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 | Active Not Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: BN42489Other2022-001991-322023-503928-10-00
• Study Type: interventional
• Target: 301
• Locations: 14 countries
• Sites: 69

Brief 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).

Conditions

Huntington Disease

Keywords

Prodromal and Early Manifest Huntington's Disease

Outcome Measures

Primary Outcomes (11)

• 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 Outcomes (18)

• 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

  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

Study Arms (3)

Tominersen 60 milligrams (mg)

EXPERIMENTAL

60 mg tominersen administered intrathecally (IT) every 16 weeks (Q16W). Tominersen will be administered in the DB period and the OLE period.

Drug: Tominersen

Placebo

PLACEBO COMPARATOR

Placebo will be administered IT, Q16W in the DB period.

Drug: Placebo

Tominersen 100 mg

EXPERIMENTAL

100 mg tominersen administered IT, Q16W. Tominersen will be administered in the DB period and the OLE period.

Drug: Tominersen

Interventions

Placebo DRUG

Matching placebo administered IT, Q16W during the DB period.

Placebo

Tominersen DRUG

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

Also known as: RO7234292;, RG6042

Tominersen 100 mg; Tominersen 60 milligrams (mg)

Eligibility Criteria

• Age: 25 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (70)

Uab Medicine

Birmingham, Alabama, 35294, United States

Location

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

University of California Davis Medical System

Sacramento, California, 95817, United States

Location

CenExel Rocky Mountain Clinical Research, LLC

Englewood, Colorado, 80113, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007, United States

Location

University of Florida

Gainesville, Florida, 32608, United States

Location

University of South Florida

Tampa, Florida, 33612, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

John Hopkins University School of Medicine

Baltimore, Maryland, 21287, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Dent Neurological Institute

Amherst, New York, 14226, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

Location

The University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

EvergreenHealth Investigational Drug Services

Kirkland, Washington, 98034, United States

Location

Inland Northwest Research

Spokane, Washington, 99202, United States

Location

CINME

Buenos Aires, C1056ABI, Argentina

Location

Hospital Ramos Mejía

CABA, C1221ADC, Argentina

Location

INEBA

Capital Federal, C1192AAX, Argentina

Location

Hospital Britanico de Buenos Aires

Ciudad Autonoma Buenos Aires, C1284AEB, Argentina

Location

Monash Medical Centre

Clayton, Victoria, 3168, Australia

Location

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Perron Institute for Neurological and Translational Science

Nedlands, Western Australia, 6009, Australia

Location

Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck

Innsbruck, 6020, Austria

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2G3, Canada

Location

Montreal Neurological Inst

Montreal, Quebec, H3A 2B4, Canada

Location

Rigshospitalet, Hukommelsesklinikken

København Ø, 2100, Denmark

Location

CHU Angers, Batiement Larrey 2, Neurologie

Angers, 49933, France

Location

Groupe Hospitalier Pellegrin

Bordeaux, 33076, France

Location

Hopital Henri Mondor

Créteil, 94010, France

Location

Hopital Roger Salengro Service de Neurologie

Lille, DUMMY_VALUE, France

Location

CHU de la Timone - Hopital d Adultes

Marseille, 13005, France

Location

Hopital Gui de Chauliac

Montpellier, 34295, France

Location

CHU Strasbourg Hpital Hautepierre

Strasbourg, 67098, France

Location

CHU toulouse - Hôpital Purpan

Toulouse, 31059, France

Location

Uniklinik RWTH Aachen

Aachen, 52074, Germany

Location

Charité - Universitätsmed. Berlin, Klinik für Psychiatrie und Psychotherapie

Berlin, 10117, Germany

Location

St. Josef-Hospital, Neurologische Klinik der Ruhr-Uni

Bochum, 44791, Germany

Location

German Center for Neurodegenerative Diseases (DZNE)

Bonn, 53127, Germany

Location

Universitätsklinikum Erlangen, Abteilung Molekulare Neurologie

Erlangen, 91054, Germany

Location

Universitätsklinikum Schleswig-Holstein / Campus Lübeck

Lübeck, 23538, Germany

Location

kbo - Isar-Amper-Klinikum Taufkirchen

Taufkirchen, 84416, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Ospedale Bellaria

Bologna, Emilia-Romagna, 40139, Italy

Location

Azienda Ospedaliera Sant'Andrea

Rome, Lazio, 00189, Italy

Location

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Lombardy, 20133, Italy

Location

New Zealand Brain Research Institute

Christchurch, 8011, New Zealand

Location

Waikato Hospital

Hamilton, 3240, New Zealand

Location

Szpital Sw. Wojciecha

Gdansk, 80-462, Poland

Location

Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii K

Krakow, 31-505, Poland

Location

Wojskowy Instytut Medycyny Lotniczej

Warsaw, 01-755, Poland

Location

Hospital de Santa Maria

Lisbon, 1649-035, Portugal

Location

CNS - Campus Neurológico

Torres Vedras, 2560-280, Portugal

Location

Hospital de Cruces

Barakaldo, Vizcaya, 48903, Spain

Location

Hospital Universitario de Badajoz

Badajoz, 06080, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Hospital Universitario de Burgos. Servicio de Neurología

Burgos, 09006, Spain

Location

Hospital Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

Location

Hospital Universitario la Fe

Valencia, 46026, Spain

Location

Universitätsspital Basel

Basel, 4031, Switzerland

Location

Neurozentrum Siloah

Gümligen, 3073, Switzerland

Location

University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2TH, United Kingdom

Location

Addenbrookes Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Chapel Allerton Hospital

Leeds, LS7 4SA, United Kingdom

Location

UCL Hospital NHS Trust

London, NW1 2PG, United Kingdom

Location

John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

Location

Southampton University Hospitals NHS Trust

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 38055260 DERIVED

MeSH Terms

Conditions

Huntington Disease

Interventions

tominersen

Condition Hierarchy (Ancestors)

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

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2022
• First Posted: January 17, 2023
• Study Start: February 3, 2023
• Primary Completion: May 14, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

CA (2); FR (8); DK (1); DE (8); ES (7); GB (6); PL (3); AR (4); NZ (2); AU (3); PT (2); US (18); IT (3); CH (2)