Reviewed: Tian J, Shi J, Li T, et al. Efficacy and safety of an herbal therapy in patients with amnestic mild cognitive impairment: A 24-week randomized phase III trial. Evid Based Complement Alternat Med. 2017;2017:4251747. doi: 10.1155/2017/4251747.
Mild cognitive impairment (MCI) refers to a stage of cognitive impairment between what is expected with normal aging and the onset of Alzheimer’s disease (AD). Amnestic MCI (aMCI) is the most common subtype of MCI and is characterized by impairment of episodic memory without impairment of activities of daily living (ADL). Treating aMCI may prevent or delay the onset of AD. The purpose of this multicenter, randomized, double-blind, double-placebo, parallel-controlled, phase III study was to evaluate the efficacy and safety of a Chinese herbal formulation to improve cognition and memory in patients with aMCI.
Chinese-speaking adults (N = 324; 55-80 years of age) with MCI who were living in the community (as opposed to senior care facilities) were recruited from nine memory clinics in China from September 2008 to May 2010.
Included patients had memory complaints that were corroborated by an informant; abnormal memory function according to the Chinese version of the Adult Memory and Information Processing Battery (AMIPB) Logical Memory Delayed Story Recall (DSR) subtest; normal general cognition based on the Mini-Mental State Examination (MMSE); no or minimal impairments in ADL; scores of 12 or less on the Hamilton Depression Rating Scale (HAM-D) and 4 or less on the Hachinski Ischemic Score (HIS) scale; adequate vision and hearing; and no or mild medial temporal atrophy or hippocampal volume atrophy on a magnetic resonance imaging (MRI) scan. In addition, included patients were not significantly impaired cognitively or functionally according to the National Institute of Neurological Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association criteria for AD and met the criteria for stage 2-3 on the Global Deterioration Scale (GDS).
Patients were excluded if they had evidence of a focal brain lesion; a previous head injury with loss of consciousness or immediate confusion after the injury; a neurologic disease that might affect cognition; uncontrolled hypertension or diabetes mellitus; a history of significant cerebrovascular disease, a central nervous system infarct or infection, a major psychiatric disorder, or alcohol or substance abuse. Patients also were excluded if they had documented evidence of an active gastric or duodenal ulcer within the previous three months; active malignancy or prostate cancer within the preceding 24 months; or chronic or acute renal, hepatic, or metabolic disorder; among other criteria.
Following a two-week placebo run-in phase, patients had an MRI scan and then were randomly assigned to receive for 24 weeks either an herbal capsule (five capsules three times per day) and a placebo that was identical to donepezil tablets (Aricept; Eisai Inc.; Tokyo, Japan) (n = 216), or 5 mg per day donepezil and a placebo that was identical to the herbal capsules (n = 108).
The herbal capsule (shenwu capsule; North China Pharmaceutical Group Corporation; Hebei Province, China) contained 4.24% Asian ginseng (Panax ginseng, Araliaceae) root, 21.28% he shou wu (Polygonum multiflorum, Polygonaceae) tuber, 14.89% epimedium (Epimedium brevicornum, Berberidaceae) leaf, 14.89% Acorus tatarinowii (Acoraceae) rhizome, 14.90% Sichuan lovage (Ligusticum sinense, Apiaceae) rhizome, and 29.80% lobed kudzu vine (Pueraria spp., Fabaceae) root extracts.
Cognition was the primary outcome assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcomes measured memory with the DSR logical memory subtest. Assessments were made at screening and weeks 12 and 24. An additional evaluation was carried out at week 48, although with a limited number of participants (n = 23). The safety assessment included examinations of general physical vital signs (e.g., breathing, heart rate, and blood pressure), electrocardiography (ECG), laboratory testing, and documentation of adverse events (AEs).
A total of 44 patients discontinued treatment, with two patients in the herbal therapy group discontinuing due to AEs. Baseline demographics and characteristics (including MMSE, GDS, and HAM-D scores) were not significantly different between groups. Both groups had excellent compliance (herbal therapy: 92.6% and donepezil: 95.3%). ADAS-cog and DSR scores were significantly improved from baseline to week 24 in both treatment groups (P < .001), and there were no significant between-group differences in these scores at 24 weeks. The inferiority analysis showed that the herbal treatment was not inferior to donepezil. The herbal therapy produced an average 4.19-point improvement in ADAS-cog scores from baseline to week 24 (an improvement of at least 3.3 points is considered clinically significant). At week 48 (24 weeks after the treatment period ended), scores for both groups trended toward original baseline values. The rate of conversion from MCI to AD in 23 subjects (11 patients from the herbal therapy group and 12 patients from the donepezil group) was assessed at one site. At week 24, none of the patients converted to AD in either group.
AEs were reported by 18.1% of the herbal therapy group and 57.4% of the donepezil group. The most frequent AEs assessed as probably related to the herbal therapy were thirst (6.5%) and sore throat (4.2%). The herbal therapy group compared to the donepezil group had significantly lower rates of diarrhea (0% vs. 12.5%, respectively), nausea (2.1% vs. 16.7%), and insomnia or abnormal dreams (2.3% vs. 16.7%) (P < .05 for all). There were no significant changes in vital signs, physical examination findings, ECG status, or laboratory values.
The authors concluded that the herbal therapy was safe and has similar clinical benefits to donepezil with fewer AEs in patients with confirmed MCI. A limitation of the study is that there was no true placebo group. Although there was a positive control (donepezil), all patients knew that they were being treated with one of two active preparations, so a placebo response cannot be ruled out. Another limitation is that 24 weeks may not be long enough to see a long-term response in patients with MCI. Additional research is needed to identify the key bioactive constituents of these plants that may be responsible for the observed effects and confirm whether the herbal therapy delays the progression from MCI to dementia.
—Heather S. Oliff, PhD