Alzheimer's Disease, Dementia, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Neurodegenerative Diseases, Neurocognitive Disorders, Mental Disorders
Conditions
Brief summary
This study will investigate different donanemab dosing regimens and their effect on the frequency and severity of ARIA-E in adults with early symptomatic Alzheimer's disease (AD) and explore participant characteristics that might predict risk of ARIA. Approximately 375 additional participants will be enrolled per addendum. The study will last approximately 91 weeks and include up to 26 visits in the main study.
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Phase 3b
Eligibility
Sex/Gender
ALL
Age
60 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Gradual and progressive change in memory function reported by the participant or informant for ≥6 months. * A mini mental state examination (MMSE) score of 20 to 28 (inclusive) at screening. * Have an amyloid PET scan result from central read, consistent with the presence of amyloid pathology.
Exclusion criteria
* Have significant neurological disease affecting the central nervous system other than AD, that may affect cognition or ability to complete the study, including but not limited to, other dementias, serious infection of the brain, Parkinson's disease, multiple concussions, or epilepsy or recurrent seizures, except febrile childhood seizures. * Has current serious or unstable illnesses including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses in this study. * A life expectancy of \<24 months. * Contraindication to MRI or PET scans * Have had prior treatment with a passive anti-amyloid immunotherapy. * Have a presence or history of malignant neoplasms within the past 5 years prior to Visit 1. Exceptions: * non-metastatic basal- or squamous-cell skin cancer * Stage 0 non-invasive carcinoma of the cervix * Stage 0 non-invasive prostate cancer, or * other cancers with low risk of recurrence or spread
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Edema/Effusion (ARIA-E) | 24 Weeks | Percentage of participants with occurrence of ARIA-E at Week 24 is reported here. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Any Occurrence of ARIA-E | 52 Weeks | Outcome data will be provided after the study is completed. |
| Change From Baseline in Brain Amyloid Plaque Deposition As Measured By Amyloid Positron Emission Tomography (PET) Scan | Baseline, 76 Weeks | Outcome data will be provided after the study is completed. |
| Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Hemorrhage/Hemosiderin Deposits (ARIA-H) | 24 Weeks | Percentage of participants with occurrence of ARIA-H at Week 24 is reported here. |
| Pharmacokinetics (PK): Average Serum Concentration of Donanemab | Baseline to 76 Weeks | Outcome data will be provided after the study is completed. |
| Percentage of Participants With Maximum Severity of ARIA-E or ARIA-H | 76 Weeks | Outcome data will be provided after the study is completed. |
| Number of Participants With Anti-Drug Antibodies (ADAs) Against Donanemab, Including Treatment Emergent ADAs and Neutralizing Antibodies | Baseline to End of Follow-Up (91 Weeks) | Outcome data will be provided after the study is completed. |
| Percentage of Participants With ARIA-H | 52 Weeks | Outcome data will be provided after the study is completed. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
Current results reporting is for primary results completion date (16-May-2024) i.e., up to week 24. Data beyond week 24 will be reported at the time of final results reporting.
Pre-assignment details
Addendum recruited a separate cohort of participants than the main study (recruitment started on 14 July 2025). Data for the addendum arms will not be reported for Primary Outcome Measures. Participant Flow, Baseline Characteristics, and Adverse Events data for the addendum arms will be reported at the time of final results reporting.
Participants by arm
| Arm | Count |
|---|---|
| 1400 mg Donanemab - Standard Regimen Participants received:
* 700 mg donanemab administered IV at baseline, week 4, and 8.
* placebo administered IV at week 2, 6, 10, and 14.
* 1400 mg of donanemab administered IV at week 12, 16, 20, and 24. | 207 |
| 1400 mg Donanemab - Dose Skipping Participants received:
* 700 mg donanemab administered IV at baseline.
* placebo administered IV at week 2, 4, 6, 10, and 14.
* 1400 mg of donanemab administered IV at week 8, 12, 16, 20, and 24. | 210 |
| 1400 mg Donanemab - Titration Participants received:
* 350 mg donanemab administered IV at baseline.
* placebo administered IV at week 2, 6, 10, and 14.
* 700 mg donanemab administered IV at week 4.
* 1050 mg of donanemab administered IV at week 8.
* 1400 mg of donanemab administered IV at week 12, 16, 20, and 24. | 212 |
| 1400 mg Donanemab - Cmax Participants received:
* 350 mg donanemab administered IV at baseline, weeks 2, 4, 6, 8, and 10.
* 700 mg donanemab administered IV at weeks 12 and 14.
