A Study to Evaluate Efficacy and Safety of Intravenous Sabirnetug in Participants With Early Alzheimer's Disease (ALTITUDE-AD)

1. Change from Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) Score

   Timeframe: Baseline up to Week 80

   iADRS is a validated composite of cognition and function made up of Alzheimer's Disease Assessment Scale - Cognitive Subscale 13-item (ADAS-Cog13) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living scale (ADCS-iADL). ADAS-Cog13 is a rater-administered instrument consisting of 13 items assessing cognitive function areas most typically impaired in AD. ADAS-Cog13 scores range from 0 to 85, with higher scores indicating a greater deficit of global cognition. The ADCS-iADL is a subset of the 23-item ADCS-ADL (items 6a and 7 to 23). The iADLs are more complex skills required to successfully live independently. iADL-items score ranges from 0 to 59 (lower scores indicating greater impairment). The iADRS is calculated as a linear combination of total scores from the ADAS-Cog13 and ADCS-iADL. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance.

1. Change from Baseline in ADCS-iADL Score

   Timeframe: Baseline up to Week 80

   The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire to be answered by a participant's study partner, where a participant's performance level is rated over the last 4 weeks, based on a set of performance descriptions. The ADCS-iADL is a subset of the 23-item ADCS-ADL (items 6a and 7 to 23). The iADLs are more complex skills required to successfully live independently, and include shopping, keeping appointments, traveling outside of the home, making a meal or snack, and reading and writing. The iADL-items score ranges from 0 to 59 with lower scores indicating greater impairment.

2. Change from Baseline in ADAS-Cog13 Score

   Timeframe: Baseline up to Week 80

   ADAS-Cog is a rater-administered instrument, designed to assess the severity of dysfunction in cognition, characteristic of persons with AD. The ADAS-Cog13, the cognitive subscale of the ADAS, consists of 13 items assessing cognitive function areas most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, and digit cancellation. The scores range from 0 to 85, with higher scores indicating a greater deficit of global cognition.

3. Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB)

   Timeframe: Baseline up to Week 80

   The CDR is obtained through semi-structured interviews of individuals with AD and informants. The ratings are obtained in six domains: memory, orientation, judgment \& problem-solving, community affairs, home \& hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0 = no impairment; 0.5 = questionable impairment; 1 = mild impairment; 2 = moderate impairment; and 3 = severe impairment. CDR-SB score is obtained by summing each of the domain scores, with scores ranging from 0 to 18. Higher scores reflect greater cognitive and functional impairment.

4. Change from Baseline in Mini-Mental State Examination (MMSE)

   Timeframe: Baseline up to Week 80

   MMSE is a standard staging and assessment tool in AD, designed for grading the cognitive state of individuals with AD. The scale comprises tasks concerning orientation, memory, attention, language, and praxis to evaluate an individual's cognitive state. MMSE total score ranges from 0 to 30, with lower scores indicative of greater cognitive impairment.

5. Change from Baseline in Quality of Life in Alzheimer's Disease (QoL-AD)

   Timeframe: Baseline up to Week 80

   The QOL-AD tool is a 13-item assessment with each question scored on a 4-point scale where 1 = poor quality of life and 4 = excellent quality of life. Scores range from 13 to 52 with higher scores indicating better quality of life.

6. Change from Baseline in Neuropsychiatric Inventory Questionnaire (NPI-Q) Score

   Timeframe: Baseline up to Week 80

   NPI-Q is a validated questionnaire completed by informants about participants for whom they care. Each of the 12 NPI-Q domains contains a survey question (answered in Yes/No) that reflects the cardinal symptoms of that domain. If the domain response is "Yes," the informant then rates the severity of the symptoms present within the last month on a 3-point scale and the distress of the symptom using a 5-point scale. The total NPI-Q severity score is the sum of the individual severity scores for each symptom and ranges from 0 to 36, with higher scores indicating more severe behavioral impairment. The total NPI-Q distress score is the sum of the individual distress scores for each symptom and ranges from 0 to 60, with higher scores indicating greater caregiver distress.

