Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 443139 in Participants With Early Manifest Huntington's Disease
Sponsor
Ionis Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02519036
Collaborator
(none)
46
9
6
27.1
5.1
0.2
Study Details
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 |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Study Type:
Interventional
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
:
Aug 6, 2015
Actual Primary Completion Date
:
Nov 8, 2017
Actual Study Completion Date
:
Nov 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 Names:
|
| 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 Names:
|
| 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 Names:
|
| 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 Names:
|
| 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 Names:
|
| 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
- 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 Outcome Measures
- Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 [Days 1, 29, 57, 85, and 113 or 141]
Other Outcome Measures
- Maximum Plasma Concentration (Cmax) for ISIS 443139 [Days 1 and 85]
- Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 [Days 1 and 85]
- 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.
- Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) [Screening, Days 113, and 197]
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
25 Years
to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of British Columbia | Vancouver | British Columbia | Canada | V6T 2B5 |
| 2 | Charite University Berlin | Berlin | Germany | 10117 | |
| 3 | Ruhr-University of Bochum | Bochum | Germany | 44791 | |
| 4 | Ulm University Hospital | Ulm | Germany | 89081 | |
| 5 | University Hospitals Birmingham | Birmingham | United Kingdom | B15 2TH | |
| 6 | Cambridge University Hospital | Cambridge | United Kingdom | CB2 0PY | |
| 7 | University Hospital of Wales | Cardiff | United Kingdom | CF14 4XN | |
| 8 | University College London | London | United Kingdom | WC1N 3BG | |
| 9 | University of Manchester, St. Mary's Hospital | Manchester | United Kingdom | M13 9WL |
Sponsors and Collaborators
- Ionis Pharmaceuticals, Inc.
Investigators
None specified.Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02519036
Other Study ID Numbers:
- ISIS 443139-CS1
- 2015-000381-66
First Posted:
Aug 10, 2015
Last Update Posted:
May 31, 2019
Last Verified:
May 1, 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.
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | 46 participants were enrolled in the United Kingdom, Canada and Germany. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Period Title: Overall Study | ||||||
| STARTED | 12 | 3 | 6 | 6 | 9 | 10 |
| COMPLETED | 12 | 3 | 6 | 6 | 9 | 10 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Total of all reporting groups |
| Overall Participants | 12 | 3 | 6 | 6 | 9 | 10 | 46 |
| Age (years) [Mean (Standard Deviation) ] | |||||||
| Mean (Standard Deviation) [years] |
49
(10)
|
44
(17)
|
53
(7)
|
43
(11)
|
46
(10)
|
45
(10)
|
47
(10)
|
| Sex: Female, Male (Count of Participants) | |||||||
| Female |
4
33.3%
|
1
33.3%
|
1
16.7%
|
3
50%
|
3
33.3%
|
6
60%
|
18
39.1%
|
| Male |
8
66.7%
|
2
66.7%
|
5
83.3%
|
3
50%
|
6
66.7%
|
4
40%
|
28
60.9%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||||
| White |
11
91.7%
|
3
100%
|
5
83.3%
|
6
100%
|
9
100%
|
9
90%
|
43
93.5%
|
| Black |
1
8.3%
|
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
2
4.3%
|
| Other Race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
10%
|
1
2.2%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||||
| Not Hispanic or Latino |
12
100%
|
3
100%
|
6
100%
|
6
100%
|
9
100%
|
10
100%
|
46
100%
|
Outcome Measures
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety set included all participants who were randomized and received at least one dose of study drug. |
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 12 | 3 | 6 | 6 | 9 | 10 |
| Count of Participants [Participants] |
12
100%
|
3
100%
|
6
100%
|
6
100%
|
9
100%
|
9
90%
|
| Title | Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139 |
|---|---|
| Description | |
| Time Frame | Days 1, 29, 57, 85, and 113 or 141 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 3 | 6 | 6 | 9 | 10 |
| Day 1 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Day 29 |
NA
(NA)
|
NA
(NA)
|
1.77
(1.61)
|
1.55
(1.06)
|
2.06
(1.01)
|
| Day 57 |
NA
(NA)
|
1.69
(0.530)
|
2.77
(2.04)
|
2.36
(1.34)
|
2.40
(1.24)
|
| Day 85 |
NA
(NA)
|
1.96
(1.22)
|
2.88
(2.54)
|
2.05
(1.25)
|
2.53
(0.628)
|
| Day 113 |
NA
(NA)
|
1.63
(0.250)
|
1.84
(1.71)
|
2.28
(0.438)
|
2.70
(1.20)
|
| Day 141 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Title | Maximum Plasma Concentration (Cmax) for ISIS 443139 |
|---|---|
| Description | |
| Time Frame | Days 1 and 85 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 3 | 6 | 6 | 9 | 10 |
| Day 1 |
74.0
(24.3)
|
203
(81.9)
|
500
(39.0)
|
600
(94.9)
|
717
(69.2)
|
| Day 85 |
124
(73.6)
|
179
(55.1)
|
396
(77.2)
|
439
(86.0)
|
731
(90.6)
|
| Title | Time to Maximum Plasma Concentration (Tmax) for ISIS 443139 |
|---|---|
| Description | |
| Time Frame | Days 1 and 85 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 3 | 6 | 6 | 9 | 10 |
| Day 1 |
3.03
|
3.03
|
1.99
|
3.05
|
4.00
|
| Day 85 |
2.02
|
2.03
|
2.02
|
3.02
|
4.03
|
| 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug. |
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 12 | 3 | 6 | 6 | 9 | 10 |
| Baseline |
109.13
(42.57)
|
143.65
(49.74)
|
119.83
(45.27)
|
116.70
(30.46)
|
104.99
(65.01)
|
95.87
(35.11)
|
| Change from Baseline |
4.08
(28.47)
|
-31.28
(25.71)
|
-31.98
(24.96)
|
-30.83
(17.17)
|
-45.76
(27.65)
|
-38.41
(21.59)
|
| 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug. |
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 12 | 3 | 6 | 6 | 9 | 10 |
| Baseline |
2774
(767)
|
2697
(1909)
|
2548
(916)
|
2280
(976)
|
2328
(951)
|
2551
(872)
|
| Change from Baseline |
324
(371)
|
77
(223)
|
202
(493)
|
274
(301)
|
1161
(2980)
|
628
(1128)
|
| Title | Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI) |
|---|---|
| Description | |
| Time Frame | Screening, Days 113, and 197 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug. |
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 12 | 3 | 6 | 6 | 9 | 10 |
| Screening |
35.58
(19.02)
|
17.88
(12.20)
|
33.02
(17.46)
|
31.90
(13.21)
|
39.33
(23.52)
|
27.53
(19.31)
|
| Day 113 |
36.11
(19.37)
|
18.66
(12.84)
|
33.56
(17.87)
|
32.04
(14.26)
|
42.24
(25.80)
|
30.36
(21.80)
|
| Day 197 |
36.46
(18.97)
|
19.69
(13.03)
|
34.82
(18.16)
|
34.57
(14.82)
|
44.43
(27.37)
|
33.02
(24.61)
|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per protocol set included all participants who were randomized and received all doses of the protocol-specified study drug. |
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. |
| Measure Participants | 12 | 3 | 6 | 6 | 9 | 10 |
| Baseline |
-0.0860
(0.2941)
|
0.2979
(0.5157)
|
0.0839
(0.5108)
|
-0.0404
(0.3976)
|
-0.1483
(0.3284)
|
0.1212
(0.3877)
|
| Change at Day 84 |
-0.0403
(0.2261)
|
0.1314
(0.3670)
|
-0.0430
(0.3585)
|
-0.0338
(0.2756)
|
0.1297
(0.2560)
|
-0.0920
(0.1668)
|
| Change at Day 141 |
0.0432
(0.1829)
|
0.4441
(0.8487)
|
-0.1065
(0.2112)
|
-0.1792
(0.2298)
|
0.2194
(0.2224)
|
-0.0547
(0.2136)
|
| Change at Day 197 |
-0.0778
(0.2881)
|
0.4202
(1.0482)
|
-0.0469
(0.3151)
|
-0.1633
(0.1170)
|
0.0827
(0.2897)
|
-0.1387
(0.2717)
|
Adverse Events
| Time Frame | Up to approximately 28 weeks | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Safety set included all participants who were randomized and received at least one dose of study drug. | |||||||||||
| Arm/Group Title | Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg | ||||||
| Arm/Group Description | Participants received placebo, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 30 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 60 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 90 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | Participants received ISIS 443139, 120 mg, by intrathecal injection, at 4 week intervals over the course of a 13 week treatment period. | ||||||
All Cause Mortality |
||||||||||||
| Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
Serious Adverse Events |
||||||||||||
| Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Post lumbar puncture syndrome | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
| Placebo | ISIS 443139 10 mg | ISIS 443139 30 mg | ISIS 443139 60 mg | ISIS 443139 90 mg | ISIS 443139 120 mg | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 12/12 (100%) | 3/3 (100%) | 6/6 (100%) | 6/6 (100%) | 9/9 (100%) | 9/10 (90%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Lymphadenopathy | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Cardiac disorders | ||||||||||||
| Bundle branch block right | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Ventricular extrasystoles | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Ear pain | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Eye disorders | ||||||||||||
| Ocular discomfort | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Vision blurred | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Diarrhoea | 1/12 (8.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Toothache | 0/12 (0%) | 0/3 (0%) | 2/6 (33.3%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Abdominal pain upper | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Dental caries | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Dyspepsia | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Gastritis | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Nausea | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Vomiting | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| General disorders | ||||||||||||
| Fatigue | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 1/6 (16.7%) | 1/9 (11.1%) | 2/10 (20%) | ||||||
| Asthenia | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Chills | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Discomfort | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Malaise | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Peripheral swelling | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Nasopharyngitis | 2/12 (16.7%) | 1/3 (33.3%) | 0/6 (0%) | 1/6 (16.7%) | 3/9 (33.3%) | 2/10 (20%) | ||||||
| Upper respiratory tract infection | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 3/6 (50%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Rhinitis | 2/12 (16.7%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 2/9 (22.2%) | 0/10 (0%) | ||||||
