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

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ClinicalTrials.gov Identifier: NCT03728634
Recruitment Status : Recruiting
First Posted : November 2, 2018
Last Update Posted : January 9, 2019
Sponsor:
Information provided by (Responsible Party):
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 ION-TTR-LRx administered subcutaneously to healthy volunteers and patients with Hereditary Transthyretin-Mediated Amyloidosis (hATTR ).

Condition or disease Intervention/treatment Phase
Healthy Volunteers hATTR Amyloidosis Drug: ION-TTR-LRx Drug: Placebo Phase 1 Phase 2

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 and will consist of 1 single-dose cohort and 2 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  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 21, 2018
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

Arm Intervention/treatment
Experimental: ION-TTR-LRx
Single and multiple doses of ION-TTR-LRx administered subcutaneously
Drug: ION-TTR-LRx
Single and multiple doses of ION-TTR-LRx administered subcutaneously
Other Name: ION-682884

Placebo Comparator: Placebo
Placebo comparator calculated volume to match active comparator administered subcutaneously
Drug: Placebo
Placebo comparator calculated volume to match active comparator administered subcutaneously




Primary Outcome Measures :
  1. Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event [ Time Frame: Up to 176 Days ]
  2. Safety and Tolerability as Measured by the Number of Participants with clinically significant lab values [ Time Frame: Up to 176 Days ]
  3. Safety and Tolerability as Measured by the Number of Participants with clinically significant physical examination findings [ Time Frame: Up to 176 Days ]
  4. Safety and Tolerability as Measured by the Number of Participants with clinically significant ECG values [ Time Frame: Up to 176 Days ]

Secondary Outcome Measures :
  1. Cmax: maximum observed drug concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  2. Tmax: time taken to reach maximal concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  3. AUCt: area under the plasma concentration-time curve from time zero to time t for ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  4. CL/F: apparent total clearance of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  5. t1/2λz: termination half-life of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
  6. The amount of administered dose of ION-TTR-LRx excreted in urine over a 24-hour period [ Time Frame: Up to Day 86 ]
  7. 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) ]
  8. 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) ]


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

  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, and C)

  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03728634


Contacts
Contact: Ionis Pharmaceuticals 800-679-4747 patients@ionisph.com

Locations
Canada, Ontario
Bio Pharma Services, Inc. Recruiting
Toronto, Ontario, Canada, M9L 3A2
Contact    +1 (416) 747-8484    info@biopharmaservices.com   
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.

Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03728634     History of Changes
Other Study ID Numbers: ION-682884-CS1
First Posted: November 2, 2018    Key Record Dates
Last Update Posted: January 9, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases