Huntington's Disease
Conditions
Keywords
Huntington's Disease, HTTRx, 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.
Interventions
DRUGISIS 443139 10 mg
ISIS 443139, 10 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
DRUGISIS 443139 30 mg
ISIS 443139, 30 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
DRUGISIS 443139 60 mg
ISIS 443139, 60 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
DRUGISIS 443139 90 mg
ISIS 443139, 90 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
DRUGISIS 443139 120 mg
ISIS 443139, 120 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
OTHERPlacebo
Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events (TEAEs) | 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
| Measure | Time frame |
|---|---|
| Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Days 1, 29, 57, 85, and 113 or 141 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | 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 | Baseline to Final Assessment (Day 85 or 113) | Baseline was defined as the last non-missing measure prior to the first dose. |
| Maximum Plasma Concentration (Cmax) for ISIS 443139 | Days 1 and 85 | — |
| Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | 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. |
| Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Screening, Days 113, and 197 | — |
| Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Days 1 and 85 | — |
Countries
Canada, Germany, United Kingdom
Participant flow
Recruitment details
46 participants were enrolled in the United Kingdom, Canada and Germany.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | 12 |
| ISIS 443139 10 mg Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | 3 |
| ISIS 443139 30 mg Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | 6 |
| ISIS 443139 60 mg Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | 6 |
| ISIS 443139 90 mg Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | 9 |
| ISIS 443139 120 mg Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | 10 |
| Total | 46 |
Baseline characteristics
| Characteristic | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 10 | 44 years STANDARD_DEVIATION 17 | 53 years STANDARD_DEVIATION 7 | 43 years STANDARD_DEVIATION 11 | 46 years STANDARD_DEVIATION 10 | 45 years STANDARD_DEVIATION 10 | 47 years STANDARD_DEVIATION 10 |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 12 Participants | 3 Participants | 6 Participants | 6 Participants | 9 Participants | 10 Participants | 46 Participants |
| Race/Ethnicity, Customized Other Race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 3 Participants | 5 Participants | 6 Participants | 9 Participants | 9 Participants | 43 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 6 Participants | 18 Participants |
| Sex: Female, Male Male | 8 Participants | 2 Participants | 5 Participants | 3 Participants | 6 Participants | 4 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 12 / 12 | 3 / 3 | 6 / 6 | 6 / 6 | 9 / 9 | 9 / 10 |
| serious Total, serious adverse events | 1 / 12 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Up to approximately 28 weeks
Population: Safety set included all participants who were randomized and received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment-related Adverse Events (TEAEs) | 12 Participants |
| ISIS 443139 10 mg | Number of Participants With Treatment-related Adverse Events (TEAEs) | 3 Participants |
| ISIS 443139 30 mg | Number of Participants With Treatment-related Adverse Events (TEAEs) | 6 Participants |
| ISIS 443139 60 mg | Number of Participants With Treatment-related Adverse Events (TEAEs) | 6 Participants |
| ISIS 443139 90 mg | Number of Participants With Treatment-related Adverse Events (TEAEs) | 9 Participants |
| ISIS 443139 120 mg | Number of Participants With Treatment-related Adverse Events (TEAEs) | 9 Participants |
Secondary
Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139
Time frame: Days 1, 29, 57, 85, and 113 or 141
Population: Pharmacokinetic (PK) population included all participants who were randomized to ISIS 443139, received at least one dose and had sufficient sampling to permit PK evaluation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 85 | NA nanograms per milliliter (ng/mL) | — |
| Placebo | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 29 | NA nanograms per milliliter (ng/mL) | — |
| Placebo | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 113 | NA nanograms per milliliter (ng/mL) | — |
| Placebo | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 1 | NA nanograms per milliliter (ng/mL) | — |
| Placebo | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 57 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 10 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 1 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 10 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 141 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 10 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 113 | 1.63 nanograms per milliliter (ng/mL) | Standard Deviation 0.25 |
