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

Phase 2Active Not RecruitingNCT05686551

Hoffmann-La Roche301 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

301

Conditions

Huntington Disease

Interventions

TominersenDRUG

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

PlaceboDRUG

Matching placebo administered IT, Q16W during the DB period.

Eligibility

Sex: ALLMin age: 25 YearsMax age: 50 Years

Medical Language ↔ Plain English

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.

Locations (70)

Outcomes

Primary Outcomes

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

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

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

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

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

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

Time frame: Baseline, Month 9

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

Change in scores on the scale.

Time frame: Baseline to 16 months

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

Change in scores on the scale.

Time frame: Baseline to 16 months

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

Time frame: Up to approximately 29 months

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

Data from ClinicalTrials.gov

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Uab Medicine

Birmingham, Alabama, United States

Barrow Neurological Institute

Phoenix, Arizona, United States

University of California Davis Medical System

Sacramento, California, United States

CenExel Rocky Mountain Clinical Research, LLC

Englewood, Colorado, United States

Georgetown University

Washington D.C., District of Columbia, United States

University of Florida

Gainesville, Florida, United States

University of South Florida

Tampa, Florida, United States

Northwestern University

Chicago, Illinois, United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

John Hopkins University School of Medicine

Baltimore, Maryland, United States

...and 60 more locations

Secondary Outcomes

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

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

C-SSRS=Columbia-suicide Severity Rating Scale

Time frame: Up to approximately 36 months

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

Time frame: Baseline to 16 months

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

Time frame: Baseline to 16 months

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

Time frame: Baseline to 16 months

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

Time frame: Baseline to 16 months

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

Time frame: Baseline to 16 months

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

Time frame: Baseline to 16 months

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

DB Period: Titers Determined if ADAs are Identified

Time frame: Baseline up to approximately 36 months

OLE Period: Change Over Time in TFC Score

Time frame: Up to approximately 29 months

OLE Period: Change Over Time in cUHDRS Score

Time frame: Up to approximately 29 months

OLE Period: Change Over Time in SDMT Score

Time frame: Up to approximately 29 months

OLE Period: Change Over Time in TMS

Time frame: Up to approximately 29 months

OLE Period: Change Over Time in SWR Score

Time frame: Up to approximately 29 months

OLE Period: Change Over Time in MoCA Score

Time frame: Up to approximately 29 months

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

OLE Period: Incidence of ADAs at Specified Timepoints

Time frame: Up to approximately 29 months