A Study to Evaluate the Safety and Tolerability of ALN-APP in Patients With EOAD

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of single intrathecal (IT) doses of ALN-APP in adult patients with early-onset Alzheimer's Disease (EOAD). Maximum treatment duration for Part A: single dose. Maximum treatment for Part B: 12 months.

Official Title
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A Randomized, Double-blind, Placebo-controlled Single Ascending Dose and Open-label Multi-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ALN-APP in Adult Patients With Early-onset Alzheimer's Disease (EOAD)

Conditions
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Early-Onset Alzheimer Disease

Intervention / Treatment
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* Drug: ALN-APP
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has mild cognitive impairment or mild dementia due to EOAD Has Clinical Dementia Rating (CDR) global score 0.5 or 1.0 and Mini Mental State Examination (MMSE) >20 Exclusion Criteria: Has Non-Alzheimer's disease dementia Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2×upper limit of normal (ULN) Has estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m^2 at Screening Has recently received an investigational agent Has recent treatment with amyloid-targeting antibody

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Maximum treatment duration for Part A: single dose. Maximum treatment for Part B: 12 months.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: ALN-APP<br>Participants will be administered a single dose of ALN-APP. | Drug: ALN-APP<br>* ALN-APP will be administered intrathecally (IT)<br>|
| Placebo Comparator: Part A: Placebo<br>Participants will be administered a single dose of placebo. | Drug: Placebo<br>* Placebo will be administered IT<br>|
| Experimental: Part B:<br>Participants will be administered multiple doses of ALN-APP. | Drug: ALN-APP<br>* ALN-APP will be administered intrathecally (IT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Frequency of Adverse Events |  | Up to 14 months | 
| Part B: Frequency of Adverse Events |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Change from Baseline in Levels of Cerebrospinal Fluid (CSF) Soluble Amyloid Precursor Protein Alpha (sAPPα) and Soluble Amyloid Precursor Protein Beta (sAPPβ) |  | Part A up to 14 months; Part B up to 24 months | 
| Part A and Part B: Area Under the Plasma Concentration-time Curve (AUC) of ALN-APP and of Potential Metabolites |  | Part A up to 14 months; Part B up to 24 months | 
| Part A and Part B: Maximum Observed Plasma Concentration (Cmax) of ALN-APP and of Potential Metabolites |  | Part A up to 14 months; Part B up to 24 months | 
| Part A: Fraction of ALN-APP and Potential Metabolites Excreted in the Urine (fe) |  | Up to 14 months | 
| Part A and Part B: Concentration at Time 't' (Ct) of ALN-APP and Potential Metabolites |  | Part A up to 14 months; Part B up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EOAD