A Phase 2 interventional study of LY3372689 and LY3372689 in Alzheimer Disease, sponsored by Eli Lilly and Company. Completed at 69 sites in 5 countries. Open to participants aged 60 Years to 85 Years. Per ClinicalTrials.gov, last updated 2026-06-12.
Sponsored by Eli Lilly and Company · Phase 2, Interventional, and Treatment
The purpose of this study is to assess the safety, tolerability and effect of study drug LY3372689 in participants with early symptomatic Alzheimer's Disease
3,965 studies on the registry are indexed under Alzheimer Disease; 926 are open to participants now.
This study's enrollment of 327 is above the median of 70 across 3,019 interventional studies indexed under Alzheimer Disease.
Browse Alzheimer Disease studies →Eli Lilly and Company is the lead sponsor of 2,106 studies on the registry; 152 are open to participants now.
Of its 536 completed or terminated interventional studies of FDA-regulated products, 357 (67%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
MMSE and MoCA
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Double-blind treatment period: Participants received 0.75 mg LY3372689 administered orally once daily for up to 124 weeks. Post treatment follow up period: Participants who received 0.75 mg LY3372689 during the double-blind treatment period entered a post-treatment follow-up period for 4 weeks after last blinded treatment dose. No study intervention was administered during this period, and participants were followed for safety monitoring. Post treatment observational extension period: Participants who received 0.75 mg LY3372689 during the double-blind treatment period had the option to enter post-treatment observational extension period for approximately 9 months on average since last blinded treatment dose. No study intervention was administered during this period, and participants were followed for safety, other/exploratory efficacy and biomarker monitoring.
Drug: LY3372689
Double-blind treatment period: Participants received 3 mg LY3372689 administered orally once daily for up to 124 weeks. Post treatment follow up period: Participants who received 3 mg LY3372689 during the double-blind treatment period entered a post-treatment follow-up period for 4 weeks after last blinded treatment dose. No study intervention was administered during this period, and participants were followed for safety monitoring. Post treatment observational extension period: Participants who received 3 mg LY3372689 during the double-blind treatment period had the option to enter post-treatment observational extension period for approximately 9 months on average since last blinded treatment dose. No study intervention was administered during this period, and participants were followed for safety, other/exploratory efficacy and biomarker monitoring.
Drug: LY3372689
Double-blind treatment period: Participants received placebo administered orally once daily for up to 124 weeks. Post treatment follow up period: Participants who received placebo during the double-blind treatment period entered a post-treatment follow-up period for 4 weeks after last blinded treatment dose. No study intervention was administered during this period, and participants were followed for safety monitoring. Post treatment observational extension period: Participants who received placebo during the double-blind treatment period had the option to enter post-treatment observational extension period for approximately 9 months on average since last blinded treatment dose. No study intervention was administered during this period, and participants were followed for safety, other/exploratory efficacy and biomarker monitoring.
Drug: Placebo
Change From Baseline to End Time Point in Integrated Alzheimer's Disease Rating Scale (iADRS) (Intermediate (Low-medium) Tau Population)
iADRS is a simple linear combination of scores from 13-item alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). It is used to assess whether LY3372689 slows down the cognitive and functional decline associated with early symptomatic Alzheimer's Disease, compared to placebo. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance and higher score better performance. Change from baseline was calculated using Bayesian disease progression model (DPM) adjusted for age at baseline, AChEI/Memantine use at baseline, pooled investigator. Data presented are posterior mean with 95% credible interval.
Time frame: Baseline, Week 100
Change From Baseline to End Time Point in iADRS (Overall Population)
iADRS is a simple linear combination of scores from 13-item alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). It is used to assess whether LY3372689 slows down the cognitive and functional decline associated with early symptomatic Alzheimer's Disease, compared to placebo. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance and higher score better performance. Change from baseline was calculated using Bayesian disease progression model (DPM) adjusted for age at baseline, baseline tau PET category, AChEI/Memantine use at baseline, pooled investigator. Data presented are posterior mean with 95% credible interval.
