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

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

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 Overview

• Status: Active, not recruiting
• Conditions: Huntington Disease
• Intervention / Treatment: Drug: Tominersen; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 301
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1056ABI
    • CINME
  • CABA, Argentina, C1221ADC
    • Hospital Ramos Mejía
  • Capital Federal, Argentina, C1192AAX
    • INEBA
  • Ciudad Autonoma Buenos Aires, Argentina, C1284AEB
    • Hospital Britanico de Buenos Aires
• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Perron Institute for Neurological and Translational Science
• Austria
  • Innsbruck, Austria, 6020
    • Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2G3
      • University of Alberta Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Inst
• Denmark
  • København Ø, Denmark, 2100
    • Rigshospitalet, Hukommelsesklinikken
• France
  • Angers, France, 49933
    • CHU Angers, Batiement Larrey 2, Neurologie
  • Bordeaux, France, 33076
    • Groupe Hospitalier Pellegrin
  • Créteil, France, 94010
    • Hôpital Henri Mondor
  • Lille, France, DUMMY_VALUE
    • Hopital Roger Salengro Service de Neurologie
  • Marseille, France, 13005
    • CHU de la Timone - Hopital d Adultes
  • Montpellier, France, 34295
    • Hôpital Gui de Chauliac
  • Strasbourg, France, 67098
    • CHU Strasbourg Hpital Hautepierre
  • Toulouse, France, 31059
    • CHU Toulouse - Hopital Purpan
• Germany
  • Aachen, Germany, 52074
    • Uniklinik RWTH Aachen
  • Berlin, Germany, 10117
    • Charité - Universitätsmed. Berlin, Klinik für Psychiatrie und Psychotherapie
  • Bochum, Germany, 44791
    • St. Josef-Hospital, Neurologische Klinik der Ruhr-Uni
  • Bonn, Germany, 53127
    • German Center for Neurodegenerative Diseases (DZNE)
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen, Abteilung Molekulare Neurologie
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein / Campus Lübeck
  • Taufkirchen, Germany, 84416
    • kbo - Isar-Amper-Klinikum Taufkirchen
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40139
      • Ospedale Bellaria
  • Lazio
    • Rome, Lazio, Italy, 00189
      • Azienda Ospedaliera Sant'Andrea
  • Lombardy
    • Milan, Lombardy, Italy, 20133
      • Fondazione IRCCS Istituto Neurologico Carlo Besta
• New Zealand
  • Christchurch, New Zealand, 8011
    • New Zealand Brain Research Institute
  • Hamilton, New Zealand, 3240
    • Waikato Hospital
• Poland
  • Gdansk, Poland, 80-462
    • Szpital Sw. Wojciecha
  • Krakow, Poland, 31-505
    • Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii K
  • Warsaw, Poland, 01-755
    • Wojskowy Instytut Medycyny Lotniczej
• Portugal
  • Lisbon, Portugal, 1649-035
    • Hospital de Santa Maria
  • Torres Vedras, Portugal, 2560-280
    • CNS - Campus Neurológico
• Spain
  • Badajoz, Spain, 06080
    • Hospital Universitario de Badajoz
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Burgos, Spain, 09006
    • Hospital Universitario de Burgos. Servicio de Neurología
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Seville, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital de Cruces
• Switzerland
  • Basel, Switzerland, 4031
    • Universitätsspital Basel
  • Gümligen, Switzerland, 3073
    • Neurozentrum Siloah
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • University Hospitals Birmingham NHS Foundation Trust
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrookes Hospital
  • Leeds, United Kingdom, LS7 4SA
    • Chapel Allerton Hospital
  • London, United Kingdom, NW1 2PG
    • UCL Hospital NHS Trust
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton University Hospitals NHS Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB Medicine
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Medical System
  • Colorado
    • Englewood, Colorado, United States, 80113
      • CenExel Rocky Mountain Clinical Research, LLC
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurological Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
  • Washington
    • Kirkland, Washington, United States, 98034
      • EvergreenHealth Investigational Drug Services
    • Spokane, Washington, United States, 99202
      • Inland Northwest Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tominersen 60 milligrams (mg); 60 mg tominersen administered intrathecally (IT) every 16 weeks (Q16W). Tominersen will be administered in the DB period and the OLE period.	Drug: Tominersen; Tominersen will be administered at the dose and schedule specified in the protocol.; Other Names: RO7234292;; RG6042
Placebo Comparator: Placebo; Placebo will be administered IT, Q16W in the DB period.	Drug: Placebo; Matching placebo administered IT, Q16W during the DB period.
Experimental: Tominersen 100 mg; 100 mg tominersen administered IT, Q16W. Tominersen will be administered in the DB period and the OLE period.	Drug: Tominersen; Tominersen will be administered at the dose and schedule specified in the protocol.; Other Names: RO7234292;; RG6042

