Hekun Decoction versus Femoston for women with amnestic mild cognitive impairment in early menopause: a randomized, three-arm, double-blind clinical trial

Guangyao Lin¹Ziqi Zhai¹思儒 陈¹Huicong Liu¹Rui Yuan²Xianwei Gao¹Xiaorong Ni³Mingjie Shen³Haiying Fan³Wenjun Wang⁴Yan Zhao⁵Yan Wu⁵Chao Gu¹Chao Cong¹Shan Xiao¹Yue Zhang¹Jingchang Zhao¹Jiayao Xu²Ye Wang⁵Jie Chen³Yishuang Chen¹Yan Zong¹Qianjue Tang¹Shengnan Li^1*Zhijie Zhang^2*Lianwei Xu^1*

• ¹Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
• ²Fudan University, Shanghai, Shanghai Municipality, China
• ³Shanghai University of Traditional Chinese Medicine, Shanghai, Shanghai Municipality, China
• ⁴Obstetrics and Gynecology Hospital, Fudan University, Shanghai, Shanghai Municipality, China
• ⁵Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China

Background: Amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer's disease (AD), carries a high risk of progression to dementia. However, few clinical trials have focused on interventions to delay this progression. Hekun Decoction, an herbal-based oral medicine, has shown potential in improving memory loss during early menopause. Here we performed a randomized controlled trial to evaluate the efficacy and safety of Hekun Decoction in women with aMCI. Methods: This prospective, randomized, three-arm, double-blind clinical trial enrolled women aged 40 to 60 years with aMCI during early menopause. Participants were randomized to Hekun Decoction, Femoston, or placebo for 24 weeks. The primary outcome was the change in MoCA score at 0 and 24 weeks. The secondary outcomes included the Menopause Rating Scale (MRS), Modified Kupperman Index, and Insomnia Severity Index (ISI), along with adverse events. Results: Between October 2021 and February 2024, a total of 292 patients were randomized to Hekun Decoction (n = 98), Femoston (n = 98), and placebo (n = 96).After 24 weeks, both Hekun Decoction (MD = 3.18, 95% CI [2.44 to 3.92]) and Femoston (MD = 3.67, 95% CI [2.93 to 4.42]) were more effective than placebo in improving MoCA scores. Meanwhile, better outcomes were observed in the Hekun Decoction group and Femoston group compared with the placebo group for MRS (MD = -5.87, 95% CI [-7.02, -4.71], and MD = -6.01, 95% CI [-7.02, -5.01]), KI (MD = -6.74, 95% CI [-8.16, -5.33], and MD = -6.93, 95% CI [-8.27, -5.59]), and ISI (MD = -6.53, 95% CI [-7.66, -5.39], and MD = -6.51, 95% CI [-7.58, -5.43]). As for the adverse events, no cases of abdominal distension, pain, breast pain, or abnormal uterine bleeding were observed in the Hekun Decoction group.In women with aMCI during early menopause, Hekun Decoction demonstrated non-inferior efficacy to Femoston in improving cognitive function over 24 weeks, with a favorable safety profile. Notably, women in the Hekun Decoction group showed less adverse events compared with Femoston. However, further trials with longer follow-up periods are needed to confirm the efficacy of Hekun Decoction in women with aMCI.