Clinical trial NCT05469360: Study of Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of NIO752 in Early Alzheimer's Disease Participants
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Alzheimer Disease
Mild Cognitive Impairment
Keywords: Alzheimer Disease
Autosomal dominant Alzheimer disease
Early onset Alzheimer disease
Familial Alzheimer disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Memory loss
Placebo
Adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-07-21
Enrollment: 36
Sex: ALL
Minimum age (years): 30
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Phase 1b
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in cerebrospinal total tau from baseline to Day 85
timeFrame: Baseline, Day 85
Secondary outcomes:
measure: Number of adverse events and serious adverse events
timeFrame: 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)
measure: Concentration of NIO752 in cerebrospinal fluid (CSF)
timeFrame: 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)
measure: Cmax, Ctrough in plasma
timeFrame: 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)
measure: Tmax in blood plasma
timeFrame: 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)
measure: AUC-last in blood plasma
timeFrame: 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)
measure: AUC-inf in blood plasma
timeFrame: 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)
measure: Change in CSF total Tau
timeFrame: 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)
Other outcomes:
Locations:
city: Kuopio
country: Finland
facility: Novartis Investigative Site
city: Turku
country: Finland
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Malmo
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Madhav Thambisetty, MD PhD
role: STUDY_DIRECTOR
References: