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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Intervention / Treatment: Drug: NIO752; Drug: NIO752; Drug: Matching placebo; Drug: NIO752; Drug: NIO752; Drug: NIO752; Drug: Matching placebo

Detailed Description

This is a phase 1b, randomized, double-blind, placebo-controlled study, in which 36 patients with early AD will be enrolled in one of three cohorts.

Cohorts 1 & 2 will receive a single intrathecal (IT) dose of NIO752 or placebo in the placebo-controlled part of the study, and multiple administrations of NIO752 in the open-label extension (OLE) part of the study.

Cohort 3 will receive two single IT doses of NIO752 or placebo in the placebo-controlled part of the study, and a single administration of NIO752 in the OLE part of the study.

Each cohort will enroll 12 participants, and they will be randomized into receiving NIO752 or placebo in 2:1 ratio. Participants in cohorts 1& 2 will remain in this study for approximately ~19 months, including ~18 in-clinic follow up visits during that period of time. In cohort 3, participants will remain in this study for a follow up period of approximately ~18 months including ~10 in-clinic follow up visits.

Cohorts will be enrolled sequentially.

Participants who complete 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. All OLE participants will receive either two (cohorts 1 & 2) or one (cohort 3) dose of NIO752.

Study assessments will include physical and neurological examinations, ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), routine laboratory evaluation of CSF collected through lumbar puncture, adverse event, and serious adverse event monitoring. Cohort 3 participation will also require 3 MRI scans and 3 PET scans throughout the 18 months of the study.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• Finland
  • Kuopio, Finland, 70210
    • Novartis Investigative Site
  • Turku, Finland, 20520
    • Novartis Investigative Site
• France
  • Lille, France, 59037
    • Novartis Investigative Site
  • Paris, France, 75013
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Valencia
    • Valencia, Valencia, Spain, 46017
      • Novartis Investigative Site
• Sweden
  • Malmö, Sweden, 221 85
    • Novartis Investigative Site
  • Stockholm, Sweden, 141 86
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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-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 (Cohorts 1 & 2 only) 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 to the study site, if necessary.
• Participant is able to undergo lumbar puncture (LP), CSF collections, and blood draws, tolerate brain MRI and PET scanning, 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-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.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NIO752 - Dose A - Cohort 1; A single intrathecal injection of Dose A	Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 of Dose A; Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 at dose B; Drug: NIO752; Multiple intrathecal injections of NIO752 of Dose A; Drug: NIO752; Two intrathecal injections of NIO752 at dose C; Drug: NIO752; Single intrathecal injection of NIO752 at dose C
Placebo Comparator: Matching placebo - Cohort 1; A single intrathecal injection of artificial cerebrospinal fluid (CSF)	Drug: Matching placebo; A single intrathecal injection of matching placebo; Drug: Matching placebo; Two intrathecal injections of matching placebo
Experimental: NIO752 Dose B - Cohort 2; A single intrathecal injection of Dose B	Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 of Dose A; Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 at dose B; Drug: NIO752; Multiple intrathecal injections of NIO752 of Dose A; Drug: NIO752; Two intrathecal injections of NIO752 at dose C; Drug: NIO752; Single intrathecal injection of NIO752 at dose C
Placebo Comparator: Matching placebo - Cohort 2; A single intrathecal injection of artificial cerebrospinal fluid (CSF)	Drug: Matching placebo; A single intrathecal injection of matching placebo; Drug: Matching placebo; Two intrathecal injections of matching placebo
Experimental: NIO752 OLE - Cohorts 1 and 2; Multiple intrathecal injections of Dose A	Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 of Dose A; Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 at dose B; Drug: NIO752; Multiple intrathecal injections of NIO752 of Dose A; Drug: NIO752; Two intrathecal injections of NIO752 at dose C; Drug: NIO752; Single intrathecal injection of NIO752 at dose C
Experimental: NIO752 - Dose C - Cohort 3; Two intrathecal injections of Dose C	Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 of Dose A; Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 at dose B; Drug: NIO752; Multiple intrathecal injections of NIO752 of Dose A; Drug: NIO752; Two intrathecal injections of NIO752 at dose C; Drug: NIO752; Single intrathecal injection of NIO752 at dose C
Placebo Comparator: Matching Placebo - Cohort 3; Two intrathecal injections of artificial cerebrospinal fluid (CSF)	Drug: Matching placebo; A single intrathecal injection of matching placebo; Drug: Matching placebo; Two intrathecal injections of matching placebo
Experimental: NIO752 OLE - Cohort 3; Single intrathecal injection of Dose C	Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 of Dose A; Drug: NIO752; A single intrathecal (cerebrospinal) injection of NIO752 at dose B; Drug: NIO752; Multiple intrathecal injections of NIO752 of Dose A; Drug: NIO752; Two intrathecal injections of NIO752 at dose C; Drug: NIO752; Single intrathecal injection of NIO752 at dose C

What is the study measuring?

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 assessed 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.	Cohort 1 & 2: Baseline up to 170 days (placebo-controlled part) and up to 589 days (OLE part), Cohort 3: Baseline up to 169 days (placebo-controlled part) and up to 507 days (OLE part)
Concentration of NIO752 in cerebrospinal fluid (CSF)	Concentration of NIO752 in CSF	Cohorts 1 & 2: Pre-dose, Days 57, 85, 170 (placebo-controlled part) and Days 252, 420, and 588 (OLE part), Cohort 3: Pre-dose, day 1, 57, 85, 169 (placebo-controlled part) and Days 388 and 506 (OLE part)
Cmax, Ctrough in plasma	Maximum and trough level concentrations of NIO752 in plasma	Cohorts 1, 2 & 3: Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post first dose. Cohort 1 & 2: Days 14, 57, 85 and 170 (pbo-controlled part) and 252, 253, 420, 421, and 588 (OLE) Cohort 3: Days 14, 57, 85 and 169 (pbo-controlled part) and 338 and 506 (OLE)
Tmax in blood plasma	Time of Cmax in plasma post-IT injection	Cohorts 1, 2 & 3: Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post first dose. Cohort 1 & 2: Days 14, 57, 85 and 170 (pbo-controlled part) and 252, 253, 420, 421, and 588 (OLE) Cohort 3: Days 14, 57, 85 and 169 (pbo-controlled part) and 338 and 506 (OLE)
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)	Cohorts 1, 2 & 3: Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post first dose. Cohort 1 & 2: Days 14, 57, 85 and 170 (pbo-controlled part) and 252, 253, 420, 421, and 588 (OLE) Cohort 3: Days 14, 57, 85 and 169 (pbo-controlled part) and 338 and 506 (OLE)
AUC-inf in blood plasma	The AUC from time zero to infinity (mass x time x volume-1)	Cohorts 1, 2 & 3: Pre-dose, 0.5, 1, 2, 3 4, 5, 6, 24 hours post first dose. Cohort 1 & 2: Days 14, 57, 85 and 170 (pbo-controlled part) and 252, 253, 420, 421, and 588 (OLE) Cohort 3: Days 14, 57, 85 and 169 (pbo-controlled part) and 338 and 506 (OLE)
Change in CSF total Tau	Evaluating the ability of NIO752 to lower CSF total tau in participants with early AD when administered as multiple doses	Cohorts 1 & 2: Pre-dose, Days 57, 85, 170 (placebo-controlled part) and Days 252, 420, and 588 (OLE part), Cohort 3: Pre-dose, day 1, 57, 85, 169 (placebo-controlled part) and Days 388 and 506 (OLE part)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Madhav Thambisetty, MD PhD, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2023
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): September 24, 2027

Study Registration Dates

• First Submitted: July 11, 2022
• First Submitted That Met QC Criteria: July 19, 2022
• First Posted (Actual): July 21, 2022

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Nervous System Diseases; Dementia; Alzheimer Disease; Adult; Central Nervous System Diseases; Neurodegenerative Diseases; Placebo; Brain Diseases; Neurocognitive Disorders; Memory loss; Tauopathies; Autosomal dominant Alzheimer disease; Early onset Alzheimer disease; Familial Alzheimer disease
• Additional Relevant MeSH Terms: Neurologic Manifestations; Mental Disorders; Neurobehavioral Manifestations; Cognition Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cognitive Dysfunction; Alzheimer Disease; Dementia; Brain Diseases; Nervous System Diseases; Neurodegenerative Diseases; Central Nervous System Diseases; Neurocognitive Disorders; Memory Disorders; Tauopathies
• Other Study ID Numbers: CNIO752B12201; 2024-514004-14 (Other Identifier: EU CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No