- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03728634
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 ).
November 23, 2022 updated by: Ionis Pharmaceuticals, Inc.
This Was 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 Consisted 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 Was Conducted at Multiple Centers.
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 ).
Study Overview
Status
Completed
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
47
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Ontario
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Toronto, Ontario, Canada, M9L 3A2
- Bio Pharma Services, Inc.
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
16 years to 63 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E)
- Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
- Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method
- Weight ≥ 50 kg and BMI < 32 kg/m^2
Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E)
- Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion including abnormal safety labs
- Drug or alcohol dependency or abuse
- Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer
- Blood donation within 28 days
- Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study
Inclusion Criteria for hATTR Patients (Cohort D)
- Aged 18 to 82 years at the time of informed consent
- Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
- Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method
- Diagnosis of hereditary transthyretin-mediated polyneuropathy
- BMI > 16 kg/m2
Exclusion Criteria for hATTR Patients (Cohort D)
- Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to abnormal safety labs
- Karnofsky performance status ≤ 50
- Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
- Prior liver transplant or anticipated liver transplant within 1-yr of Screening
- New York Heart Association (NYHA) functional classification of ≥ 3
- Acute coronary syndrome or major surgery within 3 months of Screening
- Other types of amyloidosis
- Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Multiple Dose Cohort: 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.
|
Placebo comparator calculated volume to match ION-682884 administered SC
Oral supplement
|
Experimental: Multiple Dose Cohort A: ION-682884 45 mg
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.
|
Oral supplement
ION-682884 administered SC
Other Names:
|
Experimental: Multiple Dose Cohort E: ION-682884 60 mg
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.
|
Oral supplement
ION-682884 administered SC
Other Names:
|
Experimental: Multiple Dose Cohort B: ION-682884 90 mg
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.
|
Oral supplement
ION-682884 administered SC
Other Names:
|
Placebo Comparator: Single Dose Cohort: 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.
|
Placebo comparator calculated volume to match ION-682884 administered SC
Oral supplement
|
Experimental: Single Dose Cohort C: ION-682884 120 mg
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.
|
Oral supplement
ION-682884 administered SC
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
Time Frame: 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.
|
Up to Day 176
|
Percentage of Participants Using Concomitant Medications
Time Frame: 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.
|
Up to Day 176
|
Number of Participants With Clinically Significant Laboratory Values
Time Frame: 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.
|
Up to Day 176
|
Number of Participants With Clinically Significant Physical Examination Findings
Time Frame: 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.
|
Up to Day 176
|
Number of Participants With Clinically Significant Electrocardiogram (ECG) Values
Time Frame: 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.
|
Up to Day 176
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cmax: Maximum Observed Plasma Drug Concentration of ION-TTR-LRx
Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85
|
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
Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Days 1 and 85
|
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
Time Frame: 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
|
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
|
|
CL/F: Apparent Total Clearance of ION-TTR-LRx
Time Frame: 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
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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
Time Frame: Up to 92 hours; post-dose on Day 85 for Cohorts A, B, and E, and on Day 1 for Cohort C
|
Up to 92 hours; post-dose on Day 85 for Cohorts A, B, and E, and on Day 1 for Cohort C
|
|
Ae0-24h: Amount of Administered Dose of ION-TTR-LRx Excreted in Urine Over a 24-Hour Period
Time Frame: From 0 to 24 hours post-dose on Days 1 and 85
|
From 0 to 24 hours post-dose on Days 1 and 85
|
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Change From Baseline in Plasma Transthyretin (TTR) Levels Following Single and Multiple-dose Administration of ION-TTR-LRx
Time Frame: Baseline, Days 29 and 99
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Baseline, Days 29 and 99
|
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Change From Baseline in Plasma Retinol Binding Protein 4 (RBP4) Levels Following Single and Multiple-Dose Administration of ION-TTR-LRx
Time Frame: Baseline, Days 29 and 99
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Baseline, Days 29 and 99
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Percent Abundance of ION-682884 Antisense Oligonucleotide (ASO) Species (Metabolite) Following Administration of ION-682884 90 mg
Time Frame: 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.
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2 hours post-dose on Day 85
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Diep JK, Yu RZ, Viney NJ, Schneider E, Guo S, Henry S, Monia B, Geary R, Wang Y. Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis. Br J Clin Pharmacol. 2022 Dec;88(12):5389-5398. doi: 10.1111/bcp.15468. Epub 2022 Aug 7.
- Viney NJ, Guo S, Tai LJ, Baker BF, Aghajan M, Jung SW, Yu RZ, Booten S, Murray H, Machemer T, Burel S, Murray S, Buchele G, Tsimikas S, Schneider E, Geary RS, Benson MD, Monia BP. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Fail. 2021 Feb;8(1):652-661. doi: 10.1002/ehf2.13154. Epub 2020 Dec 7.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
December 21, 2018
Primary Completion (Actual)
February 20, 2020
Study Completion (Actual)
February 20, 2020
Study Registration Dates
First Submitted
October 31, 2018
First Submitted That Met QC Criteria
October 31, 2018
First Posted (Actual)
November 2, 2018
Study Record Updates
Last Update Posted (Actual)
December 19, 2022
Last Update Submitted That Met QC Criteria
November 23, 2022
Last Verified
November 1, 2022
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- ION-682884-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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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