Trial Outcomes & Findings for A Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) (NCT NCT03367403)

Last Updated: 2022-10-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

272 participants

Primary outcome timeframe

Baseline, 76 Weeks

Results posted on

2022-10-13

Participant Flow

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 12 milligram (mg) of LY3202626 slowing cognitive decline. Clinical efficacy was not reported for this group.

Participant milestones

Participant milestones
Measure	Donanemab Monotherapy (Donanemab-M) Participants received 700 mg donanemab intravenously (IV) every 4 weeks (Q4W) x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo Participants received placebo IV Q4W for up to 72 weeks.	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 daily orally for up to 72 weeks.
Overall Study STARTED	131	126	15
Overall Study Received at Least One Dose of Study Drug	131	125	15
Overall Study COMPLETED	94	93	12
Overall Study NOT COMPLETED	37	33	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Donanemab Monotherapy (Donanemab-M) Participants received 700 mg donanemab intravenously (IV) every 4 weeks (Q4W) x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo Participants received placebo IV Q4W for up to 72 weeks.	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 daily orally for up to 72 weeks.
Overall Study Adverse Event	20	6	2
Overall Study Withdrawal by Subject	12	13	1
Overall Study Death	1	2	0
Overall Study Physician Decision	0	1	0
Overall Study Protocol Violation	1	1	0
Overall Study Withdrawal Due to Caregiver Circumstances	0	2	0
Overall Study COVID-19	3	6	0
Overall Study Abuse of Alcohol Intake	0	1	0
Overall Study Subject and Study Partner do not believe study has been Beneficial and Cognition has Declined	0	1	0

Baseline Characteristics

All randomized participants with non-missing iADRS data.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Donanemab Monotherapy (Donanemab-M) n=131 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=126 Participants Participants received placebo IV Q4W for up to 72 weeks.	Donanemab in Combination With LY3202626 (Donanemab-C) n=15 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W in combination with 12 mg of LY3202626 daily orally for up to 72 weeks.	Total n=272 Participants Total of all reporting groups
Age, Continuous	74.95 years STANDARD_DEVIATION 5.58 • n=131 Participants	75.35 years STANDARD_DEVIATION 5.43 • n=126 Participants	75.20 years STANDARD_DEVIATION 5.99 • n=15 Participants	75.15 years STANDARD_DEVIATION 5.52 • n=272 Participants
Sex: Female, Male Female	68 Participants n=131 Participants	65 Participants n=126 Participants	12 Participants n=15 Participants	145 Participants n=272 Participants
Sex: Female, Male Male	63 Participants n=131 Participants	61 Participants n=126 Participants	3 Participants n=15 Participants	127 Participants n=272 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=131 Participants	3 Participants n=126 Participants	1 Participants n=15 Participants	9 Participants n=272 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	126 Participants n=131 Participants	123 Participants n=126 Participants	14 Participants n=15 Participants	263 Participants n=272 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=131 Participants	0 Participants n=126 Participants	0 Participants n=15 Participants	0 Participants n=272 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=131 Participants	0 Participants n=126 Participants	0 Participants n=15 Participants	2 Participants n=272 Participants
Race (NIH/OMB) Asian	1 Participants n=131 Participants	2 Participants n=126 Participants	0 Participants n=15 Participants	3 Participants n=272 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=131 Participants	0 Participants n=126 Participants	0 Participants n=15 Participants	0 Participants n=272 Participants
Race (NIH/OMB) Black or African American	5 Participants n=131 Participants	3 Participants n=126 Participants	0 Participants n=15 Participants	8 Participants n=272 Participants
Race (NIH/OMB) White	122 Participants n=131 Participants	121 Participants n=126 Participants	15 Participants n=15 Participants	258 Participants n=272 Participants
Race (NIH/OMB) More than one race	1 Participants n=131 Participants	0 Participants n=126 Participants	0 Participants n=15 Participants	1 Participants n=272 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=131 Participants	0 Participants n=126 Participants	0 Participants n=15 Participants	0 Participants n=272 Participants
Region of Enrollment Canada	10 Participants n=131 Participants	11 Participants n=126 Participants	0 Participants n=15 Participants	21 Participants n=272 Participants
Region of Enrollment United States	121 Participants n=131 Participants	115 Participants n=126 Participants	15 Participants n=15 Participants	251 Participants n=272 Participants
Integrated Alzheimer's Disease Rating Scale (iADRS)	106.20 score on a scale STANDARD_DEVIATION 13.03 • n=130 Participants • All randomized participants with non-missing iADRS data.	105.88 score on a scale STANDARD_DEVIATION 13.22 • n=126 Participants • All randomized participants with non-missing iADRS data.	108.93 score on a scale STANDARD_DEVIATION 10.17 • n=15 Participants • All randomized participants with non-missing iADRS data.	106.20 score on a scale STANDARD_DEVIATION 12.96 • n=271 Participants • All randomized participants with non-missing iADRS data.

PRIMARY outcome

Timeframe: Baseline, 76 Weeks

Population: All participants randomized to donanemab monotherapy or placebo with a baseline and at least one non-missing postbaseline iADRS data. Per protocol, outcomes were analyzed by comparing donanemab Monotherapy (Donanemab-M) and placebo.

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=93 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=91 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) Score	-6.86 score on a scale Standard Error 1.135	-10.06 score on a scale Standard Error 1.141

SECONDARY outcome

Timeframe: Baseline, 76 Weeks

Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline ADAS-Cog13 data. Per protocol, outcomes were analyzed by comparing donanemab Monotherapy (Donanemab-M) and placebo.

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.

