Effects of Kami Guibi-tang in patients with mild cognitive impairment: study protocol for a phase III, randomized, double-blind, and placebo-controlled trial

Study design

This trial was designed based on our previous pilot study [11]. It will be a single-center, randomized, double-blind, placebo-controlled clinical trial with a 24-week intervention and a 36th week follow-up examination. It has been initiated at the Kyung Hee University Hospital at Gangdong, Seoul, Korea, in December 2021 and will be continued till May 2025. A flowchart of this trial is shown in Fig. 1. The schedules for enrollment, interventions, and assessments are presented in Table 1.

Fig. 1figure 1

Flowchart of the trial design

Table 1 Schedule of enrollment, interventions, and assessmentsParticipantsInclusion criteria

Participants who meet the following criteria will be included: (1) adults aged 55–90 years, with complaints of impaired memory; (2) objective cognitive decline as measured using the Seoul Neuropsychological Screening Battery (SNSB), with a score of 0.5 on the Clinical Dementia Rating (CDR), 3 on the Global Deterioration Scale (GDS), and a normal score on the Korean MMSE (K-MMSE); (3) diagnosed with amnestic MCI by a neurologist; (4) not taking any medication that could affect cognitive function (e.g., gliatilin, gliatamine, ginexin, tanamin, or other psychoactive drugs) within 2 weeks; (4) no change in medication for underlying diseases within 2 weeks, and no expected change in medication during the trial; (5) no difficulty in communication.

Exclusion criteria

Participants who meet any of the following criteria will be excluded: (1) diagnosed with AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA); (2) diagnosed with vascular dementia according to the criteria of the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN); (3) with brain disorders that cause neurologic symptoms, other than cognitive impairment; (4) with other neurodegenerative disorders (e.g., Huntington’s disease, Parkinson’s disease, Creutzfeldt-Jakob disease and Down’s syndrome); (5) cognitive decline due to other diseases (e.g., vitamin deficiency, brain tumor, head trauma, encephalitis, hypoxic brain damage, neurosyphilis); (6) with history of major depressive disorder; (7) with psychiatric disorders or behavioral problems requiring antipsychotic medication; (8) with history of convulsive disorder, except for febrile convulsions during childhood; (9) with life-threatening or unstable medical conditions; (10) uncontrolled hypertension; (11) with heart or renal diseases; (12) with edema; (13) gastrointestinal symptoms (e.g., diarrhea, nausea, anorexia, abdominal pain); (14) use of medication that may induce myopathy or hypokalemia; (15) with hypersensitivity to ingredients in study medication; (16) abnormal range of liver and kidney function (serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels more than two-fold the upper reference limit, or serum creatinine (Cr) levels more than 10% of the upper reference limit); (17) participating in other clinical trials within 4 weeks; (18) with illiteracy; (19) those who are contraindicated for Brain MRI; (20) any other possible conditions considered inappropriate to participate in the trial.

Drop-out criteria

Participants will be withdrawn from the trial if they meet the following criteria: (1) occurrence of any severe adverse events; (2) voluntary withdrawal from the trial; (3) not following the study protocol (i.e., drug compliance below 80%); (4) use of additional medication to improve cognitive function during the trial; (5) considered unsuitable by the principal investigator; (6) loss of ability to communicate and express their opinions.

Enrollment

We plan to recruit a total of 84 amnestic MCI patients through physician referrals and newspaper advertisements. Candidates with memory complaints will be screened using the eligibility criteria, and the screening tools including the Korean Dementia Screening Questionnaire (KDSQ) and K-MMSE. SNSB will be conducted for potentially eligible participants, and those who are diagnosed with amnestic MCI will be enrolled. A clinical research coordinator and investigators will provide the participants with a detailed explanation of the study procedures, potential benefits and risks of participation. Informed consent will be obtained from all participants prior to enrollment.

Allocation and blinding

An independent statistician will generate a random sequence using R Software version 4.1.3. All individuals will be randomly assigned to either KGT or placebo group, in a ratio of 1:1 using a block randomization with a block size of four. The random sequence will be sent to the pharmaceutical company as an encoded file, which will label and package the investigational drugs. Participants will be sequentially assigned and provided with the drug according to the randomization code in the order of enrollment. The participants, clinical psychologists, neuroimaging specialists, a clinical pharmacist, clinical research coordinator (CRC), clinical research associates (CRA), project manager (PM) of contract research organization (CRO), and study investigators will be blinded to treatment allocation until the completion of the study. Only if serious adverse events (SAEs) occur, the cases will be unblinded and the participants will be taken off trial.

