NCT05313529
Active, not recruiting
Not Applicable
Effects of Liraglutide, Empagliflozin and Linagliptin on Mild Cognitive Impairment Remission in Type 2 Diabetes (LIGHT-MCI): A Multicentre, Randomised Controlled Trial With An Extension Phase
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School5 sites in 1 country396 target enrollmentStarted: October 8, 2022Last updated:
Overview
- Phase
- Not Applicable
- Status
- Active, not recruiting
- Sponsor
- The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
- Enrollment
- 396
- Locations
- 5
- Primary Endpoint
- Mild cognitive impairment (MCI) remission rate
Overview
Brief Summary
This is an investigator-led prospective, randomized, open label, parallel study to explore and evaluate the therapeutic effects of Liraglutide, Empagliflozin and Linagliptin on the cognitive function in T2DM patients with mild cognitive impairment (MCI), consisting of a 48-week core study followed by a 28-week extension phase.
Detailed Description
The LIGHT-MCI trial is an investigator-led, prospective, randomized, open label, parallel, multi-center study to explore and evaluate the therapeutic effects of Liraglutide, Empagliflozin and Linagliptin on the MCI remission in T2DM patients with MCI inadequately controlled with metformin monotherapy. The trial consists of a 48-week core study followed by an extension phase through to 76 weeks and the investigators will screen in the outpatient and inpatient departments to enroll 396 patients (132 for each arm) totally with the inclusion and exclusion criteria. The patients will be randomized at a 1:1:1 ratio into Liraglutide, Empagliflozin and Linagliptin 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 8-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. Participants who complete the 48-week core study will have the option to receive an additional 28 weeks of intervention after signing an extension consent form. At 48 and 76 weeks of treatment, all of the assessments will be performed again for all recruited subjects, including early withdrawal patients.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 40 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants aged ≥40 and ≤75 years, of any gender.
- •Type 2 diabetes diagnosed according to the American Diabetes Association criteria
- •Mild cognitive impairment diagnosed according to the established criteria
- •Cognitive concern from the patient, or an informant or skilled clinicians
- •Objective evidence of cognitive impairment: education-adjusted MoCA score ≤ 25 and ≥ 18; or ≥1.0 standard deviation below the mean of age- and education-specific groups on any cognitive subdomain
- •Preservation of independence in daily living abilities: Barthel Index score ≥ 60
- •Absence of dementia
- •Treatment with a stable glucose lowering regimen of metformin monotherapy (≥ 1,000 mg daily) or combination with sulfonylurea/glibenclamide/glycosidase inhibitor/basal insulin over the previous 3 months
- •Glycosylated hemoglobin (HbA1c) during screening between ≥7.0% and ≤10.0%
- •BMI of ≥ 19 kg/m2
Exclusion Criteria
- •History of other dementia-related neurological diseases, depression within the past 2 years, developmental disorders, mania, depression, schizophrenia, etc.
- •Significant nasal sinusitis, nasal cavity and sinus polyps, cranial or nasopharyngeal tumors and other space-occupying lesions, congenital diseases and trauma of the nose, maxillofacial area, and skull base that affect olfaction. Symptoms of upper respiratory tract infection on the day of MRI examination, including nasal congestion, rhinorrhea, fever, etc.
- •Acute metabolic complications such as diabetic ketoacidosis, hyperglycemic hyperosmolar state and hypoglycemic coma within the previous 6 months
- •Severe organ dysfunction of heart, liver, kidneys, and thyroid, including unstable angina, myocardial infarction, or grade II and above cardiac insufficiency within 3 months before screening; estimated glomerular filtration rate (eGFR) by CKD-EPI formula \<45 mL/min/1.73 m², alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater exceeding twice the upper limit of normal, hyperthyroidism or uncontrolled hypothyroidism
- •History of medullary thyroid carcinoma, pancreatitis, multiple endocrine neoplasia syndrome type 2, recurrent urinary tract infections, severe gastrointestinal diseases or history of gastrointestinal surgery, history of malignant tumors
- •With MRI contraindications, such as implanted metal prosthesis, claustrophobia, etc.
- •Females who are pregnant, lactating, breast feeding or of child bearing age without effective contraception
- •Participated in other clinical trials within the previous 6 months
- •Known or suspected allergy to the study drugs
- •Received treatment with GLP-1RAs, dual GLP-1R/GCGR agonist, SGLT-2 inhibitors or DPP4 inhibitors in the past 3 months
Arms & Interventions
Liraglutide
Experimental
Liraglutide will be titrated from 0.6mg/day to a final dose 1.8mg/day during the first 2 weeks, if well tolerated.
Meanwhile, All patients will also continue on their existing dose and regimen of metformin throughout the study. Visits at 8-week intervals will be performed to evaluate the safety of drugs. Metformin dose can be reduced in response to hypoglycaemia, but liraglutide 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.