Time frame: Baseline, Week 100
Change From Baseline to End Time Point in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) (Intermediate (Low-medium) Tau Population)
CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score are assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) (Overall Population)
CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) (Intermediate (Low-medium) Tau Population)
The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviours characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) (Overall Population)
The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviours characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living Inventory (ADCS-iADL) (Intermediate (Low-medium) Tau Population)
The ADCS-iADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-iADL measures both basic and instrumental activities (instrumental activity items 6a, 7-23) of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living Inventory (ADCS-iADL) (Overall Population)
The ADCS-iADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-iADL measures both basic and instrumental activities (instrumental activity items 6a, 7-23) of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Mini Mental State Examination (MMSE) (Intermediate (Low-medium) Tau Population)
MMSE is an instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures). Total score ranges from 0 to 30; lower score indicates greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Mini Mental State Examination (MMSE) (Overall Population)
MMSE is an instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures). Total score ranges from 0 to 30; lower score indicates greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point In Brain Tau Deposition as Measured by Flortaucipir F18 Positron Emission Tomography (PET) Scan (Intermediate (Low-medium) Tau Population)
Flortaucipir PET imaging was used as a quantitative tau biomarker. Quantitative tau burden was formalized using Standardized Uptake Value Ratio (SUVR) from the following composite brain regions: frontal, parietal, occipital, and temporal lobes and the Alzheimer's disease (AD) neocortical signature. The AD neocortical signature region of interest refers to a weighted Alzheimer's Disease specific neocortical region derived from Multiblock Barycentric Discriminant Analysis. Cerebellar gray matter was used as a reference region to derive an SUVr. Larger SUVR reflects larger tau burden. LS Mean change from baseline was calculated using ANCOVA adjusted for baseline score, age and treatment (Type III sum of squares).
Time frame: Baseline, Week 76
Change From Baseline to End Time Point In Brain Tau Deposition as Measured by Flortaucipir F18 Positron Emission Tomography (PET) Scan (Overall Population)
Flortaucipir PET imaging was used as a quantitative tau biomarker. Quantitative tau burden was formalized using Standardized Uptake Value Ratio (SUVR) from the following composite brain regions: frontal, parietal, occipital, and temporal lobes and the Alzheimer's disease (AD) neocortical signature. The AD neocortical signature region of interest refers to a weighted Alzheimer's Disease specific neocortical region derived from Multiblock Barycentric Discriminant Analysis. Cerebellar gray matter was used as a reference region to derive an SUVr. Larger SUVR reflects larger tau burden. LS Mean change from baseline was calculated using ANCOVA adjusted for baseline score, baseline tau PET category, age and treatment (Type III sum of squares).
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Volumetric Magnetic Resonance Imaging (vMRI) Measures (Intermediate (Low-medium) Tau Population)
MRI scans at baseline and at 76 weeks after the first treatment were used to quantitatively estimate change in brain atrophy. Volumetric MRI (vMRI) parameters were measured in brain regions: bilateral hippocampus, bilateral whole lateral ventricles, and bilateral whole brain. The atrophy was assessed by tensor-based morphometry, which captures volume changes within the deformation map. LS Mean change from baseline was determined by mixed model repeated measures (MMRM) model with fixed effects of treatment, visit, treatment-by-visit interaction, and adjusted for baseline volume, age at baseline.
Time frame: Baseline, Week 76
Change From Baseline to End Time Point in Volumetric Magnetic Resonance Imaging (vMRI) Measures (Overall Population)
MRI scans at baseline and at 76 weeks after the first treatment were used to quantitatively estimate change in brain atrophy. Volumetric MRI (vMRI) parameters were measured in brain regions: bilateral hippocampus, bilateral whole lateral ventricles, and bilateral whole brain. The atrophy was assessed by tensor-based morphometry, which captures volume changes within the deformation map. LS Mean change from baseline was determined by mixed model repeated measures (MMRM) model with fixed effects of treatment, visit, treatment-by-visit interaction, and adjusted for baseline volume, baseline tau PET category, age at baseline.
Time frame: Baseline, Week 76
Pharmacokinetics (PK): Plasma Concentrations of LY3372689
Blood samples were measured at week 64 to assess the concentration of LY3372689 in the plasma.
