Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-MAPTRx in Patients With Mild Alzheimer's Disease

A Randomized, Double-Blind, Placebo-Controlled Study, Followed by an Open-Label Extension, to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of Intrathecally Administered ISIS 814907 in Patients With Mild Alzheimer's Disease

The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS-MAPTRx in patients with Mild Alzheimer's Disease

Study Overview

• Status: Completed
• Conditions: Mild Alzheimer's Disease
• Intervention / Treatment: Drug: IONIS MAPTRx; Other: Placebo

Detailed Description

This is a randomized, double-blind, placebo-controlled study, followed by an Open-Label Extension in up to 44 participants. This study will consist in two parts:

Part 1: a randomized, double-blind, placebo-controlled multiple ascending dose period in participants with Mild Alzheimer's Disease, followed by Part 2: the open-label, long-term extension period.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada
    • Montreal Neurological Hospital
• Finland
  • Turku, Finland
    • Clinical Research Services Turku CRST
• Germany
  • Bochum, Germany
    • St Josef Hospital
  • Bonn, Germany, 53127
    • Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE)
  • Mittweida, Germany
    • MVZ Mittweida Gbr
  • Ulm, Germany
    • Universittsklinikum Ulm
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center
  • Groningen, Netherlands, 9713 AG
    • QPS Netherlands BV
• Sweden
  • Mölndal, Sweden
    • Minnesmottagningen
  • Stockholm, Sweden
    • Karolinska University Hospital Huddinge
• United Kingdom
  • Liverpool, United Kingdom
    • Royal Liverpool University Hospital
  • London, United Kingdom
    • University College London Hospitals NHS Foundation Trust
  • Sheffield, United Kingdom
    • Sheffield Institute for Translational Neuroscience (SITraN)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for Part 1:

• Males or females aged 50-74 years, inclusive, at the time of informed consent
• Diagnosed with mild Alzheimers disease, including CSF biomarkers consistent with this diagnosis
• Body Mass Index BMI ≥ 18 and ≤ 35 kg/m2 and total body weight > 50 kg (110 lbs)
• Able and willing to meet all study requirements, including toleration for MRI scans, blood draws and lumbar punctures, travel to Study Center and participation in all procedures and measurements at study visits
• Have a trial partner who is reliable, competent and at least 18 years of age, is willing to accompany the patient to select trial visits and to be available to the Study Center by phone if needed
• Reside within 4 hours travel of the Study Center

Exclusion Criteria for Part 1:

• Treatment with another Study Drug, biological agent, or device within one-month of Screening or 5 half-lives of investigational agent, whichever is longer
• Clinically significant medical condition which would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study
• Use of a disallowed CNS-active or antipsychotic medication within 4 weeks prior to Screening punctures

Inclusion Criteria for Part 2:

• Must have completed the Treatment Evaluation and Post-Treatment Periods in Part 1

Exclusion Criteria for Part 2 (only applicable to participants in Cohorts A and B, as participants from Cohorts C and D will seamlessly transition to Part 2):

• Treatment with another Study Drug, biological agent, or device within one-month of Screening or 5 half-lives of investigational agent, whichever is longer
• Clinically significant medical condition which would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study
• Use of a disallowed CNS-active or antipsychotic medication within 4 weeks prior to Screening punctures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IONIS-MAPTRx; IONIS MAPTRx (Study Drug)	Drug: IONIS MAPTRx; Part 1: IONIS MAPTRx is administered intrathecally at 4 week intervals over the course of a 13 week treatment period for dose levels A, B, C, and D. Part 2: IONIS MAPTRx is administered intrathecally at quarterly intervals for 48 weeks.; Other Names: ISIS 814907
Placebo Comparator: Placebo; Artificial CSF	Other: Placebo; A placebo is administered intrathecally at 4 week intervals over the course of 13 weeks in Part 1. No placebo is given in Part 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of adverse events that are related to treatment with IONIS MAPTRx	The safety and tolerability of ascending dose-levels of multiple IT bolus administrations of IONIS MAPTRx will be assessed by determining the incidence, severity, and dose relationship of adverse events that are related to treatment with IONIS MAPTRx	Up to Week 72 of Part 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) after ascending dose-levels of multiple IT bolus administrations of IONIS MAPTRx (trough concentration)	The cerebrospinal fluid (CSF) trough concentrations of IONIS MAPTRx will be assessed after ascending dose-levels of multiple IT bolus administrations of IONIS MAPTRx	Up to Week 72 of Part 2
Pharmacokinetics (PK) after ascending dose-levels of multiple IT bolus administrations of IONIS MAPTRx (maximum observed drug concentration or Cmax)	The Plasma pharmacokinetics (maximum observed drug concentration or Cmax)) of IONIS MAPTRx will be assessed after ascending dose-levels of multiple IT bolus administrations of IONIS MAPTRx	Up to Week 72 of Part 2
Pharmacokinetics after ascending dose-levels of multiple IT bolus administrations on IONIS MAPTRx (time taken to reach maximal concentration or Tmax)	The plasma pharmacokinetics (time taken to reach maximal concentration or Tmax) of IONIS MAPTRx will be assessed following single and multiple dose IT administration	Up to Week 72 of Part 2
Pharmacokinetics after ascending dose-levels of multiple IT bolus administrations on IONIS MAPTRx (Plasma terminal elimination half-life (t1/2λz)	The plasma pharmacokinetics (Plasma terminal elimination half-life (t1/2λz) of IONIS-MAPTRx will be assessed following single and multiple dose IT administration	Up to Week 72 of Part 2
Pharmacokinetics after ascending dose-levels of multiple IT bolus administrations on IONIS MAPTRx (Partial areas under the plasma concentration-time curve from zero time (predose) to selected times (t) after the IT administration (AUCt)	The plasma pharmacokinetics (Partial areas under the plasma concentration-time curve from zero time (predose) to selected times (t) after the IT administration (AUCt) of IONIS MAPTRx will be assessed following single and multiple dose IT administration	Up to Week 72 of Part 2

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2017
• Primary Completion (Actual): May 12, 2022
• Study Completion (Actual): May 13, 2022

Study Registration Dates

• First Submitted: June 6, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Estimate): February 27, 2023
• Last Update Submitted That Met QC Criteria: February 16, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimers; Memory Loss; Mild Alzheimer's Disease; ISIS 814907; MAPT
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: ISIS 814907-CS1; NL60032.000.16 (Other Identifier: CCMO); 2016-002713-22 (EudraCT Number)

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes