Clinical trial NCT05313529: Evaluating the Effects of Liraglutide, Empagliflozin and Linagliptin on Mild Cognitive Impairment Remission in Patients With Type 2 Diabetes: a Multi-center, Randomized, Parallel Controlled Clinical Trial With an Extension Phase
Official title: An Investigator-initiated, Prospective, Randomized, Open Label, Parallel Study to Explore and Evaluate the Therapeutic Effects of Liraglutide, Empagliflozin and Linagliptin on the Cognitive Function, Olfactory Function, and Odor-induced Brain Activation in T2DM Patients With Mild Cognitive Impairment.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Mild Cognitive Impairment
Keywords: Functional MRI
cognition
Olfactory function
Liraglutide, Empagliflozin and Linagliptin
Lead sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Sponsor class: OTHER
Collaborators: name: Nanjing First Hospital, Nanjing Medical University
name: The Affiliated Jiangning Hospital of Nanjing Medical University
name: Wuxi People's Hospital
name: Changzhou No.2 People's Hospital
First posted: 2022-04-06
Enrollment: 396
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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, olfactory function, and odor-induced brain activation 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 , olfactory function, and odor-induced brain activation 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.

Eligibility criteria: Inclusion criteria

1. Participants aged ≥40 and ≤75 years, of any gender.
2. Type 2 diabetes diagnosed according to the American Diabetes Association criteria
3. Mild cognitive impairment diagnosed according to the established criteria

   1. Cognitive concern from the patient, or an informant or skilled clinicians
   2. 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
   3. Preservation of independence in daily living abilities: Barthel Index score ≥ 60
   4. Absence of dementia
4. 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
5. Glycosylated hemoglobin (HbA1c) during screening between ≥7.0% and ≤10.0%
6. BMI of ≥ 19 kg/m2
7. Education duration of ≥6 years
8. Right-handed participants
9. Understanding of the research procedures and methods, potential benefits and risks of the trial, and sign written informed consent

Exclusion criteria

1. History of other dementia-related neurological diseases, depression within the past 2 years, developmental disorders, mania, depression, schizophrenia, etc.
2. 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.
3. Acute metabolic complications such as diabetic ketoacidosis, hyperglycemic hyperosmolar state and hypoglycemic coma within the previous 6 months
4. 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 \&lt;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
5. 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
6. With MRI contraindications, such as implanted metal prosthesis, claustrophobia, etc.
7. Females who are pregnant, lactating, breast feeding or of child bearing age without effective contraception
8. Participated in other clinical trials within the previous 6 months
9. Known or suspected allergy to the study drugs
10. Received treatment with GLP-1RAs, dual GLP-1R/GCGR agonist, SGLT-2 inhibitors or DPP4 inhibitors in the past 3 months
11. Known history of drug or alcohol abuse within the past 6 months

Primary outcomes:
measure: Mild cognitive impairment (MCI) remission rate at week48
timeFrame: The core study spans from baseline to 48 weeks
Secondary outcomes:
measure: Change of general cognitive function (MMSE) from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of general cognitive function (MoCA) from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of general cognitive function (RBANS) from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of cognitive subdomains from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of processing speed from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of executive function from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of total brain volume from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of grey matter volume from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of white matter volume from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of cerebrospinal fluid volume from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of white matter hyperintensity volume from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of deep grey subcortical structure volumes from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of lobar grey volume from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of AD signature region volumes from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of odor-induced brain activation from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of resting-state functional connectivity from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of olfactory function from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of HbA1c from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of fasting and 2-hour postprandial plasma glucose from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of fasting and 2-hour postprandial plasma C-peptide levels from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of lipid metabolism indicators from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of blood pressure from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of body weight from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of body mass index from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of waist circumference from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of hip circumference from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of waist to hip ratio from baseline to 24, 48 and 76 weeks
timeFrame: Baseline, 24, 48 and 76 weeks
measure: Change of basic activities of daily living ability from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
measure: Change of instrumental activities of daily living ability from baseline to 48 and 76 weeks
timeFrame: Baseline, 48 and 76 weeks
Other outcomes:
measure: Mild cognitive impairment (MCI) remission rate at week76
timeFrame: The extension phase extends from baseline to 76 weeks.
Locations:
city: Changzhou
country: China
facility: Department of Endocrinology, Changzhou No.2 People's Hospital, the Affiliated Hospital of Nanjing Medical University
state: Jiangsu
city: Nanjing
country: China
facility: Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University
state: Jiangsu
city: Nanjing
country: China
facility: Department of Endocrinology, the Affiliated Drum Tower Hospital of Nanjing University Medical School
state: Jiangsu
city: Nanjing
country: China
facility: Department of Endocrinology, the Affiliated Jiangning Hospital of Nanjing Medical University
state: Jiangsu
city: Wuxi
country: China
facility: Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University
state: Jiangsu
Study officials:
affiliation: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
name: Yan Bi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhang Z, Zhang B, Wang X, Zhang X, Yang QX, Qing Z, Zhang W, Zhu D, Bi Y. Olfactory Dysfunction Mediates Adiposity in Cognitive Impairment of Type 2 Diabetes: Insights From Clinical and Functional Neuroimaging Studies. Diabetes Care. 2019 Jul;42(7):1274-1283. doi: 10.2337/dc18-2584. Epub 2019 May 21.
citation: Zhang Z, Zhang B, Wang X, Zhang X, Yang QX, Qing Z, Lu J, Bi Y, Zhu D. Altered Odor-Induced Brain Activity as an Early Manifestation of Cognitive Decline in Patients With Type 2 Diabetes. Diabetes. 2018 May;67(5):994-1006. doi: 10.2337/db17-1274. Epub 2018 Mar 2.
citation: Cheng H, Zhang Z, Zhang B, Zhang W, Wang J, Ni W, Miao Y, Liu J, Bi Y. Enhancement of Impaired Olfactory Neural Activation and Cognitive Capacity by Liraglutide, but Not Dapagliflozin or Acarbose, in Patients With Type 2 Diabetes: A 16-Week Randomized Parallel Comparative Study. Diabetes Care. 2022 May 1;45(5):1201-1210. doi: 10.2337/dc21-2064.