Intervention

The participants assigned to intervention group will take KGT granules (3 g /1pack) and those assigned to control group will take placebo granules (3 g /1pack). KGT is an herbal formula composed of 15 medicinal herbs. The amount and composition of each compound are presented in Table 2. Dimocarpus Longan, one of the herbal drugs of KGT, is a subtropical and tropical fruit of the Sapindaceae family. D. longan used in this trial was cultivated for medicinal purposes, not harvested from the wild. It is imported for medicinal use, and standardized, regulated, and quality controlled by the Korean Ministry of Food and Drug Safety (KMFDS) guidelines such as Korean Pharmacopoeia (KP) and Korean Herbal Pharmacopoeia (KHP). KGT will be manufactured by Han Poong Pharmaceutical Co., Ltd. (Jeonju, Korea), certified for Good Manufacturing Practices (GMP). Placebo drugs will be produced by the same manufacturer using the standard method of placebo manufacturing according to the Korean GMP guidelines. Their taste, color, shape, smell, and package will be made similar to KGT granules.

Table 2 Composition of Kami Guibi-tang

An independent clinical pharmacist will distribute the granules to participants in each group. Participants will be instructed to dissolve the granules in a glass of warm water and take the solution 30 minutes before or between meals, thrice daily. The investigators and CRC will make weekly reminder phone calls to the participants during the intervention period, in order to help them adhere to medication schedule. Participants will be allowed to take drugs for underlying medical conditions during the study period; however, they will not be allowed to take any medicine that may affect cognitive function. They will be required to report all the drugs taken during the study period. The name and dosage of the medication will be recorded in the case report form (CRF). Participants will be asked to return the leftover drugs at each study visit, and the number of returned drugs will be counted for assessing drug compliance. Those who take less than 80% of study medication will be withdrawn from the study.

Outcome

The primary outcome includes changes in cognitive performance after the administration of KGT or placebo granules. SNSB, which is composed of various cognitive tests such as CDR, GDS, and MMSE will be conducted to assess the cognitive function, and changes in SNSB results will be analyzed. The secondary outcomes include the rate of progression to AD at the endpoint, according to NINCDS-ADRDA and CDR-GS score ≥ 1. In addition, we will measure neuroimaging signals and blood-based biomarkers. Structural MRI and functional MRI (fMRI) will be adopted to observe neuroimaging signal changes. The changes in gray matter volume will be measured using structural MRI. Also, Rs-fMRI and task-based fMRI will be performed to compare the changes in functional connectivity among working memory and default mode networks and to measure the changes in brain activation during the face–name association task and one-back working memory task. Levels of plasma Aβ42 and Aβ40 will be measured as blood-based biomarkers. The safety outcomes include electrocardiogram (ECG) and blood chemistry (Na, K, Cl, AST, ALT, BUN, Cr, glucose, LDH, CPK).

AssessmentK-MMSE and SNSB

K-MMSE will be performed at the screening visit and at 12th week for evaluating the general cognitive status. It is one of the most widely used screening tests to estimate the cognitive functioning [12]. SNSB-II will be conducted at baseline, 24th week, and 36th week, to measure the effect of KGT on cognitive function. Changes in the mean SNSB scores will be analyzed as a primary outcome. SNSB is a neuropsychological test battery most commonly used in South Korea to estimate global cognitive function. The test is composed of various cognitive subtests that assess five domains: memory, attention, language, visuospatial function, and executive function. It also includes other related tests including CDR, K-MMSE, Korean-Instrumental Activities of Daily Living (K-IADL), Barthel-Activities of Daily Living (BADL), and Short-form Geriatric Depression Scale (SGDS) [13]. We will use a modified version of SNSB for dementia (SNSB-D), to obtain a global cognitive function (GCF) score, which is the sum of all the test scores of five domains. The maximum GCF score is 300 points: 150/300 (50%) for memory, 17/300 (6%) for attention, 27/300 (9%) for language, 36/300 (12%) for visuospatial function, and 70/300 (23%) for frontal/executive function [14]. The detailed contents of SNSB-D are presented in Table 3.

Table 3 Contents of Seoul Neuropsychological Battery for dementia (SNSB-D)MRI

Brain MRI scans will be conducted at baseline and 24th week using a 3.0 T MRI system (Philips Ingenia, Best, The Netherlands) to observe the neurophysiological changes. During the resting acquisition, participants will be asked to be in a supine position, with their head positioned in the 32-channel head coil, fixed by soft foam pads to minimize the head movement, and to remain awake with their eyes closed. Task-based fMRI data will be obtained while participants perform a face–name association task and one-back working memory task. Blood oxygenation level-dependent (BOLD) data will be acquired using a T2-weighted gradient echo, echo-planar imaging (EPI) sequence with the following acquisition parameters: repetition time (TR) = 2000 ms; echo time (TE) = 30 ms; flip angle (FA) = 70°; field of view (FOV) = 210 × 210 × 96 mm, matrix = 70 × 70; number of slices = 32; slice thickness = 3 mm; slice gap = 0 mm; multi-band factor = 2; SENSE factor = 2; voxels = 3 × 3 × 4 mm3. A sagittal structural 3D T1-weighted (3D T1W) image will be acquired before and after contrast injection with a turbo fast field echo sequence, similar to the magnetization-prepared rapid acquisition of the gradient echo (MPRAGE) sequence with the following acquisition parameters: repetition time (TR) = 8.1 ms, echo time (TE) = 3.7 ms, flip angle (FA) = 8°, field-of-view (FOV) = 236 × 236 mm2, and voxel size = 1 × 1 × 1 mm3.

