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NCT Number: NCT05686551

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

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).

Active, Not Recruiting

This study is active but is not currently recruiting participants.

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Key information

Conditions

Huntington Disease Basal Ganglia Diseases Brain Diseases Central Nervous System Diseases Chorea Cognition Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Dementia Dyskinesias Genetic Diseases, Inborn Heredodegenerative Disorders, Nervous System Mental Disorders Movement Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases

Age range

25 year–50 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

CINME, Buenos Aires, Argentina

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

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.

Treatment and study plan

Tominersen

Drug

Tominersen will be administered at the dose and schedule specified in the protocol.

Other names: RO7234292;, RG6042

Placebo

Drug

Matching placebo administered IT, Q16W during the DB period.

Primary outcomes

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

    Time frame: Up to approximately 36 months

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

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

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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: Up to approximately 29 months

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

    Time frame: Up to approximately 24 months

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

    Time frame: 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

    Time frame: Up to approximately 29 months

Secondary outcomes

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

    Time frame: 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

    Time frame: 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

    Time frame: Baseline to 16 months

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

    Time frame: Baseline to 16 months

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

    Time frame: Baseline to 16 months

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

    Time frame: Baseline to 16 months

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

    Time frame: Baseline to 16 months

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

    Time frame: Baseline to 16 months

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

    Time frame: Baseline up to approximately 36 months

  10. DB Period: Titers Determined if ADAs are Identified

    Time frame: Baseline up to approximately 36 months

  11. OLE Period: Change Over Time in TFC Score

    Time frame: Up to approximately 29 months

  12. OLE Period: Change Over Time in cUHDRS Score

    Time frame: Up to approximately 29 months

  13. OLE Period: Change Over Time in SDMT Score

    Time frame: Up to approximately 29 months

  14. OLE Period: Change Over Time in TMS

    Time frame: Up to approximately 29 months

  15. OLE Period: Change Over Time in SWR Score

    Time frame: Up to approximately 29 months

  16. OLE Period: Change Over Time in MoCA Score

    Time frame: 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

    Time frame: Up to approximately 29 months

  18. OLE Period: Incidence of ADAs at Specified Timepoints

    Time frame: Up to approximately 29 months

Sponsors and collaborators

Lead sponsor

Hoffmann-La Roche

Industry

Registry information

Official study 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

Important dates

Study start
2023
Primary completion
2026
Study completion
2027
First posted
Jan 17, 2023
Registry last updated
May 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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