7. Change from Baseline in EuroQoL 5-Dimension 5-Level (EQ-5D-5L)

   Timeframe: Baseline up to Week 80

   EQ-5D-5L is a self-report survey that measures quality of life. The EQ-5D-5L consists of an EQ-5D descriptive system and EQ visual analog scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels, each assigned a unique 1-digit number: no problems, slight problems, moderate problems, severe problems, and extreme problems. The digits are combined into a 5-digit number that describes the participant's health state. The EQ VAS records the participant's health on a vertical visual analog scale, where the endpoints are labeled 0= the best health you can imagine, and 100= the worst health you can imagine.

8. Change from Baseline in Resource Utilization in Dementia (RUD)

   Timeframe: Baseline up to Week 80

   The RUD questionnaire is a standardized tool and the most widely used instrument for resource use data collection in dementia, enabling comparison of costs of care across countries with differing health care provisions. It is designed to collect data on formal and informal care resource use and to be useful in different care settings, across different countries and care systems, and in both clinical studies and observational cost-of-illness studies.

9. Change from Baseline in Zarit Burden Interview (ZBI)

   Timeframe: Baseline up to Week 80

   ZBI consists of 22 items. Twenty-one of the items are designed to measure several aspects of burden, whereas Item 22 is a global measure of burden. Response options for each item range from 0-4, and total scores range from 0-88, with higher scores indicating greater self-reported burden.

10. Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by iADRS

    Timeframe: Baseline up to Week 80

11. Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by ADCS-iADL

    Timeframe: Baseline up to Week 80

12. Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by ADAS-Cog13

    Timeframe: Baseline up to Week 80

13. Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by CDR-SB

    Timeframe: Baseline up to Week 80

14. Effect of sabirnetug on Clinical Progression as Compared to Placebo Assessed Using Time Saved Analysis as Measured by MMSE

    Timeframe: Baseline up to Week 80

15. Percentage of Participants with No Clinical Progression at One Year

    Timeframe: Baseline up to Week 80

    No clinical progression in participants will be defined as no decline in CDR-SB score. The CDR is obtained through semi-structured interviews of individuals with AD and informants. The ratings are obtained in six domains: memory, orientation, judgment \& problem-solving, community affairs, home \& hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0 = no impairment; 0.5 = questionable impairment; 1 = mild impairment; 2 = moderate impairment; and 3 = severe impairment. CDR-SB score is obtained by summing each of the domain scores, with scores ranging from 0 to 18. Higher scores reflect greater cognitive and functional impairment.

16. Number of Participants with Treatment-Related Adverse Events (TEAEs)

    Timeframe: Baseline up to Week 80

17. Number of Participants with Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)

    Timeframe: Baseline up to Week 80

18. Number of Participants who Discontinue or Withdraw due to TEAE

    Timeframe: Baseline up to Week 80

19. Number of Participants with Anti-Drug Antibodies (ADA) and Neutralizing Antibodies

    Timeframe: Baseline up to Week 80

20. Number of Participants with Amyloid-Related Imaging Abnormality with Edema/Effusions (ARIA-E) and ARIA with Hemorrhage/Hemosiderin Deposition (ARIA-H) as Measured by Magnetic Resonance Imaging (MRI)

    Timeframe: Baseline up to Week 80

21. Number of Participants with Suicidal Ideation and Behavior as Measured by Columbia-Suicide Severity Rating Scale (C-SSRS)

    Timeframe: Baseline up to Week 80

    The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). Greater lethality or potential lethality of suicidal behaviors (endorsed on the behavior subscale) indicates increased risk.

22. Serum Concentration of sabirnetug

    Timeframe: Pre-dose and multiple timepoints post dose up to 80 weeks

23. Concentration of sabirnetug in Cerebrospinal Fluid (CSF)

    Timeframe: Up to Week 76

24. CSF Concentrations of ACU193 in a Subset of Participants

    Timeframe: Up to Week 76

25. Correlation Between sabirnetug Exposure with Clinical Efficacy Measures

    Timeframe: Baseline up to 80 weeks

    Correlation between sabirnetug exposure and clinical outcomes (including iADRS, CDR-SB, ADCS-iADL, ADAS-Cog13, and MMSE) will be assessed in this study.

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