Effects of Huperzine A in Treatment of Moderate to Severe TBI

Huperzine A for the Treatment of Cognitive, Mood, and Functional Deficits After Moderate and Severe TBI

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.

Study Overview

• Status: Terminated
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Huperzine A; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Spaulding Rehabilitation Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Huperzine A; Huperzine A will be administered for 12 weeks as outlined in the Arm Description; Other Names: huperzia serrata; chinese club moss
Placebo Comparator: Placebo; Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).	Drug: Placebo; Placebo Arm (blinded randomization) for Huperzine A Intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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: California Verbal Learning Test- 2nd Edition- Total Learning [CVLT-II-TL] (Minimum score=0; Maximum score= 80); California Verbal Learning Test- 2nd Edition- Short delay free recall [CVLT-II-SDFR] (Minimum score=0; Maximum score=16); 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).	Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks.

Secondary Outcome Measures

Outcome Measure	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.	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.

Collaborators and Investigators

• Sponsor: Spaulding Rehabilitation Hospital
• Investigators: Principal Investigator: Ross Zafonte, DO, Spaulding Rehabilitation Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2013
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: August 28, 2012
• First Submitted That Met QC Criteria: August 28, 2012
• First Posted (Estimate): August 30, 2012

Study Record Updates

• Last Update Posted (Actual): November 5, 2019
• Last Update Submitted That Met QC Criteria: October 22, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: cognition; seizures; transcranial magnetic stimulation; electroencephalography; huperzine; chinese club moss
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Neuroprotective Agents; Protective Agents; Cholinesterase Inhibitors; Huperzine A
• Other Study ID Numbers: 2012-p-002490