search
Back to results

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

Primary Purpose

Huntington's Disease

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ISIS 443139 10 mg
ISIS 443139 30 mg
ISIS 443139 60 mg
ISIS 443139 90 mg
ISIS 443139 120 mg
Placebo
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Huntington's Disease focused on measuring Huntington's Disease, HTTRx, Early Manifest Huntington's Disease

Eligibility Criteria

25 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of British Columbia
  • Charite University Berlin
  • Ruhr-University of Bochum
  • Ulm University Hospital
  • University Hospitals Birmingham
  • Cambridge University Hospital
  • University Hospital of Wales
  • University College London
  • University of Manchester, St. Mary's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

ISIS 443139 10 mg

ISIS 443139 30 mg

ISIS 443139 60 mg

ISIS 443139 90 mg

ISIS 443139 120 mg

Placebo

Arm Description

Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, on Study Days 1, 29, 57, and 85.

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

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

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

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

Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85.

Outcomes

Primary Outcome Measures

Number of Participants With Treatment-related Adverse Events (TEAEs)
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

Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139

Full Information

First Posted
August 1, 2015
Last Updated
May 30, 2019
Sponsor
Ionis Pharmaceuticals, Inc.
search

1. Study Identification

Unique Protocol Identification Number
NCT02519036
Brief Title
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 443139 in Participants With Early Manifest Huntington's Disease
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
August 6, 2015 (Actual)
Primary Completion Date
November 8, 2017 (Actual)
Study Completion Date
November 8, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Huntington's Disease
Keywords
Huntington's Disease, HTTRx, Early Manifest Huntington's Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
46 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ISIS 443139 10 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, on Study Days 1, 29, 57, and 85.
Arm Title
ISIS 443139 30 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 443139, 30 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
Arm Title
ISIS 443139 60 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 443139, 60 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
Arm Title
ISIS 443139 90 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 443139, 90 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
Arm Title
ISIS 443139 120 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 443139, 120 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85.
Intervention Type
Drug
Intervention Name(s)
ISIS 443139 10 mg
Other Intervention Name(s)
IONIS HTTRx
Intervention Description
ISIS 443139, 10 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Intervention Type
Drug
Intervention Name(s)
ISIS 443139 30 mg
Other Intervention Name(s)
IONIS HTTRx
Intervention Description
ISIS 443139, 30 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Intervention Type
Drug
Intervention Name(s)
ISIS 443139 60 mg
Other Intervention Name(s)
IONIS HTTRx
Intervention Description
ISIS 443139, 60 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Intervention Type
Drug
Intervention Name(s)
ISIS 443139 90 mg
Other Intervention Name(s)
IONIS HTTRx
Intervention Description
ISIS 443139, 90 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Intervention Type
Drug
Intervention Name(s)
ISIS 443139 120 mg
Other Intervention Name(s)
IONIS HTTRx
Intervention Description
ISIS 443139, 120 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-related Adverse Events (TEAEs)
Description
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.
Time Frame
Up to approximately 28 weeks
Secondary Outcome Measure Information:
Title
Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139
Time Frame
Days 1, 29, 57, 85, and 113 or 141
Other Pre-specified Outcome Measures:
Title
Maximum Plasma Concentration (Cmax) for ISIS 443139
Time Frame
Days 1 and 85
Title
Time to Maximum Plasma Concentration (Tmax) for ISIS 443139
Time Frame
Days 1 and 85
Title
Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration
Description
Baseline was defined as the last non-missing measure prior to the first dose.
Time Frame
Baseline to Final Assessment (Day 85 or 113)
Title
Change From Baseline in CSF Neurofilament Light Chain Concentration
Description
Baseline was defined as the last non-missing measure prior to the first dose.
Time Frame
Baseline to Final Assessment (Day 85 or 113)
Title
Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI)
Time Frame
Screening, Days 113, and 197
Title
Huntington's Disease (HD) Cognitive Assessment Battery Composite Score
Description
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.
Time Frame
Baseline to Days 84, 141, and 197

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Facility Information:
Facility Name
University of British Columbia
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6T 2B5
Country
Canada
Facility Name
Charite University Berlin
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
Ruhr-University of Bochum
City
Bochum
ZIP/Postal Code
44791
Country
Germany
Facility Name
Ulm University Hospital
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
University Hospitals Birmingham
City
Birmingham
ZIP/Postal Code
B15 2TH
Country
United Kingdom
Facility Name
Cambridge University Hospital
City
Cambridge
ZIP/Postal Code
CB2 0PY
Country
United Kingdom
Facility Name
University Hospital of Wales
City
Cardiff
ZIP/Postal Code
CF14 4XN
Country
United Kingdom
Facility Name
University College London
City
London
ZIP/Postal Code
WC1N 3BG
Country
United Kingdom
Facility Name
University of Manchester, St. Mary's Hospital
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
31381524
Citation
Rodrigues FB, Ferreira JJ, Wild EJ. Huntington's Disease Clinical Trials Corner: June 2019. J Huntingtons Dis. 2019;8(3):363-371. doi: 10.3233/JHD-199003.
Results Reference
derived
PubMed Identifier
31059641
Citation
Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, Blair NF, Craufurd D, Priller J, Rickards H, Rosser A, Kordasiewicz HB, Czech C, Swayze EE, Norris DA, Baumann T, Gerlach I, Schobel SA, Paz E, Smith AV, Bennett CF, Lane RM; Phase 1-2a IONIS-HTTRx Study Site Teams. Targeting Huntingtin Expression in Patients with Huntington's Disease. N Engl J Med. 2019 Jun 13;380(24):2307-2316. doi: 10.1056/NEJMoa1900907. Epub 2019 May 6. Erratum In: N Engl J Med. 2019 Oct 3;381(14):1398.
Results Reference
derived
PubMed Identifier
29480210
Citation
Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: February 2018. J Huntingtons Dis. 2018;7(1):89-98. doi: 10.3233/JHD-189001.
Results Reference
derived
Links:
URL
http://www.ionispharma.com
Description
Ionis Pharmaceuticals, Inc. home page

Learn more about this trial

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

We'll reach out to this number within 24 hrs