Assessment of Safety, Tolerability, and Efficacy of Donanemab in Early Symptomatic Alzheimer*s Disease

1. 60 to 85 years of age inclusive, at the time of signing the informed consent.
2. Gradual and progressive change in memory function reported by the
participant or informant for >=6 months.
3. An MMSE score of 20 to 28 (inclusive) at LEAD-IN SCREENING or COMPLETE
SCREENING,
4. Meet flortaucipir F18 scan (central read) criteria
5. Meet florbetapir F18 scan (central read) criteria
6. Have a study partner who will provide written informed consent to
participate, is in frequent contact with the participant (defined as at least
10 hours per week), and will accompany the participant to study visits or be
available by telephone at designated times.
7. Have adequate literacy, vision, and hearing for neuropsychological testing
in the opinion of the investigator at the time of screening.
8. Are reliable and willing to make themselves available for the duration of
the study and are willing to follow study procedures.
9. Males and females will be eligible for this study.
10.Capable of giving signed informed consent as described in Section 10.1.3
which includes compliance with the requirements and restrictions listed in the
informed consent form (ICF) and in this protocol.

12. Significant neurological disease affecting the central nervous system
(CNS), 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).
13. 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; or has a life expectancy of <24 months.
14. History of cancer within the last 5 years, with the exception of
non-metastatic basal and/or squamous cell carcinoma of the skin, in situ
cervical cancer, nonprogressive prostate cancer, or other cancers with low risk
of recurrence or spread.
15. Participants with any current primary psychiatric diagnosis other than AD
if, in the judgment of the investigator, the psychiatric disorder or symptom is
likely to confound interpretation of drug effect, affect cognitive assessment,
or affect the participant*s ability to complete the study. Participants with
history of schizophrenia or other chronic psychosis are excluded.
16. Are, in the judgment of the investigator, actively suicidal and therefore
deemed to be at significant risk for suicide.
17. History of alcohol or drug use disorder (except tobacco use disorder)
within 2 years before the screening visit.
18. Have a history of clinically significant multiple or severe drug allergies,
significant atopy, or severe posttreatment hypersensitivity reactions
(including but not limited to erythema multiforme major, linear immunoglobulin
A dermatosis, toxic epidermal necrolysis, and/or exfoliative dermatitis).
19. Have any clinically important abnormality at screening, as determined by
investigator, in physical or neurological examination, vital signs, ECG, or
clinical laboratory test results that could be detrimental to the patient,
could compromise the study, or show evidence of other etiologies for dementia.
20. Screening MRI which shows evidence of significant abnormality that would
suggest another potential etiology for progressive dementia or a clinically
significant finding that may impact the patient*s ability to safely participate
in the study.
21. Have any contraindications for MRI, including claustrophobia or the
presence of contraindicated metal (ferromagnetic) implants/cardiac pacemaker.
22. Have a centrally read MRI demonstrating presence of ARIA-E, >4 cerebral
microhemorrhages, more than 1 area of superficial siderosis, any
macrohemorrhage or severe white matter disease at screening.
23. Sensitivity to florbetapir F18 or flortaucipir F18.
24. Poor venous access.
25. Contraindication to PET.
26. Present or planned exposure to ionizing radiation that, in combination with
the planned administration of study PET ligands, would result in a cumulative
exposure that exceeds local recommended exposure limits.
27. A corrected QT (QTcF) interval measurement >450 msec (men) or >470 msec
(women) at screening (as determined at the investigational site). The site may
request a central read prior to making determination of this criterion.
28. Calculated creatinine clearance <30 mL/min (Cockcroft-Gault formula;
Cockcroft and Gault 1976) at screening.
29. Alanine transaminase (ALT) >=2X the upper limit of normal (ULN) of the
performing laboratory, aspartate aminotransferase (AST) >=2X ULN, total
bilirubin level (TBL) >=1.5X ULN, or alkaline phosphatase (ALP) >=1.5X ULN at
screening.
30. Have received treatment with a stable dose of an acetylcholinesterase
inhibitor (AChEI) and/or memantine for less than 2 months before randomization.
[If a patient has recently stopped an AChEI and/or memantine, he or she must
have discontinued treatment at least 2 months before randomization.]
31. Changes in concomitant medications that could potentially affect cognition
and their dosing should be stable for at least 1 month before screening, and
between screening and randomization (does not apply to medications discontinued
due to exclusions or with limited duration of use, such as antibiotics).
32. Have had prior treatment with a passive anti-amyloid immunotherapy <5
half-lives prior to randomization.
33. Have received active immunization against Aβ in any other study.
34. Have known allergies to donanemab, related compounds, or any components of
the formulation.
35. Are currently enrolled in any other interventional clinical trial involving
an investigational product or any other type of medical research judged not to
be scientifically or medically compatible with this study.
36. Have participated, within the last 30 days (4 months for studies conducted
in Japan; 3 months for studies conducted in the UK), in a clinical trial
involving an investigational product. If the previous investigational product
is scientifically or medically incompatible with this study and has a long
half-life, 3 months or 5 half-lives (whichever is longer) should have passed
prior to screening (Participation in observational studies may be permitted
upon review of the observational study protocol and approval by the sponsor).
37. Have previously completed or withdrawn from this study or received
donanemab in any prior investigational study. (This exclusion criterion does
not apply to patients who are allowed to rescreen before randomization in this
study).
38. Are investigator site personnel directly affiliated with this study and/or
their immediate families. Immediate family is defined as a spouse, parent,
child, or sibling, whether biological or legally adopted.
39. Are Lilly employees or are employees of third-party organizations (TPOs)
involved in study who require exclusion of their employees, or have study
partners who are Lilly employees or are employees of TPOs involved in a study
which require exclusion of their employees.