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

May 30, 2019 updated by: Ionis Pharmaceuticals, Inc.

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

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.

Study Overview

Study Type

Interventional

Enrollment (Actual)

46

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

    • British Columbia
      • Vancouver, British Columbia, Canada, V6T 2B5
        • University of British Columbia
      • Berlin, Germany, 10117
        • Charite University Berlin
      • Bochum, Germany, 44791
        • Ruhr-University of Bochum
      • Ulm, Germany, 89081
        • Ulm University Hospital
      • Birmingham, United Kingdom, B15 2TH
        • University Hospitals Birmingham
      • Cambridge, United Kingdom, CB2 0PY
        • Cambridge University Hospital
      • Cardiff, United Kingdom, CF14 4XN
        • University Hospital of Wales
      • London, United Kingdom, WC1N 3BG
        • University College London
      • Manchester, United Kingdom, M13 9WL
        • University of Manchester, St. Mary's Hospital

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

23 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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: Quadruple

Arms and Interventions

Participant Group / 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.
ISIS 443139, 10 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Other Names:
  • IONIS HTTRx
Experimental: ISIS 443139 30 mg
Participants received ISIS 443139, 30 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
ISIS 443139, 30 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Other Names:
  • IONIS HTTRx
Experimental: ISIS 443139 60 mg
Participants received ISIS 443139, 60 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
ISIS 443139, 60 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Other Names:
  • IONIS HTTRx
Experimental: ISIS 443139 90 mg
Participants received ISIS 443139, 90 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
ISIS 443139, 90 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Other Names:
  • IONIS HTTRx
Experimental: ISIS 443139 120 mg
Participants received ISIS 443139, 120 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
ISIS 443139, 120 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Other Names:
  • IONIS HTTRx
Placebo Comparator: Placebo
Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85.
Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Up to approximately 28 weeks

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Plasma Concentration (Cmax) for ISIS 443139
Time Frame: Days 1 and 85
Days 1 and 85
Time to Maximum Plasma Concentration (Tmax) for ISIS 443139
Time Frame: Days 1 and 85
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.
Baseline to Final Assessment (Day 85 or 113)
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.
Baseline to Final Assessment (Day 85 or 113)
Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI)
Time Frame: Screening, Days 113, and 197
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.
Baseline to Days 84, 141, and 197

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

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.

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)

August 6, 2015

Primary Completion (Actual)

November 8, 2017

Study Completion (Actual)

November 8, 2017

Study Registration Dates

First Submitted

August 1, 2015

First Submitted That Met QC Criteria

August 5, 2015

First Posted (Estimate)

August 10, 2015

Study Record Updates

Last Update Posted (Actual)

May 31, 2019

Last Update Submitted That Met QC Criteria

May 30, 2019

Last Verified

May 1, 2019

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

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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