Efficacy, Safety and Response Predictors of Adjuvant Astragalus for Cognition in Orthostatic Hypotension

Study Overview
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Brief Summary
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Introduction: Orthostatic hypotension (OH) increases the risk of cognitive impairment in adults. Recent big data studies have demonstrated that add-on Astragalus can improve OH state. In vitro studies have revealed that Astragalus possesses anti-inflammatory, antioxidative, and neuroprotective effects. However, the clinical effects of add-on Astragalus in improving cognition in these patients remain unclear. Therefore, this pragmatic clinical trial aims to determine the efficacy and safety of add-on Astragalus in improving cognition in patients with OH, elucidate the underlying mechanisms, identify related response predictors, and explore effective drug components. Methods and analysis: This is an add-on, assessor-blinded, parallel, pragmatic, randomized controlled trial. At least 88 adults with OH aged >30 years will be recruited. Participants will be randomized in a 1:1 ratio to receive 24 weeks of routine care or add-on Astragalus. The primary efficacy outcome will be measured by the Montreal Cognitive Assessment-Chinese version score. Secondary efficacy outcome assessment will include neuropsychological tests, blood pressure, plasma biomarkers, multimodal electroencephalograms, and neuroimaging. Safety outcome measures will include physical examinations, vital signs, electrocardiography, laboratory tests (such as hematologic and blood chemical tests), and adverse event records. Recruitment began on June 20, 2023. Ethics and dissemination: The Ethics Committee of Fujian Medical University Union Hospital has approved this study (2021KJCX040).

Official Title
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Efficacy, Safety and Response Predictors of Adjuvant Astragalus for Cognition in Orthostatic Hypotension: an add-on, Assessor-blind, Pragmatic Randomized Controlled Trial

Conditions
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Orthostatic Hypotension

