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

Alzheimer Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05469360
• Other study ID #: CNIO752B12201
• Secondary ID: 2022-000921-26
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: February 23, 2023
• Est. completion date: October 21, 2025

Study information

• Verified date: February 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

This is a phase 1b, randomized, double-blind, placebo-controlled study, in which patients with early AD will receive a single intrathecal (IT) dose of NIO752 in the placebo-controlled part of the study and multiple administrations of NIO752 in the open-label extension (OLE) part of the study. 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. Participants who complete Day 170 visit of the placebo-controlled part of the study will be eligible to continue in an OLE part of the study regardless of randomization assignment in the placebo-controlled part. Participants in the OLE part will receive NIO752 IT injections at approximately 252 and 420 days after Day 1 (first IT injection). 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 25
• Est. completion date: October 21, 2025
• Est. primary completion date: October 21, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 74 Years

Eligibility

Main Inclusion Criteria (placebo-controlled part):

• 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-ß 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-ß 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-ß-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 Inclusion Criteria (OLE part):

• Signed informed consent of protocol version inclusive of the OLE.
• Participant must complete Day 170 of the placebo-controlled part of this study.

Main Exclusion Criteria (placebo-controlled part):

• 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-ß-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.

Main Exclusion Criteria (OLE part):

• Use of any investigational drugs, or participation in a clinical trial with an investigational new drug (other than NIO752), after completing the initial placebo-controlled part of this trial
• Participants who withdrew informed consent while participating in the main placebo-controlled part of the study

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction
• Mild Cognitive Impairment

Intervention

Drug:
• NIO752
A single intrathecal (cerebrospinal) injection of NIO752 of Dose A
• NIO752
A single intrathecal (cerebrospinal) injection of NIO752 at dose B
• Matching placebo
A single intrathecal injection of matching placebo
• NIO752
Multiple intrathecal injections of NIO752 of Dose A

Locations

Country	Name	City	State
Finland	Novartis Investigative Site	Kuopio
Finland	Novartis Investigative Site	Turku
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Paris 13
France	Novartis Investigative Site	Toulouse Cedex 9
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Malmo
Sweden	Novartis Investigative Site	Stockholm

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Finland,  France,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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 (placebo-controlled part) and up to 589 days (OLE part)
Secondary	Concentration of NIO752 in cerebrospinal fluid (CSF)	Concentration of NIO752 in CSF	Pre-dose, Days 57, 85, 170 (placebo-controlled part) and Days 252, 420, and 588 (OLE part)
Secondary	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 first dose, Days 14, 57, 85 and 170 (placebo-controlled part) and Days 252, 253, 420, 421, and 588 (OLE-part)
Secondary	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 (placebo-controlled part) and Days 252, 253, 420, 421, and 588 (OLE-part)
Secondary	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 (placebo-controlled part) and Days 252, 253, 420, 421, and 588 (OLE-part)
Secondary	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 (placebo-controlled part) and Days 252, 253, 420, 421, and 588 (OLE-part)