 | A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of gastrointestinal side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects. | Superiority |
| Genitourinary/neurological side effects statistical analysis | Chi-squared test and permutation test | 0.54 | A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of genitourinary/neurological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects | Superiority |
| Hematological side effects statistical analysis | Chi-squared test and permutation test | 0.27 | A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of hematological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects. | Superiority |
| Musculoskeletal side effects statistical analysis | Chi-squared test and permutation test | 0.41 | A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of musculoskeletal side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects. | Superiority |
| Neurological side effects statistical analysis | Chi-squared test and permutation test | 1.00 | A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of neurological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects. | Superiority |