Evaluate the Safety and Tolerability, as Well as the Pharmacokinetic and Pharmacodynamic Profiles of Single and Multiple Doses of Eplontersen Administered Subcutaneously to Healthy Volunteers and Patients With Hereditary Transthyretin-Mediated Amyloidosis (hATTR ).
- Conditions
- hATTR AmyloidosisHealthy Volunteers
- Interventions
- Registration Number
- NCT03728634
- Lead Sponsor
- Ionis Pharmaceuticals, Inc.
- Brief Summary
To evaluate the safety and tolerability, as well as the pharmacokinetic and pharmacodynamic profiles of single and multiple doses of Eplontersen administered subcutaneously to healthy volunteers and patients with Hereditary Transthyretin-Mediated Amyloidosis (hATTR ).
- Detailed Description
This will be a Phase 1/2, double-blind, randomized, placebo-controlled, dose-escalation study conducted at a single center for the healthy volunteer cohorts in up to 56 participants. It will consist of 1 single-dose cohort and 3 multiple-dose cohorts (n = 12 per cohort, 10 active:2 placebo). The open-label, hATTR patient cohort portion of the study will be conducted at multiple centers.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 47
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Multiple Dose Cohort: Placebo Placebo Participants received ION-682884 matching placebo, subcutaneously (SC) once every 4 weeks \[Q4W\] (total of 4 doses) along with daily oral supplemental doses of the recommended daily allowance (RDA) of vitamin A during the 13-week Treatment Period. Multiple Dose Cohort: Placebo Vitamin A Participants received ION-682884 matching placebo, subcutaneously (SC) once every 4 weeks \[Q4W\] (total of 4 doses) along with daily oral supplemental doses of the recommended daily allowance (RDA) of vitamin A during the 13-week Treatment Period. Multiple Dose Cohort E: ION-682884 60 mg Vitamin A Participants received ION-682884, 60 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. Multiple Dose Cohort A: ION-682884 45 mg ION-682884 Participants received ION-682884, 45 milligrams (mg), SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. Multiple Dose Cohort A: ION-682884 45 mg Vitamin A Participants received ION-682884, 45 milligrams (mg), SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. Single Dose Cohort: Placebo Vitamin A Participants received single dose of ION-682884 matching placebo, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1. Single Dose Cohort C: ION-682884 120 mg Vitamin A Participants received single dose of ION-682884, 120 mg, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1. Multiple Dose Cohort B: ION-682884 90 mg Vitamin A Participants received ION-682884, 90 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. Single Dose Cohort: Placebo Placebo Participants received single dose of ION-682884 matching placebo, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1. Single Dose Cohort C: ION-682884 120 mg ION-682884 Participants received single dose of ION-682884, 120 mg, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1. Multiple Dose Cohort B: ION-682884 90 mg ION-682884 Participants received ION-682884, 90 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. Multiple Dose Cohort E: ION-682884 60 mg ION-682884 Participants received ION-682884, 60 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period.
- Primary Outcome Measures
Name Time Method Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Up to Day 176 An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the AE was considered related to the medicinal (investigational) product. An AE was to be regarded as a TEAE if it was present prior to receiving the first dose of study drug and subsequently worsened or was not present prior to receiving the first dose of study drug but subsequently appeared.
Percentage of Participants Using Concomitant Medications Up to Day 176 A concomitant therapy was any non-protocol-specified drug or substance (including over-the-counter \[OTC\] medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the last study visit.
Number of Participants With Clinically Significant Laboratory Values Up to Day 176 Laboratory parameters included measurement of blood chemistry, hematology, coagulation, complement, or urinalysis parameters for the single-dose and multiple-dose cohorts. Number of participants with clinically significant values in laboratory based on Investigator's assessment are reported. Any value outside the normal range was to be flagged for the attention of the investigator was to assess whether or not a flagged value is of clinical significance.
Number of Participants With Clinically Significant Physical Examination Findings Up to Day 176 Physical examination included measurement of height and weight for body mass index (BMI) determination. Number of participants with clinically significant findings in physical examination based on Investigator's assessment are reported. Any value outside the normal range was to be flagged for the attention of the investigator was to assess whether or not a flagged value is of clinical significance.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Values Up to Day 176 ECG measurements included assessment of ventricular rate (VR), PR interval, QR interval, QT interval, QT corrected using Fridericia's formula (QTcF), and QT corrected using Bazett's formula (QTcB). Number of participants with clinically significant values in electrocardiogram based on Investigator's assessment are reported. Any value outside the normal range was to be flagged for the attention of the investigator was to assess whether or not a flagged value is of clinical significance.
- Secondary Outcome Measures
Name Time Method Cmax: Maximum Observed Plasma Drug Concentration of ION-TTR-LRx Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85 Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of ION-TTR-LRx Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85 AUCt: Area Under the Plasma Concentration-Time Curve From Time Zero to Time t for ION-TTR-LRx From 0 to 672 hours post-dose on Day 85 for Cohorts A, B, and E; 0 hours to extrapolation to infinity post-dose on Day 1 for Cohort C Change From Baseline in Plasma Retinol Binding Protein 4 (RBP4) Levels Following Single and Multiple-Dose Administration of ION-TTR-LRx Baseline, Days 29 and 99 Percent Abundance of ION-682884 Antisense Oligonucleotide (ASO) Species (Metabolite) Following Administration of ION-682884 90 mg 2 hours post-dose on Day 85 As prespecified in the protocol, this outcome measure was planned to be analyzed only in the Multiple Dose Cohort B: 90 mg ION-682884.
Ae0-24h: Amount of Administered Dose of ION-TTR-LRx Excreted in Urine Over a 24-Hour Period From 0 to 24 hours post-dose on Days 1 and 85 Change From Baseline in Plasma Transthyretin (TTR) Levels Following Single and Multiple-dose Administration of ION-TTR-LRx Baseline, Days 29 and 99 CL/F: Apparent Total Clearance of ION-TTR-LRx From 0 to 672 hours post-dose on Day 85 for Cohorts A, B, and E; 0 hours to extrapolation to infinity post-dose on Day 1 for Cohort C t1/2λz: Termination Half-Life of ION-TTR-LRx Up to 92 hours; post-dose on Day 85 for Cohorts A, B, and E, and on Day 1 for Cohort C
Trial Locations
- Locations (1)
Bio Pharma Services, Inc.
🇨🇦Toronto, Ontario, Canada