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

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

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.

Official Title
-----------------
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

Conditions
-----------------
Mild Alzheimer's Disease

Intervention / Treatment
-----------------
* Drug: IONIS MAPTRx
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IONIS-MAPTRx<br>IONIS MAPTRx (Study Drug) | Drug: IONIS MAPTRx<br>* 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.<br>* Other names: ISIS 814907;|
| Placebo Comparator: Placebo<br>Artificial CSF | Other: Placebo<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mild Alzheimer's Disease, ISIS 814907, Memory Loss, Alzheimers, MAPT