| ISIS 443139 10 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 85 | 1.96 nanograms per milliliter (ng/mL) | Standard Deviation 1.22 |
| ISIS 443139 10 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 57 | 1.69 nanograms per milliliter (ng/mL) | Standard Deviation 0.53 |
| ISIS 443139 10 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 29 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 30 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 113 | 1.84 nanograms per milliliter (ng/mL) | Standard Deviation 1.71 |
| ISIS 443139 30 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 141 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 30 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 1 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 30 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 29 | 1.77 nanograms per milliliter (ng/mL) | Standard Deviation 1.61 |
| ISIS 443139 30 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 57 | 2.77 nanograms per milliliter (ng/mL) | Standard Deviation 2.04 |
| ISIS 443139 30 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 85 | 2.88 nanograms per milliliter (ng/mL) | Standard Deviation 2.54 |
| ISIS 443139 60 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 113 | 2.28 nanograms per milliliter (ng/mL) | Standard Deviation 0.438 |
| ISIS 443139 60 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 85 | 2.05 nanograms per milliliter (ng/mL) | Standard Deviation 1.25 |
| ISIS 443139 60 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 1 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 60 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 29 | 1.55 nanograms per milliliter (ng/mL) | Standard Deviation 1.06 |
| ISIS 443139 60 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 141 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 60 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 57 | 2.36 nanograms per milliliter (ng/mL) | Standard Deviation 1.34 |
| ISIS 443139 90 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 141 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 90 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 1 | NA nanograms per milliliter (ng/mL) | — |
| ISIS 443139 90 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 29 | 2.06 nanograms per milliliter (ng/mL) | Standard Deviation 1.01 |
| ISIS 443139 90 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 57 | 2.40 nanograms per milliliter (ng/mL) | Standard Deviation 1.24 |
| ISIS 443139 90 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 85 | 2.53 nanograms per milliliter (ng/mL) | Standard Deviation 0.628 |
| ISIS 443139 90 mg | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 | Day 113 | 2.70 nanograms per milliliter (ng/mL) | Standard Deviation 1.2 |
Other Pre-specified
Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration
Baseline was defined as the last non-missing measure prior to the first dose.
Time frame: Baseline to Final Assessment (Day 85 or 113)
Population: Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Baseline | 109.13 ng/mL | Standard Deviation 42.57 |
| Placebo | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Change from Baseline | 4.08 ng/mL | Standard Deviation 28.47 |
| ISIS 443139 10 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Baseline | 143.65 ng/mL | Standard Deviation 49.74 |
| ISIS 443139 10 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Change from Baseline | -31.28 ng/mL | Standard Deviation 25.71 |
| ISIS 443139 30 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Change from Baseline | -31.98 ng/mL | Standard Deviation 24.96 |
| ISIS 443139 30 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Baseline | 119.83 ng/mL | Standard Deviation 45.27 |
| ISIS 443139 60 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Change from Baseline | -30.83 ng/mL | Standard Deviation 17.17 |
| ISIS 443139 60 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Baseline | 116.70 ng/mL | Standard Deviation 30.46 |
| ISIS 443139 90 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Baseline | 104.99 ng/mL | Standard Deviation 65.01 |
| ISIS 443139 90 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Change from Baseline | -45.76 ng/mL | Standard Deviation 27.65 |
| ISIS 443139 120 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Change from Baseline | -38.41 ng/mL | Standard Deviation 21.59 |
| ISIS 443139 120 mg | Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration | Baseline | 95.87 ng/mL | Standard Deviation 35.11 |
Other Pre-specified
Change From Baseline in CSF Neurofilament Light Chain Concentration
Baseline was defined as the last non-missing measure prior to the first dose.