| Bronchitis | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 1/6 (16.7%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Influenza | 0/12 (0%) | 0/3 (0%) | 2/6 (33.3%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Rhinovirus infection | 0/12 (0%) | 2/3 (66.7%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Sinusitis | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Urinary tract infection | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Bronchopneumonia | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Conjunctivitis | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Gastrointestinal infection | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Respiratory tract infection | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Viral infection | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Vulvovaginal candidiasis | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Procedural pain | 6/12 (50%) | 1/3 (33.3%) | 1/6 (16.7%) | 3/6 (50%) | 6/9 (66.7%) | 8/10 (80%) | ||||||
| Post lumbar puncture syndrome | 4/12 (33.3%) | 1/3 (33.3%) | 2/6 (33.3%) | 1/6 (16.7%) | 3/9 (33.3%) | 5/10 (50%) | ||||||
| Fall | 3/12 (25%) | 0/3 (0%) | 2/6 (33.3%) | 1/6 (16.7%) | 2/9 (22.2%) | 2/10 (20%) | ||||||
| Skin abrasion | 1/12 (8.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 2/9 (22.2%) | 2/10 (20%) | ||||||
| Contusion | 2/12 (16.7%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Joint injury | 1/12 (8.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Laceration | 1/12 (8.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Head injury | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Ligament sprain | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Muscle injury | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Muscle strain | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Tooth injury | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Upper limb fracture | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Investigations | ||||||||||||
| Blood creatine phosphokinase increased | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Blood thyroid stimulating hormone increased | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Body temperature increased | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| C-reactive protein increased | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Gamma-glutamyltransferase increased | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Thyroxine increased | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Urine analysis abnormal | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Arthralgia | 2/12 (16.7%) | 0/3 (0%) | 0/6 (0%) | 2/6 (33.3%) | 2/9 (22.2%) | 0/10 (0%) | ||||||
| Back pain | 1/12 (8.3%) | 0/3 (0%) | 2/6 (33.3%) | 2/6 (33.3%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Musculoskeletal pain | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Pain in extremity | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Coccydynia | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Muscle spasms | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Osteopenia | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Synovial cyst | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Nervous system disorders | ||||||||||||
| Headache | 6/12 (50%) | 0/3 (0%) | 1/6 (16.7%) | 1/6 (16.7%) | 1/9 (11.1%) | 3/10 (30%) | ||||||
| Hypoaesthesia | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 1/9 (11.1%) | 1/10 (10%) | ||||||
| Dizziness | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Paraesthesia | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Tension headache | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Head discomfort | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Neuropathy peripheral | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Pleocytosis | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Syncope | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Psychiatric disorders | ||||||||||||
| Anxiety | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Insomnia | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Mood altered | 0/12 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Reproductive system and breast disorders | ||||||||||||
| Erectile dysfunction | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Cough | 1/12 (8.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Epistaxis | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Oropharyngeal pain | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Throat irritation | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Alopecia | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Dermatitis allergic | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Dry skin | 1/12 (8.3%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Rash | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 1/10 (10%) | ||||||
| Rash erythematous | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Scab | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/10 (0%) | ||||||
| Skin reaction | 0/12 (0%) | 0/3 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
| Vascular disorders | ||||||||||||
| Haematoma | 0/12 (0%) | 0/3 (0%) | 2/6 (33.3%) | 1/6 (16.7%) | 0/9 (0%) | 0/10 (0%) | ||||||
Limitations/Caveats
There are no limitations or caveats for this study.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Ionis Pharmaceuticals, Inc. |
|---|---|
| Organization | Ionis Pharmaceuticals, Inc. |
| Phone | 800-679-4747 |
| patients@ionisph.com |
Responsible Party:
Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02519036
Other Study ID Numbers:
- ISIS 443139-CS1
- 2015-000381-66
First Posted:
Aug 10, 2015
Last Update Posted:
May 31, 2019
Last Verified:
May 1, 2019