Dementia, Mild, Mild Cognitive Impairment, Type 2 Diabetes
Conditions
Keywords
Type 2 Diabetes, Mild Dementia, Mild Cognitive Impairment, Dual GLP-1/Glucagon Receptor Agonist, Early-Stage Cognitive Impairment
Brief summary
The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluating the efficacy and safety of mazdutide in 420 participants with type 2 diabetes (T2D) and early-stage cognitive impairment, defined as mild cognitive impairment (MCI) or mild dementia. Participants are randomized 1:1 to receive once-weekly subcutaneous mazdutide, with dose escalation according to the protocol, or matching placebo, in addition to background glucose-lowering therapy. The primary objective is to determine whether 76 weeks of mazdutide treatment can slow cognitive and functional decline compared with placebo in this population.
Detailed description
The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluating the efficacy and safety of mazdutide in 420 participants with T2D and early-stage cognitive impairment (MCI or mild dementia). Participants will be randomized 1:1 to receive once-weekly subcutaneous mazdutide or matching placebo in addition to background glucose-lowering therapy. Mazdutide will be initiated at 2.0 mg once weekly and up-titrated to 4.0 mg, with further escalation to 6.0 mg permitted according to prespecified glycemic, weight, tolerability, and safety criteria. The primary outcome is the between-group difference in change from baseline to Week 76 in the Integrated Alzheimer's Disease Rating Scale (iADRS) score. Secondary outcomes include cognitive and functional measures, structural brain MRI measures, and metabolic outcomes. Exploratory outcomes include blood-based biomarkers, amyloid PET/MRI, CDR-based clinical stage progression, resting-state functional connectivity, and additional cardiometabolic and body-composition measures. Safety and tolerability will be assessed throughout the treatment period. Participants will generally continue their background glucose-lowering therapy during the trial. If glycemic control remains inadequate after titration to the highest tolerated study dose, additional glucose-lowering therapy may be initiated at the investigator's discretion. Permitted therapies include insulin glargine, metformin, gliclazide sustained-release, and acarbose. Study treatment may be interrupted, dose-reduced, or permanently discontinued for intolerance, adverse events, persistent glycemic instability, or other medical or safety reasons.
Interventions
DRUGMazdutide
Mazdutide is administered once weekly by subcutaneous injection using a prefilled autoinjector pen, preferably on the same day each week. Treatment is initiated at 2.0 mg once weekly and up-titrated to 4.0 mg once weekly during Weeks 4-12 according to individual tolerability. After at least 4 weeks at 4.0 mg, further escalation to 6.0 mg once weekly may be considered if prespecified criteria are met. Participants who are unable to tolerate a given dose may continue treatment at the highest tolerated dose. The total treatment duration is 76 weeks.
DRUGPlacebo
Matching placebo is administered once weekly by subcutaneous injection using a prefilled autoinjector pen. Participants will undergo the same blinded titration and dose-adjustment schedule as the mazdutide group, including corresponding 2.0 mg, 4.0 mg, and, where applicable, 6.0 mg dosing levels. Participants unable to tolerate a given dosing level may remain at the highest tolerated level. The total treatment duration is 76 weeks.
Sponsors
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Nanjing First Hospital, Nanjing Medical University
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Xiangya Hospital of Central South University
Huadong Hospital
Jiangsu Province Hospital of Traditional Chinese Medicine
Changzhou No.2 People's Hospital
The Second Affiliated Hospital of Dalian Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of type 2 diabetes according to the American Diabetes Association criteria; 2. Aged 50-75 years (inclusive), male or female. 3. Early-stage cognitive impairment (defined as mild cognitive impairment or mild dementia), with all of the following: 1. MMSE score \>20 and \<27, 2. CDR global score 0.5-1.0 (inclusive), with a CDR memory subscore ≥0.5, 3. A history of gradual and progressive cognitive decline for at least 6 months, reported by the participant or an informant. 4. Stable glycemic control regimen for ≥3 months prior to screening, meeting one of the following: 1. Lifestyle/dietary intervention alone (no glucose-lowering drugs), 2. Oral antidiabetic drugs (OADs), with or without once-daily basal insulin. 5. HbA1c 7.0-9.0% (inclusive) at screening. 6. BMI ≥20 kg/m², with stable weight (fluctuation \<5%) for ≥3 months. 7. Stable treatment regimen for cognitive impairment for at least 3 months prior to screening and commit to its continuation throughout the study period, meeting one of the following criteria: 1. No treatment: Not receiving any pharmacological or non-pharmacological interventions for cognitive impairment; 2. Non-pharmacological therapy only: Engaged exclusively in non-drug interventions (e.g., cognitive training); 3. Pharmacological therapy: Using approved symptomatic cognitive-enhancing medications (e.g., cholinesterase inhibitors, NMDA receptor antagonists), excluding disease-modifying therapies for Alzheimer's disease (AD). 8. Ability to comply with systematic cognitive and functional assessments. 9. Fully understands the trial protocol, voluntarily signs the informed consent form (ICF), and agrees to adhere to all study requirements and restrictions.
