Dementia, Mild, Mild Cognitive Impairment, Type 2 Diabetes
Conditions
Keywords
Type 2 Diabetes, Mild Dementia, Mild Cognitive Impairment, GLP-1/GCG Dual Agonist, Cognitive Dysfunction, Early Dementia
Brief summary
The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. A total of 420 type 2 diabetes patients with early dementia are randomized 1:1 to either the active treatment group (receiving subcutaneous injections of mazdutide weekly, with stepwise dose escalation to a maintenance dose per protocol) or the placebo group (receiving matched placebo injections). The primary objective is to evaluate the potential disease-modifying effects of mazdutide on cognitive dysfunction in type 2 diabetes.
Detailed description
The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial investigating the potential disease-modifying effects of the GLP-1/GCG dual receptor agonist mazdutide on cognitive dysfunction in 420 patients with type 2 diabetes (T2D) and early dementia. Participants will be randomized 1:1 to receive either weekly subcutaneous injections of mazdutide (starting at 2.0 mg, with stepwise dose escalation to a target maintenance dose of 4.0 mg and optional adaptive increase to 6.0 mg if necessary and tolerated) or matched placebo, in addition to their existing glucose-lowering therapy. The primary objective is to assess cognitive improvement, with key secondary endpoints including brain structure and function alterations, metabolic improvement, neurodegenerative biomarkers, and safety outcomes. Participants will undergo comprehensive cognitive and metabolic assessments at baseline, followed by safety visits at Week 4 and every 8 weeks thereafter for monitoring of adverse events, adherence, and metabolic parameters. Comprehensive evaluations at Weeks 28, 52, and 76 will include cognitive assessments, advanced neuroimaging, and metabolic profiling. During the study period, if a subject's study drug has been titrated to the maximum tolerated dose or the maximum protocol-specified dose (6 mg), and glycemic control remains suboptimal (fasting venous blood glucose or fingertip capillary blood glucose \> 8.5 mmol/L on two consecutive measurements) during follow-up, individualized rescue therapy may be initiated upon the investigator's judgment. The choice of rescue regimen should be based on the investigator's comprehensive assessment of the subject's specific condition, including but not limited to glycemic levels, complications, hepatic and renal function, and risk of hypoglycemia. Optional rescue medications include insulin glargine, metformin, gliclazide modified-release, and acarbose. The investigator shall closely monitor the response to rescue therapy. The study should be terminated if any of the following occurs: inadequate glycemic control after rescue therapy, intolerance to rescue medications, or any other situation necessitating withdrawal as judged by the investigator. All decision-making basis, selection of rescue regimen, and efficacy evaluations must be thoroughly documented.
Interventions
DRUGMazdutide
Mazdutide injection (pre-filled auto-injector pen) is administered subcutaneously at the same time each week. The starting dose is 2.0 mg administered once weekly (QW). Based on individual patient tolerance, the dose should be gradually increased to the target therapeutic dose of 4.0 mg QW over a period of 4 to 12 weeks. The protocol permits adaptive dose escalation up to 6.0 mg weekly when clinically indicated. For participants unable to tolerate dose increases, treatment continue at their maximum tolerated dose. The total intervention duration is 76 weeks.
