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A Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03367403
Recruitment Status : Completed
First Posted : December 8, 2017
Results First Posted : February 15, 2022
Last Update Posted : October 13, 2022
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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Brief Summary:
The purpose of this study is to evaluate the safety, tolerability and efficacy of LY3002813 in early symptomatic Alzheimer's disease.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: Donanemab Drug: Placebo Drug: LY3202626 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 272 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Assessment of Safety, Tolerability and Efficacy of LY3002813 in Early Symptomatic Alzheimer's Disease
Actual Study Start Date : December 18, 2017
Actual Primary Completion Date : December 4, 2020
Actual Study Completion Date : September 21, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Donanemab Monotherapy (Donanemab-M)
Participants received 700 milligram (mg) donanemab intravenously (IV) every 4 weeks (Q4W) x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.
 Drug: Donanemab
Administered IV
Other Name: LY3002813
Placebo Comparator: Placebo
Participants received placebo IV Q4W for up to 72 weeks.
 Drug: Placebo
Administered IV
Experimental: Donanemab in Combination With LY3202626 (Donanemab-C)

Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W in combination with 12 mg of LY3202626 orally for up to 72 weeks.

As per protocol amendment (d) approved on Oct 9, 2018, donanemab in combination with LY3202626 (donanemab-C) arm discontinued as there was a low probability of identifying a statistically significant effect of 12mg of LY3202626 slowing cognitive decline.

 Drug: Donanemab
Administered IV
Other Name: LY3002813

Drug: LY3202626
Administered orally


Outcome Measures
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Primary Outcome Measures :
  1. Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) Score [ Time Frame: Baseline, 76 Weeks ]
    Integrated Alzheimer's Disease Rating Scale is used to assess whether donanemab slows down the cognitive and functional decline associated with AD compared with placebo. iADRS is a simple linear combination of 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). The scale ranges from 0 to 144, where lower scores indicate worse performance and higher score indicates better performance. Least Squares (LS) Mean value was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, pooled investigator, acetylcholinesterase inhibitor (AChEI) and/or memantine use at baseline, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.


Secondary Outcome Measures :
  1. Change From Baseline in the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score [ Time Frame: Baseline, 76 Weeks ]
    The ADAS is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS 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 value was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, pooled investigator, AChEI and/or memantine use at baseline, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.

  2. Change From Baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Score [ Time Frame: Baseline, 76 Weeks ]
    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 value was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, pooled investigator, AChEI and/or memantine use at baseline, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.

  3. Change From Baseline in the Mini Mental State Examination (MMSE) Score [ Time Frame: Baseline, 76 Weeks ]
    MMSE is a brief screening 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 value was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, pooled investigator, AChEI and/or memantine use at baseline, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.

  4. Change From Baseline in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-iADL) Score [ Time Frame: Baseline, 76 Weeks ]
    The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL 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 value was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, pooled investigator, AChEI and/or memantine use at baseline, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.

  5. Change From Baseline in Brain Amyloid Plaque Deposition as Measured by Florbetapir F18 Positron Emission Tomography (PET) Scan [ Time Frame: Baseline, 76 Weeks ]
    Florbetapir PET imaging was used as a quantitative amyloid biomarker. Florbetapir PET scans at baseline and at 76 weeks after the first treatment were used to quantitatively estimate change in amyloid plaques. Quantitative amyloid burden was first formalized as the average Standardized Uptake Value Ratio (SUVR) in six predetermined cortical areas of the brain relative to the cerebellum as a reference region. Larger SUVR reflects the larger cortical amyloid burden relative to cerebellum. SUVR values were further calibrated to a centiloid (CL) scale. The Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scan. Least Squares mean change was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.

  6. Change From Baseline in Brain Tau Deposition as Measured by Flortaucipir F18 PET Scan [ Time Frame: Baseline, 76 Weeks ]
    Flortaucipir PET imaging was used as a quantitative tau biomarker. Flortaucipir PET scans at baseline and at 76 weeks after the first treatment were used to quantitatively estimate change in aggregated tau neurofibrillary tangles (NFTs). Quantitative tau burden was formalized using two measures: weighted average Standardized Uptake Value Ratio (MUBADA SUVR) in the brain relative to the cerebellum gray as a reference region and the global tau load (TauL) generated using a TauIQ method. Larger weighted average SUVR reflects the larger cortical tau burden relative to cerebellum gray. The TauIQ method quantifies the spatiotemporal accumulation pattern of tau and larger TauL value reflects the larger global tau level in the brain as determined using a TauIQ mathematical framework. Least Squares mean change was controlled for baseline + age + treatment (Type III sum of squares).

  7. Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) [ Time Frame: Baseline, 76 Weeks ]
    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 14 brain regions: bilateral cortical, bilateral entorhinal cortex, bilateral hippocampus, bilateral inferior parietal lobe, bilateral isthmus cingulate, bilateral lateral parietal lobe, bilateral medial temporal lobe, bilateral precuneus, bilateral prefrontal lobe, bilateral superior temporal lobe, bilateral ventricles, bilateral whole brain, bilateral whole temporal lobe, and bilateral white matter. The atrophy was assessed by tensor-based morphometry, which captures volume changes within the deformation map. LS Mean value was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, fixed covariates of baseline, and age at baseline.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Gradual and progressive change in memory function reported by participants or informants for ≥ 6 months.
  • MMSE score of 20 to 28 (inclusive) at baseline or an acceptable historical flortaucipir PET scan within 6 months prior to baseline that meets the central read criteria.
  • Meet 18F flortaucipir PET scan eligibility criteria.
  • Meet 18F florbetapir PET scan (central read) eligibility criteria.

Exclusion Criteria:

  • Have a history of long QT syndrome.
  • Have received treatment with a stable dose of an acetylcholinesterase inhibitor (AChEI) and/or memantine for less than 2 months before randomization.
  • Contraindication to MRI.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03367403


Locations
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Sponsors and Collaborators
Eli Lilly and Company
Investigators
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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
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol  [PDF] October 9, 2018
Statistical Analysis Plan  [PDF] December 7, 2020

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT03367403    
Other Study ID Numbers: 16933
I5T-MC-AACG ( Other Identifier: Eli Lilly and Company )
First Posted: December 8, 2017    Key Record Dates
Results First Posted: February 15, 2022
Last Update Posted: October 13, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Lilly provides access to the individual patient data from studies on approved medicines and indications as defined by the sponsor specific information on ClinicalStudyDataRequest.com.

This access is provided in a timely fashion after the primary publication is accepted. Researchers need to have an approved research proposal submitted through ClinicalStudyDataRequest.com. Access to the data will be provided in a secure data sharing environment after signing a data sharing agreement.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eli Lilly and Company:
TRAILBLAZER-ALZ
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
 Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders