A Study of LY3372689 to Assess the Safety, Tolerability, and Efficacy in Participants With Alzheimer's Disease

Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early Symptomatic Alzheimer's Disease

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

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: LY3372689; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 327
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Central Coast, New South Wales, Australia, 2261
      • Central Coast Neurosciences Research (Tumbi Umbi)
    • Sydney, New South Wales, Australia, 2077
      • Hornsby Ku-Ring-Gai Hospital
    • Sydney, New South Wales, Australia, 2113
      • KARA Institute for Neurological Diseases
    • Sydney, New South Wales, Australia, 2010
      • St Vincent's Hospital
    • Sydney, New South Wales, Australia, 2065
      • HammondCare Greenwich Hospital
  • Queensland
    • Southport, Queensland, Australia, 4215
      • Private Practice - Dr PL Morris
  • South Australia
    • Woodville, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Carlton, Victoria, Australia, 3053
      • NeuroCentrix
    • Glen Iris, Victoria, Australia, 3146
      • Delmont Private Hospital
    • Malvern, Victoria, Australia, 3144
      • HammondCare
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1N 5C8
      • Bruyère Research Institute
    • Ottawa, Ontario, Canada, K1Z 1G3
      • Ottawa Memory Clinic
    • Ottawa, Ontario, Canada, K1Z 1G3
      • Clinique de la Memoire de l'Outaouais
    • Toronto, Ontario, Canada, M3B 2S7
      • Toronto Memory Program
  • Quebec
    • Sherbrooke, Quebec, Canada, J1L 0H8
      • DIEX Recherche Sherbrooke Inc.
• Japan
  • Tokyo, Japan, 113-0034
    • Memory Clinic Ochanomizu
  • Aichi-ken
    • Ōbu, Aichi-ken, Japan, 4748511
      • National Center for Geriatrics and Gerontology
  • Hyōgo
    • Himeji, Hyōgo, Japan, 672-8043
      • Himeji Central Hospital Affiliated Clinic
    • Kobe, Hyōgo, Japan, 650-0047
      • Kobe City Medical Center General Hospital
  • Ibaraki
    • Toride, Ibaraki, Japan, 302-0004
      • Memory Clinic Toride
  • Oita Prefecture
    • Yufu, Oita Prefecture, Japan, 879-5593
      • Oita University Hospital
  • Okayama-ken
    • Kurashiki, Okayama-ken, Japan, 710-0813
      • Katayama Medical Clinic
  • Tokyo
    • Mitaka-shi, Tokyo, Japan, 181-0013
      • Nozomi Memory Clinic
    • Nerima City, Tokyo, Japan, 179-0072
      • Kikukawa clinic
• Poland
  • Greater Poland Voivodeship
    • Poznan, Greater Poland Voivodeship, Poland, 61-853
      • Nzoz Neuro-Kard Ilkowski i Partnerzy SPL
  • Kuyavian-Pomeranian Voivodeship
    • Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland, 85-163
      • Centrum Medyczne Neuromed
  • Lesser Poland Voivodeship
    • Krakow, Lesser Poland Voivodeship, Poland, 31-559
      • Diamond Clinic
  • Lower Silesian Voivodeship
    • Wroclaw, Lower Silesian Voivodeship, Poland, 53-203
      • Wroclawskie Centrum Alzheimerowskie
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 01-684
      • Centrum Medyczne Neuroprotect
  • Podlaskie Voivodeship
    • Bialystok, Podlaskie Voivodeship, Poland, 15-756
      • Podlaskie Centrum Psychogeriatrii
  • Pomeranian Voivodeship
    • Gdansk, Pomeranian Voivodeship, Poland, 80-546
      • Centrum Badań Klinicznych PI-House Sp. z o.o.
    • Sopot, Pomeranian Voivodeship, Poland, 81-855
      • Centrum Medyczne Senior
  • West Pomeranian Voivodeship
    • Szczecin, West Pomeranian Voivodeship, Poland, 70-111
      • Centrum Medyczne Euromedis
• United States
  • California
    • Canoga Park, California, United States, 91303
      • Hope Clinical Research, Inc.
    • Fresno, California, United States, 93710
      • Neuro-Pain Medical Center
    • Irvine, California, United States, 92614
      • Irvine Clinical Research
    • San Diego, California, United States, 92123
      • Sharp Mesa Vista Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Institute for Neurodegenerative Disorders
  • Florida
    • Atlantis, Florida, United States, 33462
      • JEM Research Institute
    • Aventura, Florida, United States, 33180
      • VIN-Julie Schwartzbard
    • Boca Raton, Florida, United States, 33428
      • Neurology Offices of South Florida
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research
    • Fort Myers, Florida, United States, 33912
      • Neuropsychiatric Research Center of Southwest Florida
    • Maitland, Florida, United States, 32751
      • K2 Medical Research
    • Melbourne, Florida, United States, 32940
      • ClinCloud - Viera
    • Merritt Island, Florida, United States, 32952
      • Merritt Island Medical Research, LLC
    • Miami, Florida, United States, 33176
      • VIN-Victor Faradji
    • Miami, Florida, United States, 33176
      • IMIC, Inc.
    • Miami, Florida, United States, 33133
      • VIN-Andrew Lerman
    • New Port Richey, Florida, United States, 34652
      • Suncoast Clinical Research, Inc.
    • Ocala, Florida, United States, 34470
      • Renstar Medical Research
    • Pembroke Pines, Florida, United States, 33026
      • VIN- Margarita Almeida El-Ramey
    • Stuart, Florida, United States, 34997
      • Brain Matters Research
    • The Villages, Florida, United States, 32162
      • Charter Research - Lady Lake
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Josephson Wallack Munshower Neurology, PC
  • Massachusetts
    • Newton, Massachusetts, United States, 02459
      • Boston Center for Memory
    • Plymouth, Massachusetts, United States, 02360
      • Donald S. Marks M.D., P.C.
    • Waltham, Massachusetts, United States, 02451
      • MedVadis Research Corporation
    • Watertown, Massachusetts, United States, 02472
      • Adams Clinical
  • New Jersey
    • Springfield, New Jersey, United States, 07081
      • The Cognitive and Research Center of New Jersey
    • Toms River, New Jersey, United States, 08755
      • Advanced Memory Research Institute of New Jersey
  • New York
    • Buffalo, New York, United States, 14203
      • University at Buffalo - UBMD Neurology
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Neurological Associates, Ltd.
    • Plymouth Meeting, Pennsylvania, United States, 19462
      • Keystone Clinical Studies
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Rhode Island Mood & Memory Research Institute
  • Texas
    • Dallas, Texas, United States, 75231
      • Kerwin Medical Center
    • Houston, Texas, United States, 77054
      • The University of Texas Health Science Center at Houston
  • Vermont
    • Bennington, Vermont, United States, 05201-9810
      • The Memory Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Gradual and progressive change in memory function reported by participants or informants for ≥ 6 months
• MMSE score of 22 to 30 (inclusive) at screening
• CDR global score of 0.5 to 1.0 (inclusive), with a memory box score ≥0.5.
• Meet 18F flortaucipir positron emission tomography (PET) scan (central analysis) criteria
• Have a study partner who will provide written informed consent to participate