Time frame: Week 64: Post-dose
| Milestone | 0.75 Milligram (mg) LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Started | 110 | 109 | 108 |
| Received at least 1 dose of study drug (safety population) | 108 | 110 | 108 |
| Completed | 86 | 70 | 89 |
| Not completed | 24 | 39 | 19 |
| Withdrew: Adverse event | 1 | 2 | 1 |
| Withdrew: Death | 0 | 1 | 1 |
| Withdrew: Lost to follow-up | 0 | 1 | 0 |
| Withdrew: Physician decision | 4 | 3 | 1 |
| Withdrew: Progressive disease | 0 | 2 | 0 |
| Withdrew: Withdrawal by subject | 17 | 26 | 14 |
| Withdrew: Withdrawal due to caregiver circumstances | 1 | 1 | 0 |
| Withdrew: Participant randomized via interactive web response system before vital signs met exclusion criteria | 1 | 0 | 0 |
| Withdrew: Participant no longer wished to continue with investigational product (ip) or follow-up visits | 0 | 0 | 1 |
| Withdrew: Discontinued due to common close design | 0 | 1 | 0 |
| Withdrew: Participant not co-operative | 0 | 1 | 0 |
| Withdrew: Participant moving to different place from where it takes 4 hours to come to site to continue | 0 | 0 | 1 |
| Withdrew: Caregiver withdrew consent due to participant moved to long term care home | 0 | 1 | 0 |
| Milestone | 0.75 Milligram (mg) LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Started | 83 | 71 | 88 |
| Completed | 80 | 64 | 83 |
| Not completed | 3 | 7 | 5 |
| Withdrew: Death | 1 | 1 | 1 |
| Withdrew: Subject moved out of state | 1 | 0 | 0 |
| Withdrew: Withdrawal by subject | 1 | 3 | 1 |
| Withdrew: Adverse event | 0 | 1 | 0 |
| Withdrew: Physician decision | 0 | 1 | 1 |
| Withdrew: Lost to follow-up | 0 | 0 | 1 |
| Withdrew: Progressive disease | 0 | 0 | 1 |
| Withdrew: Subject discontinued study | 0 | 1 | 0 |
| Milestone | 0.75 Milligram (mg) LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Started | 42 | 38 | 42 |
| Completed | 40 | 32 | 40 |
| Not completed | 2 | 6 | 2 |
| Withdrew: Death | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 2 | 5 | 2 |
iADRS is a simple linear combination of scores from 13-item alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). It is used to assess whether LY3372689 slows down the cognitive and functional decline associated with early symptomatic Alzheimer's Disease, compared to placebo. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance and higher score better performance. Change from baseline was calculated using Bayesian disease progression model (DPM) adjusted for age at baseline, AChEI/Memantine use at baseline, pooled investigator. Data presented are posterior mean with 95% credible interval.
| score on a scale | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Integrated Alzheimer's Disease Rating Scale (iADRS) (Intermediate (Low-medium) Tau Population) | NA (NA to NA) | NA (NA to NA) | NA (NA to NA) |
iADRS is a simple linear combination of scores from 13-item alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). It is used to assess whether LY3372689 slows down the cognitive and functional decline associated with early symptomatic Alzheimer's Disease, compared to placebo. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance and higher score better performance. Change from baseline was calculated using Bayesian disease progression model (DPM) adjusted for age at baseline, baseline tau PET category, AChEI/Memantine use at baseline, pooled investigator. Data presented are posterior mean with 95% credible interval.
| score on a scale | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in iADRS (Overall Population) | NA (NA to NA) | NA (NA to NA) | NA (NA to NA) |
CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score are assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) (Intermediate (Low-medium) Tau Population) | 0.91 ± 0.23 | 2.14 ± 0.24 | 1.05 ± 0.22 |
CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) (Overall Population) | 1.54 ± 0.25 | 2.81 ± 0.27 | 1.48 ± 0.25 |
The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviours characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) (Intermediate (Low-medium) Tau Population) | 4.00 ± 0.70 | 4.91 ± 0.76 | 5.14 ± 0.69 |
The ADAS-Cog13 is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviours characteristic of persons with AD. The cognitive subscale of the ADAS-Cog13 consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS-Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) (Overall Population) | 5.58 ± 0.78 | 7.61 ± 0.83 | 5.95 ± 0.76 |
The ADCS-iADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-iADL measures both basic and instrumental activities (instrumental activity items 6a, 7-23) of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living Inventory (ADCS-iADL) (Intermediate (Low-medium) Tau Population) | -2.65 ± 0.72 | -5.34 ± 0.77 | -2.82 ± 0.70 |
The ADCS-iADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-iADL measures both basic and instrumental activities (instrumental activity items 6a, 7-23) of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living Inventory (ADCS-iADL) (Overall Population) | -4.02 ± 0.79 | -7.26 ± 0.83 | -3.24 ± 0.77 |
MMSE is an instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures). Total score ranges from 0 to 30; lower score indicates greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Mini Mental State Examination (MMSE) (Intermediate (Low-medium) Tau Population) | -1.65 ± 0.38 | -2.79 ± 0.41 | -2.25 ± 0.37 |
MMSE is an instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures). Total score ranges from 0 to 30; lower score indicates greater disease severity. LS Mean change from baseline was calculated using natural cubic spline with 2 degrees of freedom (NCS2) adjusted for fixed effects of NCS basis expansion terms (two terms), NCS basis expansion term-by-treatment interaction, visit (in weeks), investigator site (pooled), age at baseline, baseline tau PET category, AChEI/Memantine use at baseline.
| score on a scale | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Change From Baseline to End Time Point in Mini Mental State Examination (MMSE) (Overall Population) | -2.52 ± 0.41 | -4.00 ± 0.44 | -2.70 ± 0.40 |
Flortaucipir PET imaging was used as a quantitative tau biomarker. Quantitative tau burden was formalized using Standardized Uptake Value Ratio (SUVR) from the following composite brain regions: frontal, parietal, occipital, and temporal lobes and the Alzheimer's disease (AD) neocortical signature. The AD neocortical signature region of interest refers to a weighted Alzheimer's Disease specific neocortical region derived from Multiblock Barycentric Discriminant Analysis. Cerebellar gray matter was used as a reference region to derive an SUVr. Larger SUVR reflects larger tau burden. LS Mean change from baseline was calculated using ANCOVA adjusted for baseline score, age and treatment (Type III sum of squares).
| standardized uptake value ratio (SUVR) | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Frontal | 0.05 ± 0.008 | 0.03 ± 0.009 | 0.04 ± 0.008 |
| Parietal | 0.05 ± 0.009 | 0.03 ± 0.010 | 0.06 ± 0.009 |
| Lateral occipital | 0.04 ± 0.015 | 0.05 ± 0.016 | 0.07 ± 0.015 |
| Lateral temporal | 0.07 ± 0.011 | 0.04 ± 0.012 | 0.07 ± 0.011 |
| AD neocortical signature (measured using MUBADA) | 0.07 ± 0.011 | 0.05 ± 0.012 | 0.08 ± 0.010 |
Flortaucipir PET imaging was used as a quantitative tau biomarker. Quantitative tau burden was formalized using Standardized Uptake Value Ratio (SUVR) from the following composite brain regions: frontal, parietal, occipital, and temporal lobes and the Alzheimer's disease (AD) neocortical signature. The AD neocortical signature region of interest refers to a weighted Alzheimer's Disease specific neocortical region derived from Multiblock Barycentric Discriminant Analysis. Cerebellar gray matter was used as a reference region to derive an SUVr. Larger SUVR reflects larger tau burden. LS Mean change from baseline was calculated using ANCOVA adjusted for baseline score, baseline tau PET category, age and treatment (Type III sum of squares).
| SUVR | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Frontal | 0.07 ± 0.011 | 0.06 ± 0.011 | 0.06 ± 0.011 |
| Parietal | 0.08 ± 0.013 | 0.08 ± 0.013 | 0.07 ± 0.012 |
| Lateral occipital | 0.08 ± 0.018 | 0.09 ± 0.018 | 0.09 ± 0.017 |
| Lateral temporal | 0.08 ± 0.015 | 0.07 ± 0.015 | 0.08 ± 0.014 |
| AD neocortical signature (measured using MUBADA) | 0.09 ± 0.014 | 0.08 ± 0.015 | 0.09 ± 0.014 |
MRI scans at baseline and at 76 weeks after the first treatment were used to quantitatively estimate change in brain atrophy. Volumetric MRI (vMRI) parameters were measured in brain regions: bilateral hippocampus, bilateral whole lateral ventricles, and bilateral whole brain. The atrophy was assessed by tensor-based morphometry, which captures volume changes within the deformation map. LS Mean change from baseline was determined by mixed model repeated measures (MMRM) model with fixed effects of treatment, visit, treatment-by-visit interaction, and adjusted for baseline volume, age at baseline.
