Clinical trial 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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Huntington Disease
Keywords: Prodromal and Early Manifest Huntington's Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2023-01-17
Enrollment: 301
Sex: ALL
Minimum age (years): 25
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: Inclusion Criteria

-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/m2)
* Study companion

Exclusion Criteria

* Current or previous use of an antisense oligonucleotide (ASO) (including small interfering ribonucleic acid \[RNA\]) or any huntingtin gene/protein (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

Primary outcomes:
measure: Incidence and Severity of Adverse Events (AEs), With Severity Determined According to the AE Severity Grading Scale
timeFrame: Up to approximately 24 months
measure: Change From Baseline in Clinical Laboratory Results - Cerebrospinal Fluid (CSF) White Blood Cell (WBC)
timeFrame: From baseline visit (Day 1), and months 4, 8, 9, 12, 16
measure: Change From Baseline in Clinical Laboratory Results CSF Protein
timeFrame: From baseline visit (Day 1), and months 4, 8, 9, 12, 16
measure: 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: From baseline, months 4, 8, 12, 16 and up to approximately month 24
measure: Percentage Change From Baseline in Geometric Means of CSF Mutant Huntingtin (mHTT) Protein Levels at Month 9
timeFrame: Baseline, Month 9
measure: 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
measure: Change From Baseline in Total Functional Capacity (TFC) Scores (U.S. Sites) at 16 Months
timeFrame: Baseline to 16 months
Secondary outcomes:
measure: Change From Baseline in Montreal Cognitive Assessment (MoCA) Scores
timeFrame: From baseline, months 4, 8, 12, 16 and up to approximately month 24
measure: Percentage of Participants With Suicidal Ideation or Behavior (I/B) as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) at Each Visit, Including Detailed Focus on Any Individual Cases Identified as Having Severe I/B During the Study Conduct
timeFrame: Up to approximately 24 months
measure: Change From Baseline at 16 Months for the Assessments of TFC (non-U.S. Sites) Scores
timeFrame: Baseline to 16 months
measure: Change From Baseline at 16 Months for the Assessments of cUHDRS (U.S. Sites) Scores
timeFrame: Baseline to 16 months
measure: Change From Baseline at 16 Months for the Assessments of Symbol Digit Modalities Test (SDMT) Scores
timeFrame: Baseline to 16 months
measure: Change From Baseline at 16 Months for the Assessments of Stroop Word Reading (SWR) Score
timeFrame: Baseline to 16 months
measure: Change From Baseline at 16 Months for the Assessment of Total Motor Score (TMS)
timeFrame: Baseline to 16 months
measure: Change From Baseline in CSF Neurofilament Light Chain (NfL) Levels at 16 Months
timeFrame: Baseline to 16 months
measure: Incidence of Anti-drug Antibodies (ADAs) at Specified Timepoints Relative to the Prevalence of ADAs at Baseline
timeFrame: From baseline, months 4, 8, 12, 16 and up to approximately month 24
measure: Titers Determined if ADAs are Identified
timeFrame: From baseline, months 4, 8, 12, 16 and up to approximately month 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Uab Medicine
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Sacramento
country: United States
facility: University of California Davis Medical System
state: California
city: Englewood
country: United States
facility: CenExel Rocky Mountain Clinical Research, LLC
state: Colorado
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: John Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Amherst
country: United States
facility: Dent Neurological Institute
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Kirkland
country: United States
facility: EvergreenHealth Investigational Drug Services
state: Washington
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
city: Buenos Aires
country: Argentina
facility: CINME
city: Caba
country: Argentina
facility: Hospital Ramos Mejía
city: Capital Federal
country: Argentina
facility: INEBA
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital Britanico de Buenos Aires
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Perron Institute for Neurological and Translational Science
state: Western Australia
city: Innsbruck
country: Austria
facility: Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Montreal
country: Canada
facility: Montreal Neurological Inst
state: Quebec
city: København Ø
country: Denmark
facility: Rigshospitalet, Hukommelsesklinikken
city: Angers Cedex 9
country: France
facility: CHU Angers, Batiement Larrey 2, Neurologie
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Lille
country: France
facility: Hopital Roger Salengro Service de Neurologie
city: Marseille
country: France
facility: CHU de la Timone - Hopital d Adultes
city: Montpellier
country: France
facility: Hopital Gui de Chauliac
city: Strasbourg
country: France
facility: CHU Strasbourg Hôpital Hautepierre
city: Toulouse
country: France
facility: CHU toulouse - Hôpital Purpan
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Berlin
country: Germany
facility: Charité - Universitätsmed. Berlin, Klinik für Psychiatrie und Psychotherapie
city: Bochum
country: Germany
facility: St. Josef-Hospital, Neurologische Klinik der Ruhr-Uni
city: Bonn
country: Germany
facility: German Center for Neurodegenerative Diseases (DZNE)
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Abteilung Molekulare Neurologie
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein / Campus Lübeck
city: Taufkirchen
country: Germany
facility: kbo - Isar-Amper-Klinikum Taufkirchen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Bologna
country: Italy
facility: Ospedale Bellaria
state: Emilia-Romagna
city: Roma
country: Italy
facility: Azienda Ospedaliera Sant'Andrea
state: Lazio
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
state: Lombardia
city: Christchurch
country: New Zealand
facility: New Zealand Brain Research Institute
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Gdansk
country: Poland
facility: Szpital Sw. Wojciecha
city: Krakow
country: Poland
facility: Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii K
city: Warszawa
country: Poland
facility: Wojskowy Instytut Medycyny Lotniczej
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria
city: Torres Vedras
country: Portugal
facility: CNS - Campus Neurológico
city: Barakaldo
country: Spain
facility: Hospital de Cruces
state: Vizcaya
city: Badajoz
country: Spain
facility: Hospital Universitario de Badajoz
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos. Servicio de Neurología
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Hospital Universitario la Fe
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Gümligen
country: Switzerland
facility: Neurozentrum Siloah
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Leeds
country: United Kingdom
facility: Chapel Allerton Hospital
city: London
country: United Kingdom
facility: UCL Hospital NHS Trust
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: