Study of Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of NIO752 in Early Alzheimer's Disease Participants

Study Overview
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Brief Summary
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Phase 1b study to assess the pharmacodynamics, safety, tolerability, and pharmacokinetics of NIO752 in patients with early Alzheimer's disease (AD)

Detailed Description
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This is a phase 1b, randomized, double-blind, placebo-controlled study, in which patients with early AD will receive a single intrathecal dose of NIO752. A total of 24 participants will be enrolled into one of two cohorts (each with 12 participants) and randomized into receiving one dose of NIO752 or placebo in 2:1 ratio. Participants will remain in this study for a 170-day follow-up period including approximately 3 in-clinic visits. Cohorts will be enrolled sequentially. Study assessments will include pharmacokinetics (PK), physical and neurological examinations, ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), CSF routine laboratory test, adverse event, and serious adverse event monitoring.

Official Title
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A Randomized, Participant and Investigator Blinded, Placebo-Controlled Study to Evaluate the Ability of a Single Intrathecally Administered Dose of NIO752 to Lower Cerebrospinal Fluid Total Tau Levels in Participants With Early Alzheimer's Disease

Conditions
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Alzheimer Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: NIO752
* Drug: NIO752
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Between 30 to 74 years old (both inclusive) at the time of informed consent. A diagnosis of mild Alzheimer's Disease (AD) or mild cognitive impairment (MCI) due to AD at screening with at least a 6-month decline in cognitive function prior to screening documented in the medical record. Both participants with sporadic AD as well as Amyloid Precursor Protein (APP), Presenilin-1 (PSEN1) or Presenilin-2 (PSEN2) mutation carriers are eligible. Participants must have a diagnosis of MCI due to AD or mild AD at screening as defined by a Clinical Dementia Rating Scale (CDR) Global Score of 0.5 or 1 and a Memory Score ≥ 0.5. A history of CSF biomarkers supporting the diagnosis of AD obtained at any time point prior to screening, including CSF amyloid (amyloid-β 42 and/or 42/40 ratio) AND tau species (total tau and/or phosphorylated tau). All participants must have documented historical confirmation of both CSF biomarkers (amyloid-β and tau species) with results supporting a diagnosis of AD prior to screening. This criterion will be determined individually for each participant taking into consideration the biomarker assay used in each case.For participants with no historical CSF biomarker information, a LP for CSF collection must be performed at the screening visit. For CSF collected at screening, participants must have confirmed positivity of amyloid-β-42 ≤ 1000 pg/mL as well as positivity on, at least, one of the following Tau biomarkers: phosphorylated-tau-181 > 12 pg/ml OR T-tau > 149.9 pg/mL as determined by the central laboratory. Participant has a reliable study partner or caregiver (e.g., spouse, sibling, close friend, adult child) who, is at least 18 years old. Participant resides in a proximity to the study site to allow a timely unscheduled visit in the study site, if necessary. Participant is able to undergo lumbar puncture (LP), CSF collections, and blood draws, tolerate brain MRI, and able to participate and tolerate all study procedures at study visit. Main Exclusion Criteria: Participant lives in a skilled nursing facility or dementia care facility. Any previous use of experimental therapy within 180 days or 5 half-lives prior to Day 1, whichever is greater. Previous exposure to anti-tau and anti-β-amyloid antibodies is allowed if at the time of screening at least 180 days have passed since the last dose. Previous exposure to amyloid vaccines or tau vaccines meant to treat AD, or previous treatment with oligonucleotides or with gene therapy at any time frame is not allowed. Any current or past non-AD neurological conditions. Other medical conditions including but not limited to poorly controlled diabetes mellitus, unstable angina, myocardial infarction, chronic heart failure, clinical significant conduction abnormalities, impaired renal or kidney function, which, in the opinion of the Investigator, would make the participant unsuitable for inclusion or could interfere with the participation in or completion of the study. Treatment with immunosuppressants, antipsychotics, lithium, neuroleptics, dopaminergic agonists, L-dopa, or monoamine oxidase inhibitors at the time of screening. Current use of medications, other than cholinesterase inhibitors and/or memantine, that could alter cognition, as determined by the Investigator. If the participant is receiving cholinesterase inhibitors and/or memantine, the dose must have been stable within 12 weeks prior to screening, and must remain stable during the duration of the study. Brain MRI at screening or within 12 months prior to screening showing evidence of cerebrovascular disease such as acute or sub-acute micro- or macrohemorrhage, significant signs of major cerebrovascular disease, or any other imaging evidence that, in the opinion of the Investigator, makes the participant unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 74 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: Sequential Assignment
Interventional Model Description: Phase 1b
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NIO752 - Dose A - Cohort 1<br>A single intrathecal injection of Dose A | Drug: NIO752<br>* A single intrathecal (cerebrospinal) injection of NIO752 of Dose A<br>|
| Placebo Comparator: Matching placebo - Cohort 1<br>A single intrathecal injection of artificial cerebrospinal fluid (CSF) | Drug: Matching placebo<br>* A single intrathecal injection of matching placebo<br>|
| Experimental: NIO752 Dose B - Cohort 2<br>A single intrathecal injection of Dose B | Drug: NIO752<br>* A single intrathecal (cerebrospinal) injection of NIO752 at dose B<br>|
| Placebo Comparator: Matching placebo - Cohort 2<br>A single intrathecal injection of artificial cerebrospinal fluid (CSF) | Drug: Matching placebo<br>* A single intrathecal injection of matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cerebrospinal total tau from baseline to Day 85 | Total tau protein levels in cerebrospinal fluid. More frequent timepoints might be added as deemed necessary per the site Investigator's judgment. | Baseline, Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events and serious adverse events | Adverse events are collected at each clinic visit. Laboratory values and other safety assessment values considered clinically significant by the investigator and meet the definition of adverse event will be reported. | Baseline up to 170 days | 
| Concentration of NIO752 in cerebrospinal fluid (CSF) | Concentration of NIO752 in CSF | Pre-dose, Days 57, 85, 170 | 
| Cmax, Ctrough in plasma | Maximum and trough level concentrations of NIO752 in plasma | Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post dose, Days 14, 57, 85 and 170 | 
| Tmax in blood plasma | Time of Cmax in plasma post-IT injection | Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post dose, Days 14, 57, 85 and 170 | 
| AUC-last in blood plasma | Area under curve (AUC) from time zero to the last measurable concentration sampling time (t-last) (mass x time x volume-1) | Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post dose, Days 14, 57, 85 and 170 | 
| AUC-inf in blood plasma | The AUC from time zero to infinity (mass x time x volume-1) | Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post dose, Days 14, 57, 85 and 170 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurodegenerative Diseases, Neurocognitive Disorders, Memory loss, Placebo, Adult, Alzheimer Disease, Autosomal dominant Alzheimer disease, Early onset Alzheimer disease, Familial Alzheimer disease, Dementia, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Tauopathies