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A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AKCEA-TTR-LRx in Healthy Volunteers and Patients With Hereditary Transthyretin-Mediated Amyloidosis

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ClinicalTrials.gov Identifier: NCT03728634
Recruitment Status : Completed
First Posted : November 2, 2018
Last Update Posted : March 13, 2020
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE October 31, 2018
First Posted Date  ICMJE November 2, 2018
Last Update Posted Date March 13, 2020
Actual Study Start Date  ICMJE December 21, 2018
Actual Primary Completion Date February 20, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 31, 2018)
  • Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event [ Time Frame: Up to 176 Days ]
  • Safety and Tolerability as Measured by the Number of Participants with clinically significant lab values [ Time Frame: Up to 176 Days ]
  • Safety and Tolerability as Measured by the Number of Participants with clinically significant physical examination findings [ Time Frame: Up to 176 Days ]
  • Safety and Tolerability as Measured by the Number of Participants with clinically significant ECG values [ Time Frame: Up to 176 Days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
  • Cmax: maximum observed drug concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • Tmax: time taken to reach maximal concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • AUCt: area under the plasma concentration-time curve from time zero to time t for ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • CL/F: apparent total clearance of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • t1/2λz: termination half-life of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • The amount of administered dose of ION-TTR-LRx excreted in urine over a 24-hour period [ Time Frame: Up to Day 86 ]
  • Change from Baseline in plasma TTR levels following single and multiple-dose administration of ION-TTR-LRx [ Time Frame: Day 29 (Cohort C); Day 99 (Cohorts A, B, C, and E) ]
  • Change from Baseline in plasma RBP4 levels following single and multiple-dose administration of ION-TTR-LRx [ Time Frame: Day 29 (Cohort C); Day 99 (Cohorts A, B, C, and E) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 31, 2018)
  • Cmax: maximum observed drug concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • Tmax: time taken to reach maximal concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • AUCt: area under the plasma concentration-time curve from time zero to time t for ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • CL/F: apparent total clearance of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • t1/2λz: termination half-life of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  • The amount of administered dose of ION-TTR-LRx excreted in urine over a 24-hour period [ Time Frame: Up to Day 86 ]
  • Change from Baseline in plasma TTR levels following single and multiple-dose administration of ION-TTR-LRx [ Time Frame: Day 29 (Cohort C); Day 99 (Cohorts A, B, and C) ]
  • Change from Baseline in plasma RBP4 levels following single and multiple-dose administration of ION-TTR-LRx [ Time Frame: Day 29 (Cohort C); Day 99 (Cohorts A, B, and C) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AKCEA-TTR-LRx in Healthy Volunteers and Patients With Hereditary Transthyretin-Mediated Amyloidosis
Official Title  ICMJE A Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ION-682884, an Antisense Inhibitor of Transthyretin Production, in Healthy Volunteers and Patients With Hereditary Transthyretin-Mediated Amyloidosis
Brief Summary To evaluate the safety and tolerability, as well as the pharmacokinetic and pharmacodynamic profiles of single and multiple doses of AKCEA-TTR-LRx 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Healthy Volunteers
  • hATTR Amyloidosis
Intervention  ICMJE
  • Drug: AKCEA-TTR-LRx
    Single and multiple doses of AKCEA-TTR-LRx administered subcutaneously
    Other Name: ION-682884
  • Drug: Placebo
    Placebo comparator calculated volume to match active comparator administered subcutaneously
Study Arms  ICMJE
  • Experimental: AKCEA-TTR-LRx
    Single and multiple doses of AKCEA-TTR-LRx administered subcutaneously
    Intervention: Drug: AKCEA-TTR-LRx
  • Placebo Comparator: Placebo
    Placebo comparator calculated volume to match active comparator administered subcutaneously
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 18, 2019)
47
Original Estimated Enrollment  ICMJE
 (submitted: October 31, 2018)
56
Actual Study Completion Date  ICMJE February 20, 2020
Actual Primary Completion Date February 20, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E)

  1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
  2. 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
  3. Weight ≥ 50 kg and BMI < 32 kg/m2

Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E)

  1. 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
  2. Drug or alcohol dependency or abuse
  3. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer
  4. Blood donation within 28 days
  5. 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)

  1. Aged 18 to 82 years at the time of informed consent
  2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
  3. 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
  4. Diagnosis of hereditary transthyretin-mediated polyneuropathy
  5. BMI > 16 kg/m2

Exclusion Criteria for hATTR Patients (Cohort D)

  1. 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
  2. Karnofsky performance status ≤ 50
  3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
  4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
  5. New York Heart Association (NYHA) functional classification of ≥ 3
  6. Acute coronary syndrome or major surgery within 3 months of Screening
  7. Other types of amyloidosis
  8. 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03728634
Other Study ID Numbers  ICMJE ION-682884-CS1
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ionis Pharmaceuticals, Inc.
Study Sponsor  ICMJE Ionis Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Ionis Pharmaceuticals, Inc.
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP