A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of IONIS FXI-LRx in up to 84 Healthy Volunteers

A Double-Blind, Placebo-Controlled, Dose-Escalation Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of ION-957943 (IONIS FXI-LRX, a GalNAc Conjugated 2'-MOE Chimeric Antisense Oligonucleotide Inhibitor of Factor XI) Administered Subcutaneously to Healthy Volunteers

To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics, including Factor XI activity and antigen levels, activated partial thromboplastin time, prothrombin time and international normalized ratio of single and multiple doses of Factor XI antisense inhibitor administered subcutaneously to healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: IONIS FXI-LRx; Drug: Placebo

Detailed Description

This will be a Phase 1, double-blind, randomized, placebo-controlled, dose-escalation study conducted at a single center. The study consists of 4 escalating single-dose cohorts (n = 8 per cohort, randomized 3 IONIS FXI-LRx active:1 placebo), 3 escalating multiple-dose cohorts with weekly Study Drug (IONIS FXI-LRx or placebo) administration for 8 healthy volunteers per cohort, randomized 3 active:1 placebo, and 1 multiple-dose cohort of 10 healthy volunteers randomized 3 active:2 placebo with Study Drug administration every 4 weeks.

Approximately 66 healthy volunteers are planned to be enrolled in this study. Additional healthy volunteers may be added to better assess the safety, tolerability or pharmacokinetic profile of IONIS FXI-LRx to meet study objectives.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M9L #A2
      • Biopharma Services Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Body mass index (BMI) ≤ 35 kg/m2
• Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
• Males must be surgically sterile, abstinent or, if engaged in sexual relations with a female of child-bearing potential, the subject must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 30 days (single-dose cohorts) or 13 weeks (multiple-dose cohorts) after the last dose of Study Drug
• Willing to refrain from strenuous exercise/activity for at least 72 hrs prior to study visits
• Must abstain from alcoholic beverages for at least 48 hrs prior to clinic visits and not increase alcohol consumption during the study

Exclusion Criteria

• Clinically-significant abnormalities in medical history, screening laboratory results, physical examination that would render a subject unsuitable for inclusion. Including but not limited to:

  • Platelet count < LLN
  • INR > 1.4
  • aPTT > ULN
  • FXI activity < 0.7 U/mL
• Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer
• Any history of previous treatment with an oligonucleotide
• History of bleeding diathesis or coagulopathy
• Uncontrolled hypertension (BP > 160/100 mm Hg)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IONIS FXI-LRx; Ascending single and multiple doses of IONIS FXI-LRx by subcutaneous (SC) injection.	Drug: IONIS FXI-LRx; Ascending single and multiple doses of IONIS FXI-LRx by subcutaneous (SC) injection
Placebo Comparator: Placebo; Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator.	Drug: Placebo; Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and Tolerability as Measured by the Number of Participants with Treatment-Emergent Adverse Events	Up to 232 Days

Secondary Outcome Measures

Outcome Measure	Time Frame
Cmax: maximum observed drug concentration in plasma of IONIS FXI-LRx	Up to 232 Days
Tmax: time taken to reach maximal concentration in plasma of IONIS FXI-LRx	Up to 232 Days
AUC: area under the plasma concentration time curve for IONIS FXI-LRx	Up to 232 Days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Factor XI antigen levels	Factor XI antigen levels will be measured with a reference range of 0.72-1.63 U/mL	Up to 232 Days
Change from Baseline in Factor XI activity levels	Factor XI activity levels will be measured with a reference range of 0.73-1.45 U/mL	Up to 232 Days
Change from Baseline in activated partial thromboplastin time (aPTT)		Up to 232 Days
Change from Baseline in prothrombin time (PT)		Up to 232 Days
Change from Baseline in the international normalized ratio (INR)		Up to 232 Days

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2018
• Primary Completion (Actual): April 26, 2019
• Study Completion (Actual): April 26, 2019

Study Registration Dates

• First Submitted: June 13, 2018
• First Submitted That Met QC Criteria: July 9, 2018
• First Posted (Actual): July 11, 2018

Study Record Updates

• Last Update Posted (Actual): January 18, 2022
• Last Update Submitted That Met QC Criteria: January 13, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Factor XI; IONIS FXI-L
• Other Study ID Numbers: ION 957943-CS1

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