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CompletedNCT02519036Updated May 31, 2019Results posted

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

A Phase 1/2 interventional study of ISIS 443139 10 mg and ISIS 443139 30 mg in Huntington's Disease, sponsored by Ionis Pharmaceuticals, Inc.. Completed at 9 sites in 3 countries. Open to participants aged 25 Years to 65 Years. Per ClinicalTrials.gov, last updated 2019-05-31.

Sponsored by Ionis Pharmaceuticals, Inc. · Phase 1/2, Interventional, and Treatment

Phase
Phase 1/2
Study type
Interventional
Enrollment
46
Allocation
Randomized
Ages
25 Years to 65 Years
Sex
All
01

Study 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.

02

Conditions studied

  • Huntington's Disease

Browse trials for

Keywords

  • Huntington's Disease
  • HTTRx
  • Early Manifest Huntington's Disease
03

In context

Huntington Disease

285 studies on the registry are indexed under Huntington Disease; 49 are open to participants now.

This study's enrollment of 46 is above the median of 40 across 203 interventional studies indexed under Huntington Disease.

Browse Huntington Disease studies →

Lead sponsor

Ionis Pharmaceuticals, Inc. is the lead sponsor of 116 studies on the registry; 10 are open to participants now.

Of its 48 completed or terminated interventional studies of FDA-regulated products, 21 (44%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
25 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

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
05

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
46 participants (actual)

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.

    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.

    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.

    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.

    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.

    Drug: ISIS 443139 120 mg

  • Placebo comparator
    Placebo

    Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85.

    Other: Placebo

Interventions

  • DrugISIS 443139 10 mg

    ISIS 443139, 10 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

    Also known as: IONIS HTTRx

  • DrugISIS 443139 30 mg

    ISIS 443139, 30 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

    Also known as: IONIS HTTRx

  • DrugISIS 443139 60 mg

    ISIS 443139, 60 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

    Also known as: IONIS HTTRx

  • DrugISIS 443139 90 mg

    ISIS 443139, 90 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

    Also known as: IONIS HTTRx

  • DrugISIS 443139 120 mg

    ISIS 443139, 120 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

    Also known as: IONIS HTTRx

  • OtherPlacebo

    Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

06

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139

    Time frame: Days 1, 29, 57, 85, and 113 or 141

Other outcomes

  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

    Baseline was defined as the last non-missing measure prior to the first dose.

    Time frame: Baseline to Final Assessment (Day 85 or 113)

  4. 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)

  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

    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

07

Results

Posted May 31, 2019
Limitations and caveats
There are no limitations or caveats for this study.

Participant flow

46 participants were enrolled in the United Kingdom, Canada and Germany.

Participant flow — Overall Study
MilestonePlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Started12366910
Completed12366910
Not completed000000

Outcome measures

PrimaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Treatment-related Adverse Events (TEAEs)
ParticipantsPlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Number of Participants With Treatment-related Adverse Events (TEAEs)1236699
SecondaryObserved Cerebrospinal Fluid (CSF) Concentration for ISIS 443139
Time frame:
Days 1, 29, 57, 85, and 113 or 141
Reported as:
Mean · nanograms per milliliter (ng/mL)
Observed Cerebrospinal Fluid (CSF) Concentration for ISIS 443139
nanograms per milliliter (ng/mL)ISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Day 1NA ± NANA ± NANA ± NANA ± NANA ± NA
Day 29NA ± NANA ± NA1.77 ± 1.611.55 ± 1.062.06 ± 1.01
Day 57NA ± NA1.69 ± 0.5302.77 ± 2.042.36 ± 1.342.40 ± 1.24
Day 85NA ± NA1.96 ± 1.222.88 ± 2.542.05 ± 1.252.53 ± 0.628
Day 113NA ± NA1.63 ± 0.2501.84 ± 1.712.28 ± 0.4382.70 ± 1.20
Day 141—NA ± NANA ± NANA ± NANA ± NA
Other pre-specifiedMaximum Plasma Concentration (Cmax) for ISIS 443139
Time frame:
Days 1 and 85
Reported as:
Geometric mean · ng/mL
Maximum Plasma Concentration (Cmax) for ISIS 443139
ng/mLISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Day 174.0 ± 24.3203 ± 81.9500 ± 39.0600 ± 94.9717 ± 69.2
Day 85124 ± 73.6179 ± 55.1396 ± 77.2439 ± 86.0731 ± 90.6
Other pre-specifiedTime to Maximum Plasma Concentration (Tmax) for ISIS 443139
Time frame:
Days 1 and 85
Reported as:
Median · hour (h)
Time to Maximum Plasma Concentration (Tmax) for ISIS 443139
hour (h)ISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Day 13.03 (2.05 to 5.95)3.03 (2.00 to 4.00)1.99 (0.533 to 3.08)3.05 (2.00 to 8.02)4.00 (2.00 to 23.8)
Day 852.02 (0.717 to 3.02)2.03 (0.550 to 3.07)2.02 (1.00 to 4.02)3.02 (0.600 to 5.02)4.03 (2.00 to 23.9)
Other pre-specifiedChange 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)
Reported as:
Mean · ng/mL
Change From Baseline in CSF Mutant Huntingtin (fM) Protein Concentration
ng/mLPlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Baseline109.13 ± 42.57143.65 ± 49.74119.83 ± 45.27116.70 ± 30.46104.99 ± 65.0195.87 ± 35.11
Change from Baseline4.08 ± 28.47-31.28 ± 25.71-31.98 ± 24.96-30.83 ± 17.17-45.76 ± 27.65-38.41 ± 21.59
Other pre-specifiedChange 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)
Reported as:
Mean · nanograms per liter (ng/L)
Change From Baseline in CSF Neurofilament Light Chain Concentration
nanograms per liter (ng/L)PlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Baseline2774 ± 7672697 ± 19092548 ± 9162280 ± 9762328 ± 9512551 ± 872
Change from Baseline324 ± 37177 ± 223202 ± 493274 ± 3011161 ± 2980628 ± 1128
Other pre-specifiedVentricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI)
Time frame:
Screening, Days 113, and 197
Reported as:
Mean · mL
Ventricular Volume as Assessed by Structural Magnetic Resonance Imaging (MRI)
mLPlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Screening35.58 ± 19.0217.88 ± 12.2033.02 ± 17.4631.90 ± 13.2139.33 ± 23.5227.53 ± 19.31
Day 11336.11 ± 19.3718.66 ± 12.8433.56 ± 17.8732.04 ± 14.2642.24 ± 25.8030.36 ± 21.80
Day 19736.46 ± 18.9719.69 ± 13.0334.82 ± 18.1634.57 ± 14.8244.43 ± 27.3733.02 ± 24.61
Other pre-specifiedHuntington'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
Reported as:
Mean · score on a scale
Huntington's Disease (HD) Cognitive Assessment Battery Composite Score
score on a scalePlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Baseline-0.0860 ± 0.29410.2979 ± 0.51570.0839 ± 0.5108-0.0404 ± 0.3976-0.1483 ± 0.32840.1212 ± 0.3877
Change at Day 84-0.0403 ± 0.22610.1314 ± 0.3670-0.0430 ± 0.3585-0.0338 ± 0.27560.1297 ± 0.2560-0.0920 ± 0.1668
Change at Day 1410.0432 ± 0.18290.4441 ± 0.8487-0.1065 ± 0.2112-0.1792 ± 0.22980.2194 ± 0.2224-0.0547 ± 0.2136
Change at Day 197-0.0778 ± 0.28810.4202 ± 1.0482-0.0469 ± 0.3151-0.1633 ± 0.11700.0827 ± 0.2897-0.1387 ± 0.2717

Adverse events

Collected over Up to approximately 28 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo0/12 (0%)1/12 (8.3%)12/12 (100%)
ISIS 443139 10 mg0/3 (0%)0/3 (0%)3/3 (100%)
ISIS 443139 30 mg0/6 (0%)0/6 (0%)6/6 (100%)
ISIS 443139 60 mg0/6 (0%)0/6 (0%)6/6 (100%)
ISIS 443139 90 mg0/9 (0%)0/9 (0%)9/9 (100%)
ISIS 443139 120 mg0/10 (0%)0/10 (0%)9/10 (90%)
Most frequent serious events
Most frequent serious events
EventPlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Post lumbar puncture syndromeInjury, poisoning and procedural complications1/120/30/60/60/90/10
Most frequent other events
Showing 10 of 87
Most frequent other events
EventPlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mg
Procedural painInjury, poisoning and procedural complications6/121/31/63/66/98/10
Rhinovirus infectionInfections and infestations0/122/31/60/60/90/10
Post lumbar puncture syndromeInjury, poisoning and procedural complications4/121/32/61/63/95/10
Upper respiratory tract infectionInfections and infestations1/120/30/63/61/90/10
HeadacheNervous system disorders6/120/31/61/61/93/10
FallInjury, poisoning and procedural complications3/120/32/61/62/92/10
NasopharyngitisInfections and infestations2/121/30/61/63/92/10
InfluenzaInfections and infestations0/120/32/61/60/90/10
ArthralgiaMusculoskeletal and connective tissue disorders2/120/30/62/62/90/10
Back painMusculoskeletal and connective tissue disorders1/120/32/62/60/90/10

Baseline characteristics

Safety set included all participants who were randomized and received at least one dose of study drug.

Age, Continuous
Age, Continuous(years)PlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mgTotal
Mean49 ± 1044 ± 1753 ± 743 ± 1146 ± 1045 ± 1047 ± 10
Sex: Female, Male
Sex: Female, Male(Participants)PlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mgTotal
Female41133618
Male82536428
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)PlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mgTotal
White113569943
Black1010002
Other Race0000011
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)PlaceboISIS 443139 10 mgISIS 443139 30 mgISIS 443139 60 mgISIS 443139 90 mgISIS 443139 120 mgTotal
Not Hispanic or Latino1236691046
08

Study locations

9 sites
  • University of British Columbia
    Vancouver, British Columbia V6T 2B5, Canada
  • Charite University Berlin
    Berlin, 10117, Germany
  • Ruhr-University of Bochum
    Bochum, 44791, Germany
  • Ulm University Hospital
    Ulm, 89081, Germany
  • University Hospitals Birmingham
    Birmingham, B15 2TH, United Kingdom
  • Cambridge University Hospital
    Cambridge, CB2 0PY, United Kingdom
  • University Hospital of Wales
    Cardiff, CF14 4XN, United Kingdom
  • University College London
    London, WC1N 3BG, United Kingdom
  • University of Manchester, St. Mary's Hospital
    Manchester, M13 9WL, United Kingdom
09

References and documents

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. PubMed 31381524 ↗
  • 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. doi: 10.1056/NEJMx190024. PubMed 31059641 ↗
  • 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. PubMed 29480210 ↗

Study documents

  • Protocol and statistical analysis plan · Mar 15, 2018

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 31, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02519036
Lead sponsor
Ionis Pharmaceuticals, Inc.
Responsible party
Sponsor
First posted
Aug 10, 2015
Start date
Aug 6, 2015
Primary completion
Nov 8, 2017
Completion
Nov 8, 2017
Results posted
May 31, 2019
Last update
May 31, 2019

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
View the source record on ClinicalTrials.gov ↗

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