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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 443139 in Participants With Early Manifest Huntington's Disease

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ClinicalTrials.gov Identifier: NCT02519036
Recruitment Status : Completed
First Posted : August 10, 2015
Results First Posted : May 31, 2019
Last Update Posted : May 31, 2019
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE August 1, 2015
First Posted Date  ICMJE August 10, 2015
Results First Submitted Date  ICMJE May 6, 2019
Results First Posted Date  ICMJE May 31, 2019
Last Update Posted Date May 31, 2019
Actual Study Start Date  ICMJE August 6, 2015
Actual Primary Completion Date November 8, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
Number of Participants With Treatment-related Adverse Events (TEAEs) [ Time Frame: Up to approximately 28 weeks ]
An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 5, 2015)
  • Safety (The number of participants with adverse events) [ Time Frame: Participants will be followed for the duration of the study; an expected 29 weeks ]
    The number of participants with adverse events
  • Tolerability (The number of participants with adverse events) [ Time Frame: Participants will be followed for the duration of the study; an expected 29 weeks ]
    The number of participants with adverse events
Change History Complete list of historical versions of study NCT02519036 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 [ Time Frame: Days 1, 29, 57, 85, and 113 or 141 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 5, 2015)
CSF Pharmacokinetics (The observed CSF drug concentration) [ Time Frame: Day 1, Day 29, Day 57, Day 85, and Day 113 or Day 141 ]
The observed CSF drug concentration
Current Other Pre-specified Outcome Measures
 (submitted: May 30, 2019)
  • Maximum Plasma Concentration (Cmax) for ISIS 443139 [ Time Frame: Days 1 and 85 ]
  • Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 [ Time Frame: Days 1 and 85 ]
  • Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration [ Time Frame: Baseline to Final Assessment (Day 85 or 113) ]
    Baseline was defined as the last non-missing measure prior to the first dose.
  • Change From Baseline in CSF Neurofilament Light Chain Concentration [ Time Frame: Baseline to Final Assessment (Day 85 or 113) ]
    Baseline was defined as the last non-missing measure prior to the first dose.
  • Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) [ Time Frame: Screening, Days 113, and 197 ]
  • Huntington's Disease (HD) Cognitive Assessment Battery Composite Score [ Time Frame: Baseline to Days 84, 141, and 197 ]
    The HD Cognitive Battery was developed as a means of measuring cognitive dysfunction in late premanifest and early manifest HD patients. The 6 tests that comprise the battery were selected based on test sensitivity, practice effects, reliability, domain coverage, feasibility for use in clinical trials, and tolerability. A composite cognitive score was calculated by the average z-score of the 6 individual tests. A positive change from baseline indicated improvement in cognitive function; a negative change indicated worsening. Baseline was defined as the last non-missing measure prior to the first dose.
Original Other Pre-specified Outcome Measures
 (submitted: August 5, 2015)
  • Peak ISIS 443139 plasma concentration, Cmax (ug/mL) [ Time Frame: Day 1 and Day 85 ]
  • Time to peak ISIS 443139 plasma concentration, Tmax (hours) [ Time Frame: Day 1 and Day 85 ]
  • CSF huntingtin protein concentration (fM) [ Time Frame: Day 1, Day 29, Day 57, Day 85, and Day 113 or Day 141 ]
  • CSF neurofilament light chain (pg/mL) [ Time Frame: Day 1, Day 29, Day 57, Day 85, and Day 113 or Day 141 ]
  • Ventricular volume (mL) [ Time Frame: Screening, Day 113, and Day 197 ]
  • Huntington's disease cognitive assessment battery composite score (unitless) [ Time Frame: Screening, Day -1, Day 84, Day 141, and Day 197 ]
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 443139 in Participants With Early Manifest Huntington's Disease
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of Intrathecally Administered ISIS 443139 in Patients With Early Manifest Huntington's Disease
Brief Summary This study tested the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of ISIS 443139 administered intrathecally to adult participants with early manifest Huntington's Disease.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Huntington's Disease
Intervention  ICMJE
  • Drug: ISIS 443139 10 mg
    ISIS 443139, 10 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Other Name: IONIS HTTRx
  • Drug: ISIS 443139 30 mg
    ISIS 443139, 30 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Other Name: IONIS HTTRx
  • Drug: ISIS 443139 60 mg
    ISIS 443139, 60 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Other Name: IONIS HTTRx
  • Drug: ISIS 443139 90 mg
    ISIS 443139, 90 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Other Name: IONIS HTTRx
  • Drug: ISIS 443139 120 mg
    ISIS 443139, 120 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Other Name: IONIS HTTRx
  • Other: Placebo
    Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Study Arms  ICMJE
  • Experimental: ISIS 443139 10 mg
    Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Intervention: Drug: ISIS 443139 10 mg
  • Experimental: ISIS 443139 30 mg
    Participants received ISIS 443139, 30 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Intervention: Drug: ISIS 443139 30 mg
  • Experimental: ISIS 443139 60 mg
    Participants received ISIS 443139, 60 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Intervention: Drug: ISIS 443139 60 mg
  • Experimental: ISIS 443139 90 mg
    Participants received ISIS 443139, 90 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Intervention: Drug: ISIS 443139 90 mg
  • Experimental: ISIS 443139 120 mg
    Participants received ISIS 443139, 120 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Intervention: Drug: ISIS 443139 120 mg
  • Placebo Comparator: Placebo
    Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85.
    Intervention: Other: Placebo
Publications *

*   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: June 22, 2017)
46
Original Estimated Enrollment  ICMJE
 (submitted: August 5, 2015)
36
Actual Study Completion Date  ICMJE November 8, 2017
Actual Primary Completion Date November 8, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Diagnosed with early manifest Huntington's disease
  • Male or female, aged 25 to 65 years, inclusive, at the time of informed consent
  • Able and willing to meet all study requirements, including travel to Study Center and participation in all procedures and measurements at study visits
  • Have a trial partner who is reliable, competent and at least 18 years of age, is willing to accompany the participant to select trial visits and to be available to the Study Center by phone if needed
  • Able to tolerate MRI scans, blood draws and lumbar punctures
  • Reside within 4 hours travel of the Study Center

Key Exclusion Criteria:

  • Clinically significant medical condition, such as severe chorea, active suicidal ideation or any other conditions which would make the participant unsuitable for inclusion or could interfere with the participant participating in or completing the study
  • Recent treatment with another investigational drug, biological agent, or device
  • Prior treatment with an antisense oligonucleotide [including small interfering ribonucleic acid (siRNA)]
  • Any history of gene therapy or cell transplantation or any other experimental brain surgery
  • Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
  • History of post-lumbar-puncture headache of moderate or severe intensity and/or blood patch
  • Malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
  • Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Germany,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02519036
Other Study ID Numbers  ICMJE ISIS 443139-CS1
2015-000381-66 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
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 May 2019

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