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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Huntington's Disease

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ISIS 443139 10 mg<br>Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, on Study Days 1, 29, 57, and 85. | Drug: ISIS 443139 10 mg<br>* ISIS 443139, 10 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.<br>* Other names: IONIS HTTRx;|
| Experimental: ISIS 443139 30 mg<br>Participants received ISIS 443139, 30 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. | Drug: ISIS 443139 30 mg<br>* ISIS 443139, 30 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.<br>* Other names: IONIS HTTRx;|
| Experimental: ISIS 443139 60 mg<br>Participants received ISIS 443139, 60 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. | Drug: ISIS 443139 60 mg<br>* ISIS 443139, 60 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.<br>* Other names: IONIS HTTRx;|
| Experimental: ISIS 443139 90 mg<br>Participants received ISIS 443139, 90 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. | Drug: ISIS 443139 90 mg<br>* ISIS 443139, 90 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.<br>* Other names: IONIS HTTRx;|
| Experimental: ISIS 443139 120 mg<br>Participants received ISIS 443139, 120 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. | Drug: ISIS 443139 120 mg<br>* ISIS 443139, 120 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.<br>* Other names: IONIS HTTRx;|
| Placebo Comparator: Placebo<br>Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85. | Other: Placebo<br>* Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Huntington's Disease, HTTRx, Early Manifest Huntington's Disease