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DB Period: Incidence and Severity of Adverse Events (AEs), With Severity Determined According to the AE Severity Grading Scale		Up to approximately 36 months
DB Period: Change From Baseline in Clinical Laboratory Results - Cerebrospinal Fluid (CSF) White Blood Cell (WBC)		Baseline visit (Day 1), and Months 4, 8, 9, 12, 16
DB Period: Change From Baseline in Clinical Laboratory Results - CSF Protein		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		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		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.	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.	Baseline to 16 months
OLE Period: Incidence and Severity of AEs, With Severity Determined According to the AE Severity Grading Scale		Up to approximately 29 months
OLE Period: Change Over Time in Clinical Laboratory Results - CSF WBC		Up to approximately 24 months
OLE Period: Change Over Time in Clinical Laboratory Results - CSF Protein		Up to approximately 24 months
OLE Period: Change From Baseline in Structural MRI Assessing Any New Abnormalities, Including Radiographic Features Consistent With Hydrocephalus and Other Relevant MRI Safety Findings		Up to approximately 29 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DB Period: Change From Baseline in Montreal Cognitive Assessment (MoCA) Scores		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	Up to approximately 36 months
DB Period: Change From Baseline at 16 Months in TFC (non-U.S. Sites) Scores		Baseline to 16 months
DB Period: Change From Baseline at 16 Months in cUHDRS (U.S. Sites) Scores		Baseline to 16 months
DB Period: Change From Baseline at 16 Months in Symbol Digit Modalities Test (SDMT) Scores		Baseline to 16 months
DB Period: Change From Baseline at 16 Months in Stroop Word Reading (SWR) Score		Baseline to 16 months
DB Period: Change From Baseline at 16 Months in Total Motor Score (TMS)		Baseline to 16 months
DB Period: Change From Baseline in CSF Neurofilament Light Chain (NfL) Levels at 16 Months		Baseline to 16 months
DB Period: Incidence of Anti-drug Antibodies (ADAs) at Specified Timepoints Relative to the Prevalence of ADAs at Baseline		Baseline up to approximately 36 months
DB Period: Titers Determined if ADAs are Identified		Baseline up to approximately 36 months
OLE Period: Change Over Time in TFC Score		Up to approximately 29 months
OLE Period: Change Over Time in cUHDRS Score		Up to approximately 29 months
OLE Period: Change Over Time in SDMT Score		Up to approximately 29 months
OLE Period: Change Over Time in TMS		Up to approximately 29 months
OLE Period: Change Over Time in SWR Score		Up to approximately 29 months
OLE Period: Change Over Time in MoCA Score		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		Up to approximately 29 months
OLE Period: Incidence of ADAs at Specified Timepoints		Up to approximately 29 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

General Publications

• McColgan P, Thobhani A, Boak L, Schobel SA, Nicotra A, Palermo G, Trundell D, Zhou J, Schlegel V, Sanwald Ducray P, Hawellek DJ, Dorn J, Simillion C, Lindemann M, Wheelock V, Durr A, Anderson KE, Long JD, Wild EJ, Landwehrmeyer GB, Leavitt BR, Tabrizi SJ, Doody R; GENERATION HD1 Investigators. Tominersen in Adults with Manifest Huntington's Disease. N Engl J Med. 2023 Dec 7;389(23):2203-2205. doi: 10.1056/NEJMc2300400. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2023
• Primary Completion (Actual): May 14, 2026
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: December 16, 2022
• First Submitted That Met QC Criteria: January 6, 2023
• First Posted (Actual): January 17, 2023

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Prodromal and Early Manifest Huntington's Disease
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurocognitive Disorders; Cognition Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Dyskinesias; Chorea; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Huntington Disease; tominersen
• Other Study ID Numbers: BN42489; Other (Other Identifier: GENERATION HD2); 2022-001991-32 (EudraCT Number); 2023-503928-10-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No