Efficacy and Safety of Guilingji Capsules (龟龄集胶囊) for Treating Mild-to-Moderate Cognitive Impairment: Study Protocol for A Randomized, Double-Blind, Positive-Controlled, Multicenter and Noninferiority Trial

Background: The incidence of cognitive impairment(CI) is gradually increasing, which has attracted more attention from medical researchers worldwide. Definitive mechanisms of pathogenesis remain elusive, and there are few medications that have been proven effective for CI. The utilization of Chinese herbal medicine has shown positive therapeutic effects for a broad spectrum of diseases, including CI. Objective: The purpose of this study is to evaluate the safety and efficacy of Guilingji Capsules(GLJC,龟龄集胶囊) in treating mild-to-moderate CI with Shen(Kidney) and marrow deficiency syndrome. Methods: This is a randomized, double-blind, positive-controlled, multicenter clinical trial with a noninferiority design that included 348 participants randomly divided into an experimental arm and an active comparator arm. Individuals in the experimental arm(174 cases) took 0.6 g of GLJC once a day and 19.2 mg of Gingko biloba extract mimetic 3 times a day. Individuals in the active comparator arm(174 cases) took 0.6 g of GLJC mimetic once a day and 19.2 mg of Gingko biloba extract in tablet form 3 times a day. The intervention period included two sessions over 24 weeks. The primary outcome be the effectiveness of GLJC on cognitive improvement after 24 weeks of treatment, which was defined as an increase in the Mini Mental State Examination(MMSE) and Montreal Cognitive Assessment(MoCA) Scale. The secondary outcomes were improvement in independence, daily living ability, and Chinese medicine(CM) syndrome, which were measured with the Alzheimer's disease Rating Scale-Cognitive Project(ADAS-Cog), Clinical Dementia Rating(CDR) Total Score, Activities of Daily Living(ADL) Total Score and the Chinese Medicine Symptom Scale(CM-SS), respectively. Serum acetylcholine, acetylcholinesterase, bax and bcl-2 were monitored to explore the mechanism of GLJC on CI. In addition, safety measures, including vital signs, electrocardiography, laboratory indicators(full blood count, kidney and liver function tests, routine urine test and routine stool test) and adverse events, were also recorded. Discussion: The purpose of this trial is to evaluate the efficacy and safety of GLJC in patients with mild-to-moderate CI with kidney and marrow deficiency syndrome. If successful, the results would provide a viable treatment for patients with mild-to-moderate CI.(Clinical Trials.gov. ID: NCT03647384. Registered on 23 August 2018)