Intervention / Treatment
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* Behavioral: Routine treatment
* Drug: AM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The inclusion criteria will be as follows: Patients aged over 30; Patients with orthostatic hypotension; Patients who presence of subjective memory complaint Patients who have objective evidence of cognitive impairment assessed using neurocognitive batteries Patients who is not depressed; Patients who have complete autonomy in daily living Participants who score below normal on one or both of the tests (Montreal Cognitive Assessment: score of ≥18 to ≤26 or Mini-Mental State Examination score of ≥24 to ≤27) Exclusion Criteria: The exclusion criteria will be as follows: Patients with secondary orthostatic hypotension; Patients with dementia diagnosed according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders; Patients allergic or contraindicated to Astragalus; Patients who have been treated or have a history of stroke or transient ischemic attack, claustrophobia, bipolar disorder, schizophrenia, seizures, drug or alcohol abuse, malignancies, kidney failure and dialysis treatment, liver disease (hepatitis) and kidney disease; Patients who refuse or have contraindications to magnetic resonance imaging (MRI) or electroencephalography (EEG) (pacemakers, coronary and peripheral artery stents, metal implants, claustrophobia, severe visual and/or hearing impairment); Patients using a cholinesterase inhibitor, psychoactive drugs, medications that affect the cardiovascular system, or any medication known to interact with Astragalus; Patients who are pregnant or lactating; Patients who have participated in other clinical studies within the past 3 months.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: add-on AM<br> | Behavioral: Routine treatment<br>* Participants will be educated on ways to avoid induced hypotensive states, such as avoiding prolonged standing, standing after exercise, being nervous, eating several carbohydrate-rich foods, drinking alcohol, and being in a warm environment (such as a sauna). Participants will be encouraged in a comfortable home environment, such as a sit-down bath. If there are no contraindications, they are advised to increase their salt intake to approximately 10 grams per day and adjust their fluid intake to 2-3 liters per day. They will also be encouraged to perform lower-body strength training and moderate, non-strenuous activities. Seriously ill patients will be proposed to raise the head of their bed during sleep, wear tight clothing, eat small meals, and reduce alcohol intake.<br>Drug: AM<br>* Patients will receive astragalus daily 15g for 24 weeks<br>|
| Experimental: Routine treatment<br> | Behavioral: Routine treatment<br>* Participants will be educated on ways to avoid induced hypotensive states, such as avoiding prolonged standing, standing after exercise, being nervous, eating several carbohydrate-rich foods, drinking alcohol, and being in a warm environment (such as a sauna). Participants will be encouraged in a comfortable home environment, such as a sit-down bath. If there are no contraindications, they are advised to increase their salt intake to approximately 10 grams per day and adjust their fluid intake to 2-3 liters per day. They will also be encouraged to perform lower-body strength training and moderate, non-strenuous activities. Seriously ill patients will be proposed to raise the head of their bed during sleep, wear tight clothing, eat small meals, and reduce alcohol intake.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary efficacy outcome measure will be the absolute change in the Montreal Cognitive Assessment(MoCA) score between baseline and week 24. | The MOCA scale scores range from 0 to 30, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The absolute scores change in the Rey-Osterrieth Complex Figure Test [ROCF] recall score between baseline and week 24. | The ROCF scale scores range from 0 to 36, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the ROCF-copy score between baseline and week 24. | The ROCF copy scale scores range from 0 to 36, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Clock-Drawing Test score between baseline and week 24. | The Clock-Drawing Test scale scores range from 0 to 5, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Trail Making Test-A score between baseline and week 24. | The Trail Making Test-A scores range from 0 to 25, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Digit Span Forward score between baseline and week 24. | TheDigit Span Forward score scores range from 0 to 10, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Trail Making Test-B score between baseline and week 24. | The Trail Making Test-B scores range from 0 to 25, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Digit Span Backward score between baseline and week 24. | TheDigit Span Forward score scores range from 0 to 9, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Verbal Fluency Test score between baseline and week 24. | The Verbal Fluency Test score scores range from 0 to 14, with higher scores indicating better. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Hamilton Anxiety Scale score between baseline and week 24. | The Hamilton Anxiety Scale score scores range from 0 to 56, with higher scores indicating worse. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute scores change in the Hamilton Depression Scale score between baseline and week 24. | The Hamilton Anxiety Scale score scores range from 0 to 96, with higher scores indicating worse. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the blood pressure between baseline and week 24. | To observe the changes of orthostatic blood pressure in patients | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the level of plasma β-amyloid40 (ng/ml) between baseline and week 24. | Amyloid is one of the main biomarkers of dementia | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the level of plasma β-amyloid42 (ng/ml) between baseline and week 24. | Amyloid is one of the main biomarkers of dementia | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the level of plasma glial fibrillary acidic protein (ng/ml) between baseline and week 24. | Glial fibrillary acidic protein is one of the main biomarkers of dementia | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the level of plasma neurofilament light chain (ng/ml) between baseline and week 24. | Neurofilament light chain is one of the main biomarkers of dementia | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the level of plasma hyper-phosphorylated tau-181 (ng/ml) between baseline and week 24. | Neurofilament light chain is one of the main biomarkers of dementia | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the P300 between baseline and week 24. | P300 is the main indicator of EEG, and its normal value range is between 320 and 420. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the VP300 between baseline and week 24. | VP300 is the main indicator of EEG, and its normal value range is between 320 and 420. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the MMN between baseline and week 24. | MMN is the main indicator of EEG, and its normal value range is between 100 and 210. | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the neurite density index between baseline and week 24. | Neurite density index is the main indicator of neurite-oriented diffusion and density imaging (NODDI) . | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the orientation dispersion index between baseline and week 24. | Orientation dispersion index is the main indicator of neurite-oriented diffusion and density imaging (NODDI) . | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in the isotropic volume fraction between baseline and week 24. | Isotropic volume fraction is the main indicator of neurite-oriented diffusion and density imaging (NODDI) . | Participants will be followed up for 24 weeks after baseline. | 
| The absolute change in theheart rate variability between baseline and week 24. | The KARDi2/4-B autonomic nervous function mapping ECG system (Nanjing Left and Right Brain Biomedical Company, NeuroMed, China) will record and analyze millivolt-level signals of ECG oscillations, complete the frequency domain and time domain index detection of heart rate variability in 3 min, and generate an autonomic nervous function status step map. | Participants will be followed up for 24 weeks after baseline. |