Phase 1b study to assess the pharmacodynamics, safety, tolerability, and pharmacokinetics of NIO752 in patients with early Alzheimer's disease (AD)
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
36
A single intrathecal (cerebrospinal) injection of NIO752 of Dose A
A single intrathecal (cerebrospinal) injection of NIO752 at dose B
A single intrathecal injection of matching placebo
Novartis Investigative Site
Kuopio, Finland
COMPLETEDNovartis Investigative Site
Turku, Finland
COMPLETEDNovartis Investigative Site
Lille, France
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.
Time frame: Baseline, Day 85
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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Novartis Pharmaceuticals
CONTACT
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Multiple intrathecal injections of NIO752 of Dose A
Two intrathecal injections of NIO752 at dose C
Single intrathecal injection of NIO752 at dose C
Two intrathecal injections of matching placebo
Novartis Investigative Site
Paris, France
RECRUITINGNovartis Investigative Site
Toulouse, France
RECRUITINGNovartis Investigative Site
Valencia, Valencia, Spain
RECRUITINGNovartis Investigative Site
Barcelona, Spain
RECRUITINGNovartis Investigative Site
Barcelona, Spain
RECRUITINGNovartis Investigative Site
Malmo, Sweden
COMPLETEDNovartis Investigative Site
Stockholm, Sweden
COMPLETEDAUC-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)
Time frame: 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)
Time frame: 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
Time frame: 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)