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

• 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: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

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.

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

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Locations

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.:

Study Protocol and Statistical Analysis Plan  [PDF] March 15, 2018

More Information

Additional Information:

Ionis Pharmaceuticals, Inc. home page 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02519036
• Other Study ID Numbers: ISIS 443139-CS1; 2015-000381-66 ( EudraCT Number )
• First Posted: August 10, 2015
• Results First Posted: May 31, 2019
• Last Update Posted: May 31, 2019
• Last Verified: May 2019

• 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:

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