GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease

NCT05686551
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Phase
Phase 2
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Recruitment status
Active, not recruiting
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Participants
301
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Lead sponsor
Hoffmann-La Roche
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Start date
2023-02-03
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Number of sites
70
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Summary
This study will evaluate the safety, biomarkers, and efficacy of tominersen compared with placebo in participants with prodromal and early manifest Huntington's Disease (HD).
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Short title
GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease
clinicaltrials.gov
Official title
A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen in Individuals With Prodromal and Early Manifest Huntington's Disease
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Control arm
Placebo
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Registry reports results
No
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Listing at source
Listed
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Recruitment status
Active, not recruiting
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Phase
Phase 2
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Study type
Interventional
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Completion date
2026-10-31
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First posted
2023-01-17
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Registry last updated
2026-08-10
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Primary completion date
2026-05-14
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Start date
2023-02-03
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Actual participants
301
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Participants
301
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Participant count basis
Actual
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Protocol amendments
8
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Number of sites
70
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Data monitoring committee
Yes
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Registry sponsor category
Industry
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Lead sponsor
Hoffmann-La Roche
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Source registry
ClinicalTrials.gov
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Registry ID
NCT05686551
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ClinicalTrials.gov ID
NCT05686551
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Registry record
Open registry record
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Allocation
Randomised
Model
Parallel groups
Purpose
Treatment
Masking
Quadruple masking
Masked roles
Participants, Care providers, Investigators, Outcome assessors
Sources for study design
clinicaltrials.gov

  1. DB Period: Incidence and Severity of Adverse Events (AEs), With Severity Determined According to the AE Severity Grading Scale

    Timeframe: Up to approximately 36 months

  2. DB Period: Change From Baseline in Clinical Laboratory Results - Cerebrospinal Fluid (CSF) White Blood Cell (WBC)

    Timeframe: Baseline visit (Day 1), and Months 4, 8, 9, 12, 16

  3. DB Period: Change From Baseline in Clinical Laboratory Results - CSF Protein

    Timeframe: Baseline visit (Day 1), and Months 4, 8, 9, 12, 16

  4. DB Period: Change From Baseline in Structural Magnetic Resonance Imaging (MRI) Assessing Any New Abnormalities Including Radiographic Features Consistent With Hydrocephalus and Other Relevant MRI Safety Findings

    Timeframe: Baseline, Months 4, 8, 12, 16 and up to approximately 36 months

  5. DB Period: Percentage Change From Baseline in Geometric Means of CSF Mutant Huntingtin (mHTT) Protein Levels at Month 9

    Timeframe: Baseline, Month 9

  6. DB Period: Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores (non-U.S. Sites) at 16 Months

    Timeframe: Baseline to 16 months

    Change in scores on the scale.

  7. DB Period: Change From Baseline in Total Functional Capacity (TFC) Scores (U.S. Sites) at 16 Months

    Timeframe: Baseline to 16 months

    Change in scores on the scale.

  8. OLE Period: Incidence and Severity of AEs, With Severity Determined According to the AE Severity Grading Scale

    Timeframe: Up to approximately 29 months

  9. OLE Period: Change Over Time in Clinical Laboratory Results - CSF WBC

    Timeframe: Up to approximately 24 months

  10. OLE Period: Change Over Time in Clinical Laboratory Results - CSF Protein

    Timeframe: Up to approximately 24 months

  11. OLE Period: Change From Baseline in Structural MRI Assessing Any New Abnormalities, Including Radiographic Features Consistent With Hydrocephalus and Other Relevant MRI Safety Findings

    Timeframe: Up to approximately 29 months

  1. DB Period: Change From Baseline in Montreal Cognitive Assessment (MoCA) Scores

    Timeframe: Baseline, Months 4, 8, 12, 16 and up to approximately 36 months

  2. DB Period: Percentage of Participants With Suicidal Ideation or Behavior (I/B), as Assessed by C-SSRS Score at Each Visit, Including Detailed Focus on Any Individual Cases Identified as Having Severe I/B During the Study Conduct

    Timeframe: Up to approximately 36 months

    C-SSRS=Columbia-suicide Severity Rating Scale

  3. DB Period: Change From Baseline at 16 Months in TFC (non-U.S. Sites) Scores

    Timeframe: Baseline to 16 months

  4. DB Period: Change From Baseline at 16 Months in cUHDRS (U.S. Sites) Scores

    Timeframe: Baseline to 16 months

  5. DB Period: Change From Baseline at 16 Months in Symbol Digit Modalities Test (SDMT) Scores

    Timeframe: Baseline to 16 months

  6. DB Period: Change From Baseline at 16 Months in Stroop Word Reading (SWR) Score

    Timeframe: Baseline to 16 months

  7. DB Period: Change From Baseline at 16 Months in Total Motor Score (TMS)

    Timeframe: Baseline to 16 months

  8. DB Period: Change From Baseline in CSF Neurofilament Light Chain (NfL) Levels at 16 Months

    Timeframe: Baseline to 16 months

  9. DB Period: Incidence of Anti-drug Antibodies (ADAs) at Specified Timepoints Relative to the Prevalence of ADAs at Baseline

    Timeframe: Baseline up to approximately 36 months

  10. DB Period: Titers Determined if ADAs are Identified

    Timeframe: Baseline up to approximately 36 months

  11. OLE Period: Change Over Time in TFC Score

    Timeframe: Up to approximately 29 months

  12. OLE Period: Change Over Time in cUHDRS Score

    Timeframe: Up to approximately 29 months

  13. OLE Period: Change Over Time in SDMT Score

    Timeframe: Up to approximately 29 months

  14. OLE Period: Change Over Time in TMS

    Timeframe: Up to approximately 29 months

  15. OLE Period: Change Over Time in SWR Score

    Timeframe: Up to approximately 29 months

  16. OLE Period: Change Over Time in MoCA Score

    Timeframe: Up to approximately 29 months

  17. OLE Period: Percentage of Participants With Suicidal I/B, as Assessed by C-SSRS Score at Each Visit, Including Detailed Focus on Any Individual Cases Identified as Having Severe I/B During the Study Conduct

    Timeframe: Up to approximately 29 months

  18. OLE Period: Incidence of ADAs at Specified Timepoints

    Timeframe: Up to approximately 29 months

Sources for outcomes
clinicaltrials.gov

Sex
All
Age groups
Adults
Minimum age
25 Years
Maximum age
50 Years
Healthy volunteers
No

DB Period:

  • HD gene expansion mutation carrier status with a cytosine-adenine-guanine-age product (CAP) score of 400-500 inclusive

  • Either:

    • Prodromal HD (defined as Diagnostic Confidence Level (DCL) 2 to 3, Independence Scale (IS) ≥70, and TFC ≥8); Or
    • Early manifest HD (defined as DCL 4, IS ≥70, and TFC ≥8)

  • Total body weight > 40 kilograms (kg) and a body mass index (BMI) within the range of 18-32 kilograms per meter square (kg/m^2)

  • Study companion

OLE Period:

  • Participants must have completed the DB treatment period
  • Participants must remain in the DB Safety follow-up period until OLE period starts

DB Period:

  • Current or previous use of an antisense oligonucleotide (ASO) (including small interfering ribonucleic acid [RNA]) or any HTT lowering therapy (including tominersen)
  • Anti-platelet or anticoagulant therapy within 14 days prior to screening or anticipated use during the study, including, but not limited to, aspirin (unless ≤ 81 milligrams per day [mg/day]), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and heparin
  • History of gene therapy, cell transplantation, or brain surgery
  • Hydrocephalus
  • Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug
  • History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening

OLE Period:

  • Early discontinuation from the DB treatment and the safety follow-up (SFU) periods
  • Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required
  • Current or previous use of an ASO other than tominersen (including small interfering RNA) or any other HTT-lowering therapy
  • Hydrocephalus
  • Received any active investigational treatment other than tominersen during or since completion of the DB treatment period

Key inclusions/exclusion criteria are listed here. Other protocol-defined I/E criteria may apply.

Sources for eligibility
clinicaltrials.gov

  • Uab MedicineBirmingham, United States
  • Barrow Neurological InstitutePhoenix, United States
  • University of California Davis Medical SystemSacramento, United States
  • CenExel Rocky Mountain Clinical Research, LLCEnglewood, United States
  • Georgetown UniversityWashington D.C., United States
  • University of FloridaGainesville, United States
  • University of South FloridaTampa, United States
  • Northwestern UniversityChicago, United States
  • University of Iowa Hospitals and ClinicsIowa City, United States
  • John Hopkins University School of MedicineBaltimore, United States
  • Beth Israel Deaconess Medical CenterBoston, United States
  • Henry Ford HospitalDetroit, United States
  • Dent Neurological InstituteAmherst, United States
  • University of PittsburghPittsburgh, United States
  • Vanderbilt University Medical CenterNashville, United States
  • The University of Texas Health Science Center at HoustonHouston, United States
  • EvergreenHealth Investigational Drug ServicesKirkland, United States
  • Inland Northwest ResearchSpokane, United States
  • CINMEBuenos Aires, Argentina
  • Hospital Ramos MejíaCABA, Argentina
  • INEBACapital Federal, Argentina
  • Hospital Britanico de Buenos AiresCiudad Autonoma Buenos Aires, Argentina
  • Monash Medical CentreClayton, Australia
  • Royal Melbourne HospitalParkville, Australia
  • Perron Institute for Neurological and Translational ScienceNedlands, Australia

And 45 more, listed on the interactive page.

Sources for sites
clinicaltrials.gov

  • 2023
  • 2023-503928-10-00
  • 2022-001991-32
  • Other
Sources for references
clinicaltrials.gov

Related records

Drugs (1)

Lead sponsors (1)

Conditions (1)

Targets (1)