Intervention: Liraglutide (Drug)
Empagliflozin
Experimental
Empagliflozin will be initiated and maintained at 10mg/ 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 8-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.
Intervention: Empagliflozin (Drug)
linagliptin
Experimental
linagliptin will be initiated at 5mg/ day every morning. Meanwhile, All patients will also continue on their existing dose and regimen of metformin throughout the study. Visits at 8-week intervals will be performed to evaluate the safety of drugs. Metformin dose can be reduced in response to hypoglycaemia, but linagliptin 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.
Intervention: Linagliptin (Drug)
Outcomes
Primary Outcomes
Mild cognitive impairment (MCI) remission rate
Time Frame: The core study spans from baseline to 48 weeks
MCI mitigation is defined by three criteria: an education-adjusted score of the Montreal Cognitive Assessment (MoCA) ≥26, no cognitive deficits in any explored cognitive subdomain, including processing speed, executive function, immediate memory, visuospatial construction ability, language, attention and delayed memory, evaluated by Trail-Making Test, Stroop Color-Word Test and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively, and preservation of ability to perform instrumental activity of daily living (IADL) with a Functional Activities Questionnaire (FAQ) score \<5.
Secondary Outcomes
- Change in score of Mini-Mental State Examination (MMSE)(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived occipital gray matter volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived insula gray matter volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in score of MoCA(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in total score of RBANS(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in the RBANS index score of immediate memory(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in the RBANS index score of visuospatial/constructional(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in the RBANS index score of language(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in the RBANS index score of attention(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in aggregate time to test completion for Trail Making Test (TMT)(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in the RBANS index score of delayed memory(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in aggregate time to test completion for Victoria Stroop Color-Word Test(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived total brain volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived total gray matter volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived total white matter volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived cerebrospinal fluid volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived white matter hyperintensity volume (WMH)(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived frontal gray matter volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived parietal gray matter volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived temporal gray matter volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived hippocampal volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived parahippocampal volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived entorhinal cortex volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived inferior parietal lobule volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived precuneus volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived cuneus volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived thalamus volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived caudate nucleus volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived putamen volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived pallidum volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived amygdala volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in MRI-derived accumbens volume(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in mean fractional anisotropy (FA) in white matter derived from diffusion tensor imaging (DTI)(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in mean diffusivity (MD) in white matter derived from DTI(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in fractional volume of free water in white matter (FW-WM)(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in diffusion tensor image analysis along the perivascular space (DTI-ALPS) index(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in perivascular space volume fraction in white matter (PVSVF-WM)(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in plasma p-tau 217 concentration(from baseline to the 48 weeks of treatment.)
- Changes in functional MRI-derived odor-induced brain activation(from baseline to the 48 weeks of treatment.)
- Changes in plasma amyloid beta (Aβ)42/Aβ40 concentration(from baseline to the 48 weeks of treatment.)
- Changes in plasma phosphorylated tau (p-tau)181 concentration(from baseline to the 48 weeks of treatment.)
- Changes in plasma neurofilament light chain (NfL) concentration(from baseline to the 48 weeks of treatment.)
- Changes in plasma glial fibrillary acidic protein (GFAP) concentration(from baseline to the 48 weeks of treatment.)
- Changes in resting-state functional MRI-derived brain network connectivity(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in olfactory threshold scores(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in olfactory identification scores(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in olfactory memory scores(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in olfactory assessment total scores(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in glycated haemoglobin (HbA1c) levels(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in fasting plasma glucose levels(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in 2-hour postprandial plasma glucose levels(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in fasting insulin(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in fasting C-peptide levels(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in 2-hour postprandial insulin(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in 2-hour postprandial C-peptide levels(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in pancreatic islet function (HOMA2-β)(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in insulin sensitivity (HOMA2-S)(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in insulin resistance indexes (HOMA2-IR)(from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in fasting serum triglyceride levels(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in fasting serum total cholesterol levels(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in fasting serum high-density lipoprotein-cholesterol levels(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in fasting serum low-density lipoprotein-cholesterol levels(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in visceral fat area(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in percent body fat(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in liver stiffness(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in liver fat controlled attenuation parameter(from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Change in blood pressure(from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).)
- Change in body weight(from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).)
- Change in body mass index(from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).)
- Change in waist circumference(from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).)
- Change in hip circumference(from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).)
- Change in waist to hip ratio(from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).)
- Changes in Barthel index(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Changes in FAQ score(from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).)
- Mild cognitive impairment (MCI) remission rate at week76(from baseline to week 76 of treatment (the week 76 assessment will be analyzed and reported after the extension phase).)
Investigators
Yan Bi
Chief Physician
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Study Sites (5)
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