Time frame: Baseline to Final Assessment (Day 85 or 113)
Population: Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CSF Neurofilament Light Chain Concentration | Baseline | 2774 nanograms per liter (ng/L) | Standard Deviation 767 |
| Placebo | Change From Baseline in CSF Neurofilament Light Chain Concentration | Change from Baseline | 324 nanograms per liter (ng/L) | Standard Deviation 371 |
| ISIS 443139 10 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Baseline | 2697 nanograms per liter (ng/L) | Standard Deviation 1909 |
| ISIS 443139 10 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Change from Baseline | 77 nanograms per liter (ng/L) | Standard Deviation 223 |
| ISIS 443139 30 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Baseline | 2548 nanograms per liter (ng/L) | Standard Deviation 916 |
| ISIS 443139 30 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Change from Baseline | 202 nanograms per liter (ng/L) | Standard Deviation 493 |
| ISIS 443139 60 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Baseline | 2280 nanograms per liter (ng/L) | Standard Deviation 976 |
| ISIS 443139 60 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Change from Baseline | 274 nanograms per liter (ng/L) | Standard Deviation 301 |
| ISIS 443139 90 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Baseline | 2328 nanograms per liter (ng/L) | Standard Deviation 951 |
| ISIS 443139 90 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Change from Baseline | 1161 nanograms per liter (ng/L) | Standard Deviation 2980 |
| ISIS 443139 120 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Baseline | 2551 nanograms per liter (ng/L) | Standard Deviation 872 |
| ISIS 443139 120 mg | Change From Baseline in CSF Neurofilament Light Chain Concentration | Change from Baseline | 628 nanograms per liter (ng/L) | Standard Deviation 1128 |
Other Pre-specified
Huntington's Disease (HD) Cognitive Assessment Battery Composite Score
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
Population: Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Baseline | -0.0860 score on a scale | Standard Deviation 0.2941 |
| Placebo | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 141 | 0.0432 score on a scale | Standard Deviation 0.1829 |
| Placebo | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 84 | -0.0403 score on a scale | Standard Deviation 0.2261 |
| Placebo | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 197 | -0.0778 score on a scale | Standard Deviation 0.2881 |
| ISIS 443139 10 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 197 | 0.4202 score on a scale | Standard Deviation 1.0482 |
| ISIS 443139 10 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 84 | 0.1314 score on a scale | Standard Deviation 0.367 |
| ISIS 443139 10 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 141 | 0.4441 score on a scale | Standard Deviation 0.8487 |
| ISIS 443139 10 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Baseline | 0.2979 score on a scale | Standard Deviation 0.5157 |
| ISIS 443139 30 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 141 | -0.1065 score on a scale | Standard Deviation 0.2112 |
| ISIS 443139 30 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 84 | -0.0430 score on a scale | Standard Deviation 0.3585 |
| ISIS 443139 30 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 197 | -0.0469 score on a scale | Standard Deviation 0.3151 |
| ISIS 443139 30 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Baseline | 0.0839 score on a scale | Standard Deviation 0.5108 |
| ISIS 443139 60 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 84 | -0.0338 score on a scale | Standard Deviation 0.2756 |
| ISIS 443139 60 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Baseline | -0.0404 score on a scale | Standard Deviation 0.3976 |
| ISIS 443139 60 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 141 | -0.1792 score on a scale | Standard Deviation 0.2298 |
| ISIS 443139 60 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 197 | -0.1633 score on a scale | Standard Deviation 0.117 |
| ISIS 443139 90 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Baseline | -0.1483 score on a scale | Standard Deviation 0.3284 |
| ISIS 443139 90 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 84 | 0.1297 score on a scale | Standard Deviation 0.256 |
| ISIS 443139 90 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 197 | 0.0827 score on a scale | Standard Deviation 0.2897 |
| ISIS 443139 90 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 141 | 0.2194 score on a scale | Standard Deviation 0.2224 |
| ISIS 443139 120 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 141 | -0.0547 score on a scale | Standard Deviation 0.2136 |
| ISIS 443139 120 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 84 | -0.0920 score on a scale | Standard Deviation 0.1668 |
| ISIS 443139 120 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Change at Day 197 | -0.1387 score on a scale | Standard Deviation 0.2717 |
