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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.

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.

Condition or disease Intervention/treatment Phase
Huntington's Disease Drug: ISIS 443139 10 mg Drug: ISIS 443139 30 mg Drug: ISIS 443139 60 mg Drug: ISIS 443139 90 mg Drug: ISIS 443139 120 mg Other: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 6, 2015
Actual Primary Completion Date : November 8, 2017
Actual Study Completion Date : November 8, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ISIS 443139 10 mg
Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, on Study Days 1, 29, 57, and 85.
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

Experimental: ISIS 443139 30 mg
Participants received ISIS 443139, 30 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
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

Experimental: ISIS 443139 60 mg
Participants received ISIS 443139, 60 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
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

Experimental: ISIS 443139 90 mg
Participants received ISIS 443139, 90 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
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

Experimental: ISIS 443139 120 mg
Participants received ISIS 443139, 120 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
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

Placebo Comparator: Placebo
Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85.
Other: Placebo
Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 [ Time Frame: Days 1, 29, 57, 85, and 113 or 141 ]

Other Outcome Measures:
  1. Maximum Plasma Concentration (Cmax) for ISIS 443139 [ Time Frame: Days 1 and 85 ]
  2. Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 [ Time Frame: Days 1 and 85 ]
  3. 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.

  4. 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.

  5. Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) [ Time Frame: Screening, Days 113, and 197 ]
  6. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   25 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT02519036


Locations
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Canada, British Columbia
University of British Columbia
Vancouver, British Columbia, Canada, V6T 2B5
Germany
Charite University Berlin
Berlin, Germany, 10117
Ruhr-University of Bochum
Bochum, Germany, 44791
Ulm University Hospital
Ulm, Germany, 89081
United Kingdom
University Hospitals Birmingham
Birmingham, United Kingdom, B15 2TH
Cambridge University Hospital
Cambridge, United Kingdom, CB2 0PY
University Hospital of Wales
Cardiff, United Kingdom, CF14 4XN
University College London
London, United Kingdom, WC1N 3BG
University of Manchester, St. Mary's Hospital
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Ionis Pharmaceuticals, Inc.:

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02519036     History of Changes
Other Study ID Numbers: ISIS 443139-CS1
2015-000381-66 ( EudraCT Number )
First Posted: August 10, 2015    Key Record Dates
Results First Posted: May 31, 2019
Last Update Posted: May 31, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Ionis Pharmaceuticals, Inc.:
Huntington's Disease
HTTRx
Early Manifest Huntington's Disease
Additional relevant MeSH terms:
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Huntington Disease
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Dementia
Chorea
Dyskinesias
Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Cognition Disorders
Neurocognitive Disorders
Mental Disorders