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.
Diagnosis of type 2 diabetes according to the American Diabetes Association criteria;
Aged 50-75 years (inclusive), male or female.
MMSE score >20 and <27,
CDR global score 0.5-1.0 (inclusive), with a CDR memory subscore ≥0.5,
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;
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.
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.
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;
Parallel
Mazdutide
DrugMazdutide 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.
Placebo
DrugMatching 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.
Integrated 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.
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.
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.
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.
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.
Incidence of Treatment-emergent Adverse Events
Difference in incidence of treatment-emergent adverse events during the trial period (treatment vs. placebo).
Incidence of Treatment-emergent Serious Adverse Events
Difference in incidence of serious adverse events during the trial period (treatment vs. placebo).
Change in Blood-based biomarkers related to AD pathology and neurodegeneration
The change in blood-based biomarkers related to AD pathology and neurodegeneration (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 brain Aβ burden assessed using [¹⁸F]florbetapir amyloid PET/MRI in participants undergoing this assessment
The change in brain Aβ burden assessed using \[¹⁸F\]florbetapir amyloid PET/MRI in participants undergoing this assessment from baseline to Week 76 will be compared between the treatment group and the placebo group.
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The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Lead sponsor
Nanjing First Hospital, Nanjing Medical University
Collaborator
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Collaborator
Xiangya Hospital of Central South University
Collaborator
Huadong Hospital
Collaborator
Jiangsu Province Hospital of Traditional Chinese Medicine
Collaborator
Changzhou No.2 People's Hospital
Collaborator
The Second Affiliated Hospital of Dalian Medical University
Collaborator