| ISIS 443139 120 mg | Huntington's Disease (HD) Cognitive Assessment Battery Composite Score | Baseline | 0.1212 score on a scale | Standard Deviation 0.3877 |
Other Pre-specified
Maximum Plasma Concentration (Cmax) for ISIS 443139
Time frame: Days 1 and 85
Population: PK population included all participants who were randomized to ISIS 443139, received at least one dose and had sufficient sampling to permit PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 1 | 74.0 ng/mL | Geometric Coefficient of Variation 24.3 |
| Placebo | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 85 | 124 ng/mL | Geometric Coefficient of Variation 73.6 |
| ISIS 443139 10 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 1 | 203 ng/mL | Geometric Coefficient of Variation 81.9 |
| ISIS 443139 10 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 85 | 179 ng/mL | Geometric Coefficient of Variation 55.1 |
| ISIS 443139 30 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 1 | 500 ng/mL | Geometric Coefficient of Variation 39 |
| ISIS 443139 30 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 85 | 396 ng/mL | Geometric Coefficient of Variation 77.2 |
| ISIS 443139 60 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 85 | 439 ng/mL | Geometric Coefficient of Variation 86 |
| ISIS 443139 60 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 1 | 600 ng/mL | Geometric Coefficient of Variation 94.9 |
| ISIS 443139 90 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 1 | 717 ng/mL | Geometric Coefficient of Variation 69.2 |
| ISIS 443139 90 mg | Maximum Plasma Concentration (Cmax) for ISIS 443139 | Day 85 | 731 ng/mL | Geometric Coefficient of Variation 90.6 |
Other Pre-specified
Time to Maximum Plasma Concentration (Tmax) for ISIS 443139
Time frame: Days 1 and 85
Population: PK population included all participants who were randomized to ISIS 443139, received at least one dose and had sufficient sampling to permit PK evaluation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 1 | 3.03 hour (h) |
| Placebo | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 85 | 2.02 hour (h) |
| ISIS 443139 10 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 1 | 3.03 hour (h) |
| ISIS 443139 10 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 85 | 2.03 hour (h) |
| ISIS 443139 30 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 1 | 1.99 hour (h) |
| ISIS 443139 30 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 85 | 2.02 hour (h) |
| ISIS 443139 60 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 85 | 3.02 hour (h) |
| ISIS 443139 60 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 1 | 3.05 hour (h) |
| ISIS 443139 90 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 1 | 4.00 hour (h) |
| ISIS 443139 90 mg | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 | Day 85 | 4.03 hour (h) |
Other Pre-specified
Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI)
Time frame: Screening, Days 113, and 197
Population: Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 113 | 36.11 mL | Standard Deviation 19.37 |
| Placebo | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Screening | 35.58 mL | Standard Deviation 19.02 |
| Placebo | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 197 | 36.46 mL | Standard Deviation 18.97 |
| ISIS 443139 10 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 113 | 18.66 mL | Standard Deviation 12.84 |
| ISIS 443139 10 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Screening | 17.88 mL | Standard Deviation 12.2 |
| ISIS 443139 10 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 197 | 19.69 mL | Standard Deviation 13.03 |
| ISIS 443139 30 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 113 | 33.56 mL | Standard Deviation 17.87 |
| ISIS 443139 30 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Screening | 33.02 mL | Standard Deviation 17.46 |
| ISIS 443139 30 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 197 | 34.82 mL | Standard Deviation 18.16 |
| ISIS 443139 60 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 113 | 32.04 mL | Standard Deviation 14.26 |
| ISIS 443139 60 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Screening | 31.90 mL | Standard Deviation 13.21 |
| ISIS 443139 60 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 197 | 34.57 mL | Standard Deviation 14.82 |
| ISIS 443139 90 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 113 | 42.24 mL | Standard Deviation 25.8 |
| ISIS 443139 90 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Screening | 39.33 mL | Standard Deviation 23.52 |
| ISIS 443139 90 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 197 | 44.43 mL | Standard Deviation 27.37 |
| ISIS 443139 120 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Screening | 27.53 mL | Standard Deviation 19.31 |
| ISIS 443139 120 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 197 | 33.02 mL | Standard Deviation 24.61 |
| ISIS 443139 120 mg | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) | Day 113 | 30.36 mL | Standard Deviation 21.8 |