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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
420
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.
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.
Department of Endocrinology, Xiangya Hospital of Central South University
Changsha, Hunan, China
NOT_YET_RECRUITINGDepartment of Endocrinology, Changzhou No.2 People's Hospital
Changzhou, Jiangsu, China
RECRUITINGDepartment of Endocrinology, Nanjing First Hospital, Nanjing Medical University
Nanjing, Jiangsu, China
RECRUITINGDepartment of Endocrinology, Endocrine and Metabolic Disease Medical Center,Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Nanjing, Jiangsu, China
RECRUITINGDepartment of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine
Nanjing, Jiangsu, China
RECRUITINGThe Second Affiliated Hospital of Dalian Medical University
Dalian, Liaoning, China
NOT_YET_RECRUITINGDepartment of Endocrinology, Shanghai General Hospital
Shanghai, Shanghai Municipality, China
RECRUITINGDepartment of Endocrinology, Huadong Hospital Affiliated to Fudan University
Shanghai, China
RECRUITINGIntegrated Alzheimer's Disease Rating Scale (iADRS) Score Change
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.
Time frame: From Baseline to Week 76
Mini-Mental State Examination (MMSE) Score Change
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.
Time frame: From Baseline to Week 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 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.
Time frame: From Baseline to Week 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 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.
Time frame: From Baseline to Week 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 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.
Time frame: From Baseline to Week 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.
Time frame: 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.
Time frame: From Baseline to Week 76
Change in hippocampal volume
Change from baseline to Week 76 in hippocampal volume assessed by structural brain MRI.
Time frame: From Baseline to Week 76
Change in entorhinal cortex volume
Change from baseline to Week 76 in entorhinal cortex volume assessed by structural brain MRI.
Time frame: From Baseline to Week 76
Change in Body Weight
Change in body weight from baseline to weeks 76.
Time frame: From Baseline to Week 76.
Change in Body Mass Index (BMI)
Change in BMI from baseline to week 76.
Time frame: From Baseline to Week 76.
Change in Glycated Haemoglobin (HbA1c) Levels
Change in HbA1c levels from baseline to week 76
Time frame: From Baseline to Week 76
Change in Fasting Plasma Glucose Levels
Change in fasting plasma glucose levels from baseline to week 76
Time frame: From Baseline to Week 76
Change in 2-hour Postprandial Plasma Glucose Levels
Change in fasting plasma glucose levels from baseline to week 76
Time frame: From Baseline to Week 76
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