DRUGPlacebo
Placebo injection (pre-filled auto-injector pen) is administered subcutaneously at the same time each week. The starting dose is 2.0 mg administered once weekly (QW). Based on individual patient tolerance, the dose should be gradually increased to the target therapeutic dose of 4.0 mg QW over a period of 4 to 12 weeks. The protocol permits adaptive dose escalation up to 6.0 mg weekly when clinically indicated. For participants unable to tolerate dose increases, treatment continue at their maximum tolerated dose. The total intervention 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. Type 2 diabetes mellitus (T2DM). 2. Aged 50-75 years (inclusive), male or female. 3. Early symptomatic dementia (Mild cognitive impairment or mild dementia), defined as: 1. MMSE score \>20 and \<27, 2. CDR global score 0.5-1.0 (inclusive), with a CDR memory subscore ≥0.5, 3. Subjective memory complaints for ≥6 months. 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. Evidence of other neurodegenerative diseases that may affect cognition, excluding Alzheimer's disease, including: 1. Frontotemporal dementia (FTD) and its variants 2. Parkinson's disease (PD), dementia with Lewy bodies (DLB) 3. Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) 4. Multiple system atrophy (MSA), multiple sclerosis (MS), Huntington's disease (HD), etc. 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. History of stroke (ischemic/hemorrhagic), transient ischemic attack (TIA), or epileptic seizure within 3 months prior to screening; Current or prior diagnosis of central nervous system (CNS) disorders that may impair cognitive function, including but not limited to: CNS infections, Intracranial tumors, Metabolic encephalopathy, Neurological disorders due 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-1R agonists, GLP-1R/GIPR dual agonists, or GLP-1R/GCGR dual agonists within 3 months prior to 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. Unstable angina, myocardial infarction (MI), or NYHA Class II+ heart failure within 3 months 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 28, 52 and 76 | The change in Integrated Alzheimer's Disease Rating Scale (iADRS) scores from baseline to Week 28, 52, and 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 28, 52 and 76 | The change in Mini-Mental State Examination (MMSE) scores from baseline to Week 28, 52 and 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 28, 52 and 76 | The change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores from baseline to Week 28, 52 and 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 28, 52 and 76 | The change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) scores from baseline to Week 28, 52 and 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 28, 52 and 76 | The change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) scores from baseline to Week 28, 52 and 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 Volume | From Baseline to Week 76 | The change in total white matter volume evaluated by structural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. |
| Change in Total Gray Matter Volume | From Baseline to Week 76 | The change in total gray matter 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 Cortical Gray Matter Lobar Volumes | From Baseline to Week 76 | The change in cortical gray matter lobar volumes evaluated by sturctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. |
| Change in Subcortical Nuclei Volumes | From Baseline to Week 76 | The change in subcortical nuclei volumes evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. |
| Changes in MRI-derived Alzheimer's disease (AD) signature region volumes | From Baseline to Week 76 | The AD signature regions included hippocampus, parahippocampal, entorhinal, inferior parietal lobule, precuneus, and cuneus. |
| Changes in cortical thickness of AD-susceptible regions | From Baseline to Week 76 | The meta- regions of interest (ROI) mean cortical thickness measure was computed from 12 brain regions previously shown to differentiate between patients with AD and healthy controls:bilateral entorhinal cortex, inferior temporal, midtemporal, inferior parietal, fusiform, and precuneus regions. |
| Change in Amyloid-beta (Aβ) plaque deposition measured by Aβ-PET/MR | From Baseline to Week 76 | The change in Aβ plaque deposition measured by Aβ-PET/MR imaging from baseline to Week 76 (subgroup analysis). |
| Change in Blood-Based Neurodegeneration Biomarkers | From Baseline to Week 76 | The change in blood-based neurodegeneration biomarkers (includingAmyloid-β (Aβ42/40 ratio), Phosphorylated tau (p-tau217), Glial fibrillary acidic protein (GFAP), and Neurofilament light chain (NfL), etc.）evaluated by Simoa from baseline to Week 76 will be compared between the treatment group and the placebo group. |
| Change in Body Weight | From Baseline to Week 12, 20, 28, 36, 44, 52, 60, 68 and 76. | Change in body weight from baseline to weeks 12, 20, 28, 36, 44, 52, 60, 68 and 76. |
| Change in Glycated Haemoglobin (HbA1c) Levels | From Baseline to Week 28, 52 and 76 | Change in HbA1c levels from baseline to weeks 28, 52 and 76 |
| Change in Fasting Plasma Glucose Levels | From Baseline to Week 28, 52 and 76 | Change in fasting plasma glucose levels from baseline to weeks 28, 52 and 76 |
| Change in Body Mass Index (BMI) | From Baseline to Week 12, 20, 28, 36, 44, 52, 60, 68 and 76. | Change in BMI from baseline to weeks 12, 20, 28, 36, 44, 52, 60, 68 and 76. |
| Change in 2-hour Postprandial Plasma Glucose Levels | From Baseline to Week 52 and 76 | Change in fasting plasma glucose levels from baseline to weeks 52 and 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