* 1400 mg of donanemab administered IV at weeks 16, 20, and 24. | 213 |
| Total | 842 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 | 4 | 5 |
| Overall Study | Assigned Treatment by Mistake | 0 | 0 | 0 | 1 |
| Overall Study | Continuing Study | 194 | 196 | 193 | 191 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 2 | 1 |
| Overall Study | Participant had Poor Venous Access | 0 | 0 | 0 | 1 |
| Overall Study | Participant was Non-ambulatory | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 2 | 4 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 5 | 7 | 13 |
| Overall Study | Withdrawal Due to Caregiver Circumstances | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 1400 mg Donanemab - Standard Regimen | Total | 1400 mg Donanemab - Cmax | 1400 mg Donanemab - Titration | 1400 mg Donanemab - Dose Skipping |
|---|---|---|---|---|---|
| Age, Continuous | 73.30 years STANDARD_DEVIATION 5.66 | 73.60 years STANDARD_DEVIATION 5.8 | 73.20 years STANDARD_DEVIATION 6.02 | 74.30 years STANDARD_DEVIATION 5.69 | 73.40 years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 46 Participants | 15 Participants | 11 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 189 Participants | 767 Participants | 190 Participants | 195 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 29 Participants | 8 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 9 Participants | 3 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 46 Participants | 13 Participants | 14 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 196 Participants | 782 Participants | 196 Participants | 193 Participants | 197 Participants |
| Region of Enrollment United Kingdom | 20 Participants | 95 Participants | 27 Participants | 20 Participants | 28 Participants |
| Region of Enrollment United States | 187 Participants | 747 Participants | 186 Participants | 192 Participants | 182 Participants |
| Sex: Female, Male Female | 120 Participants | 486 Participants | 123 Participants | 126 Participants | 117 Participants |
| Sex: Female, Male Male | 87 Participants | 356 Participants | 90 Participants | 86 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 207 | 0 / 210 | 1 / 212 | 0 / 213 |
| other Total, other adverse events | 139 / 207 | 140 / 210 | 141 / 212 | 137 / 213 |
| serious Total, serious adverse events | 18 / 207 | 18 / 210 | 23 / 212 | 20 / 213 |
Outcome results
Primary
Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Edema/Effusion (ARIA-E)
Percentage of participants with occurrence of ARIA-E at Week 24 is reported here.
Time frame: 24 Weeks
Population: All participants who received at least one dose of donanemab and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1400 mg Donanemab - Standard Regimen | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Edema/Effusion (ARIA-E) | 23.67 Percentage of participants |
| 1400 mg Donanemab - Dose Skipping | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Edema/Effusion (ARIA-E) | 18.57 Percentage of participants |
| 1400 mg Donanemab - Titration | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Edema/Effusion (ARIA-E) | 13.68 Percentage of participants |
| 1400 mg Donanemab - Cmax | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Edema/Effusion (ARIA-E) | 18.31 Percentage of participants |
Secondary
Change From Baseline in Brain Amyloid Plaque Deposition As Measured By Amyloid Positron Emission Tomography (PET) Scan
Outcome data will be provided after the study is completed.
Time frame: Baseline, 76 Weeks
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) Against Donanemab, Including Treatment Emergent ADAs and Neutralizing Antibodies
Outcome data will be provided after the study is completed.
Time frame: Baseline to End of Follow-Up (91 Weeks)
Secondary
Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Hemorrhage/Hemosiderin Deposits (ARIA-H)
Percentage of participants with occurrence of ARIA-H at Week 24 is reported here.
Time frame: 24 Weeks
Population: All participants who received at least one dose of donanemab and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1400 mg Donanemab - Standard Regimen | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Hemorrhage/Hemosiderin Deposits (ARIA-H) | 25.12 Percentage of participants |
| 1400 mg Donanemab - Dose Skipping | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Hemorrhage/Hemosiderin Deposits (ARIA-H) | 22.86 Percentage of participants |
| 1400 mg Donanemab - Titration | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Hemorrhage/Hemosiderin Deposits (ARIA-H) | 20.28 Percentage of participants |
| 1400 mg Donanemab - Cmax | Percentage of Participants With Any Occurrence of Amyloid-Related Imaging Abnormality-Hemorrhage/Hemosiderin Deposits (ARIA-H) | 20.66 Percentage of participants |
Secondary
Percentage of Participants With Any Occurrence of ARIA-E
Outcome data will be provided after the study is completed.
Time frame: 52 Weeks
Secondary
Percentage of Participants With ARIA-H
Outcome data will be provided after the study is completed.
Time frame: 52 Weeks
Secondary
Percentage of Participants With Maximum Severity of ARIA-E or ARIA-H
Outcome data will be provided after the study is completed.
Time frame: 76 Weeks
Secondary
Pharmacokinetics (PK): Average Serum Concentration of Donanemab
Outcome data will be provided after the study is completed.
Time frame: Baseline to 76 Weeks