Blood testing

Plasma Aβ42 and Aβ40 levels will be measured at baseline and at 24th week to examine the disease-modifying effects, since the ratio of Aβ42/Aβ40 reflects the AD pathology [15, 16] and associated neurodegeneration, and is related to cognitive impairment [17]. Changes in the ratio of plasma Aβ42/Aβ40 will be compared between the groups. A ratio less than 0.1218 is defined as positive amyloidosis; therefore, the conversion rate to a positive Aβ42/Aβ40 ratio will also be compared. CBC D/C, folate, and vitamin B12 levels will be measured at baseline and 24th week. HDL, LDL, TG, TFT, VDRL, and ammonia levels will be assessed at 1st week.

Safety assessment

ECG and blood tests will be conducted to examine the safety outcomes. ECG will be conducted at baseline and 24th week. Blood levels of Na, K, Cl, AST, ALT, BUN, Cr, glucose, LDH, CPK will be measured at baseline, 12th, and 24th week. Vital signs will be checked at each visit. We will closely monitor any abnormal findings in vital signs, blood tests, and ECG.

Adverse events (AEs)

Adverse events will be monitored at each visit, and by telephone, weekly during the intervention and biweekly for 12 weeks after the intervention. All AEs will be assessed for causality and severity, and the details of each AE will be recorded in CRF. If a serious adverse event (SAE) occurs, the participation will be terminated, and the institutional review board (IRB) will be reported as soon as possible. All AEs will be monitored until they stabilize.

Data management and monitoring

Data will be entered into the electronic case record form (eCRF) by CRC and the investigators. The entered data will be monitored by CRAs, through the process of source data validation (SDV). Only the monitoring agent and the investigators will have access to the dataset. The eCRF files will be stored in the password-secured database called MyTrial. All procedures will comply with the confidentiality standards for medical data. All documents and collected data will be kept for 3 years after completion of the study, after which they will be destroyed. The data will be managed by a data management project manager (DMPM) and a data management associate (DMA), according to standard operating procedures (SOPs). The trial will be monitored by a monitoring committee which is composed of PM, CRA and clinical research manager (CRM). Auditing will be conducted by the Korean Ministry of Food and Drug Safety and IRB.

StatisticsSample size calculation

The primary outcome of interest in this study is the change in the total SNSB-D score between baseline and post-intervention. The calculation of sample size is based on a superiority test, as the aim of this study is to show that KGT is superior to placebo. Our pilot study of aMCI patients treated with KGT showed that the change in the total SNSB-D score was + 22.47, compared to + 8.36 in the placebo group. The calculated effect size (Cohen’s d) was 0.70. Using G*Power software with a power of 0.80 and a two-sided type I error of 0.05, the calculated total sample size for the current study involves 66 participants, with 33 in each group. The dropout rate was 10% (3 of 33 participants) in the previous study; however, since the current study will take a longer follow-up period, we expect the dropout rate to be 20%. We plan to recruit a total of 84 participants for this RCT (42 participants in each group).

Data analyses

An independent professional statistician, who will also be blinded to the allocation, will perform data analyses using SPSS 20.0 software (IBM, Armonk, NY, USA). Efficacy analyses will be performed using the modified intention-to-treat (mITT) and per-protocol (PP) principles. The mITT population will include participants who have completed at least one examination since the beginning of the intervention. The PP population will include participants who will adhere to the trial protocol and undergo all examinations. Missing data will be adjusted using the last-observation-carried-forward (LOCF) imputation method. A safety test will be performed using the ITT principle. The ITT population will include any participants who will take at least one pack of drugs after randomization. To analyze the efficacy outcome and continuous demographic variables, we will perform the Shapiro-Wilk test to confirm the normality of the data distribution. To analyze the fMRI measures and plasma amyloid beta levels, the paired t-test will be used for intra-group comparisons and an independent t-test will be used for intergroup comparisons, for normally distributed data. Wilcoxon’s signed rank test will be used for intra-group comparisons and the Mann-Whitney U test for intergroup comparisons of non-normally distributed data. To analyze the scores of the neuropsychological test battery, repeated measures of analysis of variance will be used for parametric data, and the Friedman test for non-parametric data. Categorical demographic variables, conversion to normal cognition or dementia, conversion to positive plasma Aβ42/Aβ40 ratio (< 0.1218), and the incidence of AEs between the groups will be analyzed using the Pearson’s chi-square (χ2) test or Fisher’s exact test. Continuous demographic variables will be analyzed using the t-test or Wilcoxon signed-rank test. All statistical analyses will be two-tailed, and the significance level will be set at p < 0.05.

留言 (0)

沒有登入
gif