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=93 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=93 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score	2.91 score on a scale Standard Error 0.659	4.77 score on a scale Standard Error 0.660

SECONDARY outcome

Timeframe: Baseline, 76 Weeks

Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline CDR-SB data. Per protocol, outcomes were analyzed by comparing donanemab Monotherapy (Donanemab-M) and placebo.

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.

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=93 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=90 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Score	1.22 score on a scale Standard Error 0.176	1.58 score on a scale Standard Error 0.178

SECONDARY outcome

Timeframe: Baseline, 76 Weeks

Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline MMSE data. Per protocol, outcomes were analyzed by comparing donanemab Monotherapy (Donanemab-M) and placebo.

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.

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=91 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=90 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in the Mini Mental State Examination (MMSE) Score	-2.35 score on a scale Standard Error 0.386	-2.98 score on a scale Standard Error 0.390

SECONDARY outcome

Timeframe: Baseline, 76 Weeks

Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline ADCS-iADL data. Per protocol, outcomes were analyzed by comparing donanemab Monotherapy (Donanemab-M) and placebo.

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.

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=93 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=91 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-iADL) Score	-3.98 score on a scale Standard Error 0.738	-5.20 score on a scale Standard Error 0.743

SECONDARY outcome

Timeframe: Baseline, 76 Weeks

Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline PET amyloid data. Per protocol, outcomes were analyzed by comparing donanemab Monotherapy (Donanemab-M) and placebo.

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.

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=90 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=91 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in Brain Amyloid Plaque Deposition as Measured by Florbetapir F18 Positron Emission Tomography (PET) Scan	-84.13 centiloids Standard Error 2.723	0.93 centiloids Standard Error 2.739

SECONDARY outcome

Timeframe: Baseline, 76 Weeks

Population: All randomized participants who received at least one dose of study drug with non-missing baseline and at least one non-missing post-baseline PET tau data. Per protocol, outcomes were analyzed by comparing donanemab Monotherapy (Donanemab-M) and placebo.

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).

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=90 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=87 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in Brain Tau Deposition as Measured by Flortaucipir F18 PET Scan Tau-IQ	0.55 standardized uptake value ratio (SUVR) Standard Error 0.007	0.55 standardized uptake value ratio (SUVR) Standard Error 0.007
Change From Baseline in Brain Tau Deposition as Measured by Flortaucipir F18 PET Scan MUBADA-Cerebellum	1.54 standardized uptake value ratio (SUVR) Standard Error 0.009	1.58 standardized uptake value ratio (SUVR) Standard Error 0.010

SECONDARY outcome

Timeframe: Baseline, 76 Weeks

Population: All randomized participants who received at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value. Per protocol, outcomes were analyzed by comparing donanemab monotherapy (Donanemab-M) and placebo.

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.

Outcome measures

Outcome measures
Measure	Donanemab Monotherapy (Donanemab-M) n=82 Participants Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks.	Placebo n=83 Participants Participants received placebo IV Q4W for up to 72 weeks.
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Prefrontal Lobe	-1.50 cubic centimeter (cm^3) Standard Error 0.081	-1.11 cubic centimeter (cm^3) Standard Error 0.080
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Whole Temporal Lobe	-3.52 cubic centimeter (cm^3) Standard Error 0.126	-2.84 cubic centimeter (cm^3) Standard Error 0.126
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Inferior Parietal Lobe	-0.53 cubic centimeter (cm^3) Standard Error 0.033	-0.45 cubic centimeter (cm^3) Standard Error 0.033
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Isthmuscingulate	-0.15 cubic centimeter (cm^3) Standard Error 0.008	-0.13 cubic centimeter (cm^3) Standard Error 0.008
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Lateral Parietal Lobe	-1.60 cubic centimeter (cm^3) Standard Error 0.084	-1.26 cubic centimeter (cm^3) Standard Error 0.083
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Medial Temporal Lobe	-0.73 cubic centimeter (cm^3) Standard Error 0.025	-0.72 cubic centimeter (cm^3) Standard Error 0.025
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Precuneus	-0.71 cubic centimeter (cm^3) Standard Error 0.032	-0.55 cubic centimeter (cm^3) Standard Error 0.032
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Superior Temporal Lobe	-0.73 cubic centimeter (cm^3) Standard Error 0.031	-0.52 cubic centimeter (cm^3) Standard Error 0.031
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Ventricles	8.66 cubic centimeter (cm^3) Standard Error 0.412	6.38 cubic centimeter (cm^3) Standard Error 0.410
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Cortical	-11.18 cubic centimeter (cm^3) Standard Error 0.447	-8.51 cubic centimeter (cm^3) Standard Error 0.445
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Whole Brain	-24.53 cubic centimeter (cm^3) Standard Error 1.077	-19.95 cubic centimeter (cm^3) Standard Error 1.072
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Entorhinal Cortex	-0.17 cubic centimeter (cm^3) Standard Error 0.008	-0.17 cubic centimeter (cm^3) Standard Error 0.008
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral Hippocampus	-0.22 cubic centimeter (cm^3) Standard Error 0.013	-0.22 cubic centimeter (cm^3) Standard Error 0.013
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI) Bilateral White Matter	-11.03 cubic centimeter (cm^3) Standard Error 0.700	-8.75 cubic centimeter (cm^3) Standard Error 0.696

Adverse Events

Donanemab Monotherapy (Donanemab-M)

Serious events: 26 serious events

Other events: 118 other events

Deaths: 1 deaths

Placebo

Serious events: 25 serious events

Other events: 112 other events

Deaths: 2 deaths

Donanemab in Combination With LY3202626 (Donanemab-C)

Serious events: 3 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 30 days but less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
Publication restrictions are in place

Restriction type: OTHER