Exclusion Criteria:

• Contraindication to MRI or PET scans
• Have known allergies to LY3372689, related compounds, or any components of the formulations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 0.75 Milligram (mg) LY3372689; 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; given orally
Experimental: 3 mg 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; given orally
Placebo Comparator: Placebo; 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; given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 100

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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).	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).	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.	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.	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.	Week 64: Post-dose

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Investigators: Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Publications and helpful links

Helpful Links

• A Study of LY3372689 to Assess the Safety, Tolerability, and Efficacy in Participants With Alzheimer's Disease

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2021
• Primary Completion (Actual): July 9, 2024
• Study Completion (Actual): May 22, 2025

Study Registration Dates

• First Submitted: September 14, 2021
• First Submitted That Met QC Criteria: September 29, 2021
• First Posted (Actual): October 1, 2021

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Mild Cognitive Impairment; Dementia; Prodromal Alzheimer's Disease; Tauopathy; Tau; OGA Inhibitor
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Neurodegenerative Diseases; Frontotemporal Lobar Degeneration; Frontotemporal Dementia; Cognitive Dysfunction; Alzheimer Disease; Dementia; Pick Disease of the Brain; Tauopathies
• Other Study ID Numbers: 18094; I9X-MC-MTAE (Other Identifier: Eli Lilly and Company); 2021-000170-29 (EudraCT Number); 2024-512295-36-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing 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.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No