Effects of Huperzine A in Treatment of Moderate to Severe TBI

Phase 2

Terminated

Conditions: Traumatic Brain Injury

Interventions: Drug: Placebo
Drug: Huperzine A

Registration Number: NCT01676311

Lead Sponsor: Spaulding Rehabilitation Hospital

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).
Huperzine A	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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).