Effects of Henagliflozin on the Brain Function in T2DM Patients With Mild Cognitive Impairment: a Randomized, Parallel Controlled Clinical Trial

Study Overview
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Brief Summary
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This is a prospective, randomized, open label, parallel,6-month study to explore and evaluate the therapeutic effects of Henagliflozin on the cognitive function, olfactory function, and odor-induced brain activation in T2DM patients with mild cognitive impairment (MCI).

Detailed Description
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This is a prospective, randomized, open label, parallel, 6-month study to explore and evaluate the therapeutic effects of Henagliflozin on the cognitive function, olfactory function, and odor-induced brain activation in T2DM patients with MCI inadequately controlled with metformin monotherapy. The control group was treated with Gliclazide. We have 1 principal investigator, 6 sub-investigators and 1 nurse in research centre. The sub-investigators will screen in the outpatient and inpatient departments to enroll 60 patients (30 patients for each arm) totally with the inclusion and exclusion criteria in 9 months. The patients will be randomized at a 1:1 ratio into Henagliflozin and Gliclazide treatment group with a computer-generated random order. All patients will also continue on their existing dose and regimen of metformin throughout the study. At the baseline, clinical information collection, 100g-steamed bread meal test, biochemical measurement, body composition analysis, cognitive assessment, olfactory test and functional magnetic resonance imaging(fMRI) scan will be conducted for all patients. During the treatment period, visits at 4-week intervals will be performed to evaluate the safety of drugs and adjust the dose of metformin if hypoglycaemia occurs; meanwhile, fasting and 2-hour postprandial plasma glucose assayed by fingerstick, physical examination, and olfactory test will be conducted. At the end of the study, all of the assessments will be performed again for all recruited subjects, including early withdrawal patients.

Official Title
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A Prospective, Randomized, Open Label, Parallel, 6-month Study to Explore and Evaluate the Therapeutic Effects of Henagliflozin on the Cognitive Function, Olfactory Function, and Odor-induced Brain Activation in T2DM Patients With Mild Cognitive Impairment.

Conditions
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Type 2 Diabetes Mellitus, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Henagliflozin
* Drug: Gliclazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with type 2 diabetes mellitus ; Aged:55 -75 years ; Cognitive function assessment suggests mild cognitive impairment; A stable glucose-lowering regimen include Metformin alone or in combination with antidiabetic drugs other than SGLT2 inhibitors or sulfonylureas/glinides, or basic insulin for more than 2 months, and the dose of metformin≥1.0g/d; HbA1c 7 - 10%; ≥6 years of education; Right-handed. Exclusion Criteria: Cognitive function assessment suggests normal cognition or dementia; Other dementia related neurological diseases or depression, Mental dysplasia, mania, schizophrenia, etc in the past 2 years; Central nervous system diseases, including brain trauma, intracranial hemorrhage, acute cerebral infarction, etc; Severe sinusitis, nasal cavity and sinus polyps, skull base or nasopharyngeal tumors and other space occupying lesions; Congenital diseases and traumatic history of nose, maxillofacial and skull base affecting olfaction. With symptoms of upper respiratory tract infection, including nasal congestion, runny nose, fever, etc. on the day of MR examination; Diabetic Acute and chronic complications, including diabetic ketoacidosis, diabetic ketoacidosis; a hyperglycemic hyperosmolar state or severe hypoglycemic coma, etc. Severe impairment of heart, liver, kidney and other organs; Contraindications of MRI examination, such as implantation of metal prosthesis in vivo, claustrophobia, etc; Pregnant and lactating women; Receive other test drugs currently or within 3 months before participating in the project; Known or suspected allergic history to the test drug or similar drugs; SGLT2 inhibitor and sulfonylureas/glinides were used in recent 3 months.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Henagliflozin Group<br>Henagliflozin will be initiated and maintained at 5mg/ day every morning until the completion of the study. Meanwhile, all patients will also continue on their existing dose and regimen of metformin throughout the study. Visits at 4-week intervals will be performed to evaluate the safety of drugs. Metformin dose can be reduced in response to hypoglycaemia, but Empagliflozin could not be adjusted. If the plasma glucose still not achieve the target at the maximum dose, the maximum dose will be maintained until the completion of the study. | Drug: Henagliflozin<br>* Henagliflozin will be initiated and maintained at 5mg/day every morning. If necessary, the dose can be increased to 10mg once daily. All patients will also continue on their existing dose and regimen of metformin throughout the study.<br>* Other names: metformin;|
| Experimental: Gliclazide Group<br>Gliclazide will be initiated and maintained at 30mg/ day every morning until the completion of the study. Meanwhile, all patients will also continue on their existing dose and regimen of metformin throughout the study. Visits at 4-week intervals will be performed to evaluate the safety of drugs. Metformin dose can be reduced in response to hypoglycaemia, but Gliclazide could not be adjusted. If the plasma glucose still not achieve the target at the maximum dose, the maximum dose will be maintained until the completion of the study. | Drug: Gliclazide<br>* Gliclazide will be initiated and maintained at 30mg/day every morning. If necessary, the dose can be increased to 120mg once daily. All patients will also continue on their existing dose and regimen of metformin throughout the study.<br>* Other names: metformin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of olfactory brain activation by fMRI | Whether the activation degree of olfactory task fMRI brain area in the two groups after intervention was different from that before treatment and the difference of changes between the two groups. All patients underwent odor-induced task fMRI on a 3.0T MR scanner with 222 volumes for task fMRI and 230 volumes for resting-state fMRI. The odor-induced task consisted of fresh air rest and scent. Odor-induced brain activation was assessed by a general linear model using Statistical Parametric Mapping 12 (SPM12) software. Following extraction of the three separate conditions fresh air, scent, and rest from the whole sequence, contrasts were made for each participant between fresh air > rest and scent > rest. Odor-induced fMRI data were analyzed in the mask of the olfactory network, including the regions of bilateral parahippocampus, amygdala, piriform cortex, insula, orbitofrontal cortex, hippocampus, and entorhinal cortices. | from baseline to 6-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of cognitive function | Type 2 diabetes mellitus patients with MCI were relieved of mild cognitive impairment , which means MoCA scores were not less than 26 points after treatment, or improved referring to the MoCA score or the RBANS total score increased by 0.5 standard deviation compared with baseline after treatment. | from baseline to 6-month follow-up | 
| Olfactory threshold test | Whether the olfactory threshold scores of the two groups after intervention were higher than those before treatment and the difference of changes between the two groups. Olfactory testing was performed using Olfactory Function Assessment by Computerized Testing (OLFACT) (Osmic Enterprises, Inc.). Based on the University of Pennsylvania Smell Identification Test (UPSIT), OLFACT tests were computerized, standardized, and self-administered. Higher scores indicated better ability to detect odors. Threshold testing was performed by a series of binary dilutions of n-butanol solution in light mineral oil, and scores ranged from 1 to 13.5. | from baseline to 6-month follow-up | 
| Change of metabolism | The changes of glycosylated hemoglobin among the two groups before and after intervention. The level of glycosylated hemoglobin <7% means better glucose metabolism. | from baseline to 6-month follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional MRI, Cognition, Olfactory function, Henagliflozin and Gliclazide