| cubic centimeter (cm^3) | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Bilateral Hippocampus | -0.19 ± 0.017 | -0.16 ± 0.019 | -0.28 ± 0.016 |
| Bilateral Whole Lateral Ventricles | 3.52 ± 0.425 | 4.25 ± 0.458 | 5.89 ± 0.405 |
| Bilateral Whole Brain | -10.75 ± 1.231 | -9.56 ± 1.345 | -18.92 ± 1.186 |
MRI scans at baseline and at 76 weeks after the first treatment were used to quantitatively estimate change in brain atrophy. Volumetric MRI (vMRI) parameters were measured in brain regions: bilateral hippocampus, bilateral whole lateral ventricles, and bilateral whole brain. The atrophy was assessed by tensor-based morphometry, which captures volume changes within the deformation map. LS Mean change from baseline was determined by mixed model repeated measures (MMRM) model with fixed effects of treatment, visit, treatment-by-visit interaction, and adjusted for baseline volume, baseline tau PET category, age at baseline.
| cm^3 | 0.75mg LY3372689 | 3 mg LY3372689 | Placebo |
|---|---|---|---|
| Bilateral Hippocampus | -0.21 ± 0.018 | -0.17 ± 0.018 | -0.29 ± 0.017 |
| Bilateral Whole Lateral Ventricles | 4.95 ± 0.444 | 5.74 ± 0.455 | 7.16 ± 0.409 |
| Bilateral Whole Brain | -15.61 ± 1.292 | -14.62 ± 1.313 | -22.78 ± 1.195 |
Blood samples were measured at week 64 to assess the concentration of LY3372689 in the plasma.
| nanograms per milliliter (ng/mL) | 0.75 mg LY3372689 | 3 mg LY3372689 |
|---|---|---|
| Pharmacokinetics (PK): Plasma Concentrations of LY3372689 | 3.95 ± 163 | 12.9 ± 212 |
Collected over Up to 124 weeks (Double-blind treatment period); 9 months on average (Post-treatment follow-up and Post treatment observational extension period). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 0.75 mg LY3372689 (Double Blind Period) | 0/108 (0%) | 13/108 (12%) | 75/108 (69.4%) |
| 3 mg LY3372689 (Double Blind Period) | 1/110 (0.9%) | 29/110 (26.4%) | 72/110 (65.5%) |
| Placebo (Double Blind Period) | 1/108 (0.9%) | 16/108 (14.8%) | 81/108 (75%) |
| 0.75mg LY3372689 (Post-treatment Follow up Period and Post Treatment Observational Extension Period) | 1/83 (1.2%) | 2/83 (2.4%) | 0/83 (0%) |
| 3 mg LY3372689 (Post-treatment Follow up Period and Post Treatment Observational Extension Period) | 2/71 (2.8%) | 4/71 (5.6%) | 0/71 (0%) |
| Placebo (Post-treatment Follow up Period and Post Treatment Observational Extension Period) | 1/88 (1.1%) | 9/88 (10.2%) | 0/88 (0%) |
| Event | 0.75 mg LY3372689 (Double Blind Period) | 3 mg LY3372689 (Double Blind Period) | Placebo (Double Blind Period) | 0.75mg LY3372689 (Post-treatment Follow up Period and Post Treatment Observational Extension Period) | 3 mg LY3372689 (Post-treatment Follow up Period and Post Treatment Observational Extension Period) | Placebo (Post-treatment Follow up Period and Post Treatment Observational Extension Period) |
|---|---|---|---|---|---|---|
| Prostate cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/40 | 0/46 | 0/40 | 0/30 | 1/29 | 0/35 |
| Atrial fibrillationCardiac disorders | 0/108 | 3/110 | 1/108 | 0/83 | 0/71 | 0/88 |
| PneumoniaInfections and infestations | 1/108 | 1/110 | 2/108 | 0/83 | 1/71 | 0/88 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 0/108 | 0/110 | 2/108 | 0/83 | 0/71 | 0/88 |
| FallInjury, poisoning and procedural complications | 0/108 | 2/110 | 1/108 | 1/83 | 0/71 | 1/88 |
| Angina unstableCardiac disorders | 0/108 | 0/110 | 0/108 | 0/83 | 1/71 | 0/88 |
| Arteriosclerosis coronary arteryCardiac disorders | 0/108 | 0/110 | 0/108 | 0/83 | 1/71 | 0/88 |
| Rectal haemorrhageGastrointestinal disorders | 0/108 | 0/110 | 0/108 | 0/83 | 1/71 | 0/88 |
| Failure to thriveMetabolism and nutrition disorders | 0/108 | 0/110 | 0/108 | 0/83 | 1/71 | 0/88 |
