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GLP-1/GCG Dual Agonist in Type 2 Diabetes With Early Dementia (LIGHT-COG Study) Phase 3 420 Randomized Double-Blind Placebo-Controlled Dose Escalation

Recruiting
Clinical Trial NCT07083154 is designed to study Treatment for Dementia, Mild, Mild Cognitive Impairment, Type 2 Diabetes. It is a Phase 3 interventional study that is recruiting, having started on September 27, 2025, with plans to enroll 420 participants. Led by The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, it is expected to complete by August 1, 2029. The latest data from ClinicalTrials.gov was last updated on March 5, 2026.
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...Show More
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 ...Show More
Official Title

Efficacy, Safety, and Tolerability of a GLP-1/GCG Dual Receptor Agonist in Type 2 Diabetes With Early Dementia: A Multicenter, Randomized, Parallel-group, Double-blind, Placebo-controlled Trial

Conditions
Dementia, MildMild Cognitive ImpairmentType 2 Diabetes
Other Study IDs
  • 2025-0502-01
NCT ID Number
NCT07083154
Start Date (Actual)
2025-09-27
Last Update Posted
2026-03-05
Completion Date (Estimated)
2029-08-01
Enrollment (Estimated)
420
Study Type
Interventional
PHASE
Phase 3
Status
Recruiting
Keywords
Type 2 Diabetes
Mild Dementia
Mild Cognitive Impairment
GLP-1/GCG Dual Agonist
Cognitive Dysfunction
Early Dementia
Primary Purpose
Treatment
Design Allocation
Randomized
Interventional Model
Parallel
Masking
Quadruple
Arms / Interventions
Participant Group/ArmIntervention/Treatment
ExperimentalMazdutide group
Participants will receive 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) , in addition to their existing glucose-lowering therapy.
Mazdutide
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 ...Show More
Placebo ComparatorPlacebo group
Participants will receive weekly subcutaneous injections of matched placebo, in addition to their existing glucose-lowering therapy.
Placebo
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 pa...Show More
Primary Outcome Measures
Outcome MeasureMeasure DescriptionTime Frame
Integrated Alzheimer's Disease Rating Scale (iADRS) Score Change
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.
From Baseline to Week 28, 52 and 76
Secondary Outcome Measures
Outcome MeasureMeasure DescriptionTime Frame
Mini-Mental State Examination (MMSE) Score Change
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.
From Baseline to Week 28, 52 and 76
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score Change
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.
From Baseline to Week 28, 52 and 76
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score Change
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.
From Baseline to Week 28, 52 and 76
Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Score Change
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.
From Baseline to Week 28, 52 and 76
Change in Total Brain Volume
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.
From Baseline to Week 76
Change in Total White Matter Volume
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.
From Baseline to Week 76
Change in Total Gray Matter Volume
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.
From Baseline to Week 76
Change in Total White Matter Lesion Volume
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.
From Baseline to Week 76
Change in Cortical Gray Matter Lobar Volumes
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.
From Baseline to Week 76
Change in Subcortical Nuclei Volumes
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.
From Baseline to Week 76
Changes in MRI-derived Alzheimer's disease (AD) signature region volumes
The AD signature regions included hippocampus, parahippocampal, entorhinal, inferior parietal lobule, precuneus, and cuneus.
From Baseline to Week 76
Changes in cortical thickness of AD-susceptible regions
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.
From Baseline to Week 76
Change in Amyloid-beta (Aβ) plaque deposition measured by Aβ-PET/MR
The change in Aβ plaque deposition measured by Aβ-PET/MR imaging from baseline to Week 76 (subgroup analysis).
From Baseline to Week 76
Change in Blood-Based Neurodegeneration Biomarkers
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.
From Baseline to Week 76
Change in Body Weight
Change in body weight from baseline to weeks 12, 20, 28, 36, 44, 52, 60, 68 and 76.
From Baseline to Week 12, 20, 28, 36, 44, 52, 60, 68 and 76.
Change in Body Mass Index (BMI)
Change in BMI from baseline to weeks 12, 20, 28, 36, 44, 52, 60, 68 and 76.
From Baseline to Week 12, 20, 28, 36, 44, 52, 60, 68 and 76.
Change in Glycated Haemoglobin (HbA1c) Levels
Change in HbA1c levels from baseline to weeks 28, 52 and 76
From Baseline to Week 28, 52 and 76
Change in Fasting Plasma Glucose Levels
Change in fasting plasma glucose levels from baseline to weeks 28, 52 and 76
From Baseline to Week 28, 52 and 76
Change in 2-hour Postprandial Plasma Glucose Levels
Change in fasting plasma glucose levels from baseline to weeks 52 and 76
From Baseline to Week 52 and 76
Participation Assistant
Eligibility Criteria

Eligible Ages
Adult, Older Adult
Minimum Age
50 Years
Eligible Sexes
All

  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.

  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.

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School logoThe Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Study Responsible Party
Yan Bi, Principal Investigator, Chief Physician, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Study Central Contact
Contact: Yan Bi, MD, PhD, 6-25-83-105302., [email protected]
Contact: Zhou Zhang, MD, PhD, 86-25-83-105302, [email protected]
8 Study Locations in 1 Countries

Hunan

Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China
Jing Wu, MD, PhD, Contact
Jing Wu, MD, PhD, Principal Investigator
Not yet recruiting

Jiangsu

Department of Endocrinology, Changzhou No.2 People's Hospital, Changzhou, Jiangsu, China
Huijie Yang, MD, Contact
Xinhua Ye, MD, PhD, Principal Investigator
Huijie Yang, MD, Sub-Investigator
Recruiting
Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210000, China
Jindan Wu, MD, PhD, Contact, 86-025-52271000, [email protected]
Jindan Wu, MD, PhD, Principal Investigator
Peng Zhang, MD, Sub-Investigator
Recruiting
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center,Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210008, China
Yan Bi, MD, PhD, Contact, 86-25-83-105302, [email protected]
Zhou Zhang, MD, PhD, Contact, 86-25-83-105302, [email protected]
Yan Bi, MD, PhD, Principal Investigator
Zhou Zhang, MD, PhD, Sub-Investigator
Recruiting
Department of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
Yueting Zhao, MD, Contact
Yueting Zhao, MD, Principal Investigator
Recruiting

Liaoning

The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
Haixia Liu, MD, PhD, Contact
Haixia Liu, MD, PhD, Principal Investigator
Not yet recruiting

Shanghai Municipality

Department of Endocrinology, Shanghai General Hospital, Shanghai, Shanghai Municipality, 200080, China
Fang Fang, MD, PhD, Contact
Fang Fang, MD,PhD, Principal Investigator
Recruiting
Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China
Bin Lu, MD, PhD, Contact
Bin Lu, MD, PhD, Principal Investigator
Cuiping Jiang, MD, Sub-Investigator
Recruiting