Exclusion criteria
1. Known or suspected neurodegenerative disorders other than AD that are likely to be a major cause of cognitive impairment or to interfere with cognitive assessment, including but not limited to frontotemporal dementia and related syndromes, dementia with Lewy bodies, Parkinson's disease with cognitive impairment or dementia, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and Huntington's disease; 2. Current diagnosis of a poorly controlled or unstable psychiatric disorder (including but not limited to schizophrenia, bipolar disorder, major depressive disorder, generalized anxiety disorder, personality disorders, etc.), which, in the investigator's judgment, may interfere with study assessments, affect treatment compliance, or increase participant risk. 3. With a Patient Health Questionnaire-9 (PHQ-9) score ≥10 at screening, or a Generalized Anxiety Disorder Scale-7 (GAD-7) score ≥10 at screening. 4. Ischaemic or haemorrhagic stroke, transient ischaemic attack, or epileptic seizure within 3 months before screening; or other current or clinically significant central nervous system disorders or injuries likely to impair cognitive function or interfere with cognitive assessment, including but not limited to central nervous system infection, intracranial tumour, multiple sclerosis, metabolic encephalopathy, neurological disorders related to malnutrition, or severe traumatic brain injury; 5. Acute hyperglycemic/hypoglycemic events within 1 year, including: Diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and Hypoglycemic coma 6. Use of GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, dual GLP-1/glucagon receptor agonists, or triple GIP/GLP-1/glucagon receptor agonists within 3 months before screening; 7. Regular use (\>2 doses/week) of moderate-to-strong anticholinergic drugs within 4 weeks prior to screening; Use within 3 months prior to screening of: Anti-Parkinsonian drugs, Antiepileptic drugs, Antipsychotics, Morphine and opioid analgesics (Exemption: Short-term use \[\<5 days\] for surgery/acute injury, if completed \>4 weeks before screening); Use within 4 weeks prior to screening of: CNS stimulants; Medical/recreational cannabis, cannabinoids, or cannabidiol (CBD).a. Moderate/high anticholinergics, antiparkinsonian/antiepileptic drugs. 8. Alcohol abuse (defined as \>21 units/week for men or \>14 units/week for women; 1 unit = 360 mL beer, 150 mL wine, or 45 mL spirits). 9. Medical history of: 1. Medullary thyroid carcinoma (MTC), pancreatitis 2. Multiple endocrine neoplasia type 2 (MEN2) 3. Gallbladder/biliary disease, severe gastrointestinal disorders, or bowel resection 4. Active malignancy 10. Uncontrolled or potentially unstable diabetic retinopathy/maculopathy. 11. Severe organ dysfunction, including: 1. ALT/AST \>3× upper limit of normal (ULN); 2. eGFR \<45 mL/min/1.73m² (CKD-EPI equation); 3. History of unstable angina or myocardial infarction within 3 months before screening, or current heart failure of NYHA class II or higher. 12. Known/suspected hypersensitivity to the investigational product or related compounds 13. Pregnancy, lactation, or women of childbearing potential not using highly effective contraception. 14. MRI contraindications (e.g., metal implants, claustrophobia). 15. Participation in other clinical trials within 3 months, involving an investigational medicinal product or enrollment in any other type of medical research judged not to be scientifically or medically compatible with this study. 16. Any other condition deemed by the investigator to compromise safety or interfere with study assessments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Integrated Alzheimer's Disease Rating Scale (iADRS) Score Change | From Baseline to Week 76 | The change in Integrated Alzheimer's Disease Rating Scale (iADRS) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. iADRS is a composite endpoint that integrates cognitive and functional assessments (scores from Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living（ADCS-iADL）) to generate a total score (range: 0-144). The calculation formula is: iADRS score = (85 - ADAS-Cog13 score) + ADCS-iADL score A lower score indicates more severe cognitive and functional impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mini-Mental State Examination (MMSE) Score Change | From Baseline to Week 76 | The change in Mini-Mental State Examination (MMSE) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. It assesses multiple cognitive domains, including orientation, memory, attention and calculation, recall ability, language, and visuospatial skills. The total score ranges from 0 to 30, with higher scores indicating better cognitive function. |
| Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score Change | From Baseline to Week 76 | The change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. The score ranges from 0 to 18, with higher scores indicating greater severity of cognitive and functional impairment. |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score Change | From Baseline to Week 76 | The change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. The score ranges from 0 to 85, with higher scores indicating more significant cognitive impairment. |
| Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Score Change | From Baseline to Week 76 | The change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow functional decline. The total score ranges from 0 to 59, with lower scores indicating more severe functional impairment. |
| Change in Total Brain Volume | From Baseline to Week 76 | The change in total brain volume evaluated by structural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. |
| Change in Total White Matter Lesion Volume | From Baseline to Week 76 | The change in total white matter lesion volume evaluated by sturctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. |
| Change in hippocampal volume | From Baseline to Week 76 | Change from baseline to Week 76 in hippocampal volume assessed by structural brain MRI. |
| Change in entorhinal cortex volume | From Baseline to Week 76 | Change from baseline to Week 76 in entorhinal cortex volume assessed by structural brain MRI. |
| Change in Body Weight | From Baseline to Week 76. | Change in body weight from baseline to weeks 76. |
| Change in Body Mass Index (BMI) | From Baseline to Week 76. | Change in BMI from baseline to week 76. |
| Change in Glycated Haemoglobin (HbA1c) Levels | From Baseline to Week 76 | Change in HbA1c levels from baseline to week 76 |
| Change in Fasting Plasma Glucose Levels | From Baseline to Week 76 | Change in fasting plasma glucose levels from baseline to week 76 |
| Change in 2-hour Postprandial Plasma Glucose Levels | From Baseline to Week 76 | Change in fasting plasma glucose levels from baseline to week 76 |
Countries
China
Contacts
CONTACTYan Bi, MD, PhD
CONTACTZhou Zhang, MD, PhD
PRINCIPAL_INVESTIGATORYan Bi, MD, PhD
Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Outcome results
None listed