| Confusional statePsychiatric disorders | 1/108 | 1/110 | 0/108 | 0/83 | 1/71 | 0/88 |
| Event | 0.75 mg LY3372689 (Double Blind Period) | 3 mg LY3372689 (Double Blind Period) | Placebo (Double Blind Period) | 0.75mg LY3372689 (Post-treatment Follow up Period and Post Treatment Observational Extension Period) | 3 mg LY3372689 (Post-treatment Follow up Period and Post Treatment Observational Extension Period) | Placebo (Post-treatment Follow up Period and Post Treatment Observational Extension Period) |
|---|---|---|---|---|---|---|
| Covid-19Infections and infestations | 24/108 | 17/110 | 23/108 | 0/83 | 0/71 | 0/88 |
| FallInjury, poisoning and procedural complications | 20/108 | 16/110 | 15/108 | 0/83 | 0/71 | 0/88 |
| HeadacheNervous system disorders | 16/108 | 13/110 | 6/108 | 0/83 | 0/71 | 0/88 |
| Upper respiratory tract infectionInfections and infestations | 14/108 | 11/110 | 8/108 | 0/83 | 0/71 | 0/88 |
| DiarrhoeaGastrointestinal disorders | 13/108 | 12/110 | 12/108 | 0/83 | 0/71 | 0/88 |
| Urinary tract infectionInfections and infestations | 8/108 | 8/110 | 13/108 | 0/83 | 0/71 | 0/88 |
| Electrocardiogram qt prolongedInvestigations | 8/108 | 10/110 | 5/108 | 0/83 | 0/71 | 0/88 |
| NasopharyngitisInfections and infestations | 5/108 | 7/110 | 9/108 | 0/83 | 0/71 | 0/88 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 9/108 | 4/110 | 7/108 | 0/83 | 0/71 | 0/88 |
| Back painMusculoskeletal and connective tissue disorders | 9/108 | 5/110 | 6/108 | 0/83 | 0/71 | 0/88 |
All randomized participants.
| Age, Continuous(years) | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo | Total |
|---|---|---|---|---|
| Mean | 73.3 ± 5.40 | 73.4 ± 5.38 | 73.4 ± 5.47 | 73.4 ± 5.40 |
| Sex: Female, Male(Participants) | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo | Total |
|---|---|---|---|---|
| Female | 70 | 63 | 68 | 201 |
| Male | 40 | 46 | 40 | 126 |
| Ethnicity (NIH/OMB)(Participants) | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo | Total |
|---|---|---|---|---|
| Hispanic or Latino | 4 | 4 | 2 | 10 |
| Not Hispanic or Latino | 104 | 102 | 102 | 308 |
| Unknown or Not Reported | 2 | 3 | 4 | 9 |
| Race (NIH/OMB)(Participants) | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 12 | 14 | 11 | 37 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 3 | 1 | 3 | 7 |
| White | 95 | 94 | 94 | 283 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Region of Enrollment(Participants) | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo | Total |
|---|---|---|---|---|
| Australia | 14 | 8 | 10 | 32 |
| Canada | 12 | 12 | 10 | 34 |
| Japan | 11 | 13 | 11 | 35 |
| Poland | 16 | 21 | 18 | 55 |
| United States | 57 | 55 | 59 | 171 |
| Baseline Integrated Alzheimer's Disease Rating Scale (iADRS) Score(Score on a scale) | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo | Total |
|---|---|---|---|---|
| Mean | 111.8 ± 11.99 | 109.3 ± 13.25 | 110.4 ± 12.77 | 110.5 ± 12.68 |
| Screening Tau Category(Participants) | 0.75 mg LY3372689 | 3 mg LY3372689 | Placebo | Total |
|---|---|---|---|---|
| Intermediate (Low-medium) | 87 | 86 | 86 | 259 |
| High | 23 | 23 | 22 | 68 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
Supporting information: Study protocol, Statistical analysis plan, Clinical study report
Time frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and European Union (EU), whichever is later. Data will be indefinitely available for requesting.
Access criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
Data sharing details ↗ · www.vivli.org
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Studies of the drug tested here: LY3372689