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.

Tracking Information

• First Submitted Date: August 1, 2015
• First Posted Date: August 10, 2015
• Results First Submitted Date: May 6, 2019
• Results First Posted Date: May 31, 2019
• Last Update Posted Date: May 31, 2019
• Actual Study Start Date: August 6, 2015
• Actual Primary Completion Date: November 8, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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

• Current Secondary Outcome Measures (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 (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: 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
• 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Huntington's Disease

Intervention

• 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

• 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 *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 22, 2017): 46
• Original Estimated Enrollment (submitted: August 5, 2015): 36
• Actual Study Completion Date: November 8, 2017
• Actual Primary Completion Date: November 8, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 25 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Germany, United Kingdom

Administrative Information

• NCT Number: NCT02519036
• Other Study ID Numbers: 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: Not Provided
• Current Responsible Party: Ionis Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Ionis Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Ionis Pharmaceuticals, Inc.
• Verification Date: May 2019