Huperzine A for the treatment of cognitive, mood, and functional deficits after moderate and severe TBI (HUP-TBI): results of a Phase II randomized controlled pilot study: implications for understanding the placebo effect

ABSTRACT

Objective: To investigate the effect of Huperzine A on memory and learning in individuals with moderate-severe traumatic brain injury (TBI).

Design: Randomized, double-blind, placebo-controlled Phase II clinical trial.

Methods: Subjects were randomly assigned to receive Huperzine A or placebo for 12 weeks and were assessed during in-person visits at screening/baseline, and 6, 12, 24, and 52 weeks post-injury. Changes in memory and learning scores on the California Verbal Learning Test – 2nd Edition (CVLT-II) from baseline to week 12 were assessed using permutation tests and regression analyses.

Results: There was no difference between the Huperzine A and placebo groups in memory performance after 12 weeks of treatment. In the placebo group, significant improvements were noted in learning and memory scores. Both groups showed clinically important improvements in depression on the Beck Depression Index.

Conclusions: The clinically important improvements in cognitive and emotional outcomes observed in both the placebo and active treatment arms of this clinical trial of Huperzine A are best understood in the context of a placebo effect. Future trials involving patients with moderate-severe TBI in the subacute to chronic phases of recovery should be designed to account for placebo effects as failure to do so may lead to spurious conclusions.

KEYWORDS:

• Traumatic brain injury
• Huperzine A
• cognitive dysfunction
• placebo effect

Declaration of interest statement

Dr Zafonte was partially supported by the National Institute on Disability, Independent Living, and Rehabilitation Research (90DP0039-03-00, 90SI5007-02-04,90 D P0060), the National Institutes of Health (4U01NS086090-04; 5R24HD082302-02; 5U01NS091951-03), and US Army Medical Research and Materiel Command (W81XWH-112-0210). He also serves as Co-PI on a T-32 and receives funding from the Football Players Health Study at Harvard University, which is funded by the NFL Players Association. Dr Zafonte received royalties from (1) Oakstone for an educational CD- Physical Medicine and Rehabilitation: a Comprehensive Review; (2) Demos publishing for serving as co-editor of the text Brain Injury Medicine. Dr Zafonte serves on the Scientific Advisory Board of Myomo, Oxeia Biopharma, and ElMINDA. He also evaluates patients in the MGH Brain and Body-TRUST Program which is funded by the NFL Players Association.

Dr Fregni reports grants from the National Institutes of Health (1R01AT009491-01A1, 5R01HD082302-03, 1R44AG055 360-01, 5R44AT008637-02).

Dr Giacino reports grants from the National Institute on Disability, Independent Living and Rehabilitation Research (90DP0039, 90DP0060), the National Institute on Neurological Disorders and Stroke (5U01NS086090, 1R01NS102574, 5UH3NS095554), the US Department of Defense (W81XWH-112-0210, W81XWH-15-9-001, W81XWH-14-2-0176), and the James S McDonnell Foundation and philanthropic support from the Barbara Epstein Foundation.

Additional information

Funding

The research reported in this article was supported by U.S. Department of Defense Army Medical Research and Materiel Command grant W81XWH-11-2-0210. The study sponsor had no role in the design and conduct of this study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.