A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Participants With Manifest Huntington's Disease

A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Clinical Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington's Disease

This study will evaluate the efficacy, safety, and biomarker effects of RO7234292 (RG6042) compared with placebo in participants with manifest Huntington's disease (HD)

Study Overview

• Status: Completed
• Conditions: Huntingtons Disease
• Intervention / Treatment: Drug: RO7234292; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 899
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1221ADC
    • Hospital Ramos Mejía
  • Capital Federal, Argentina, C1192AAX
    • INEBA
  • Ciudad Autonoma Buenos Aires, Argentina, C1284AEB
    • Hospital Britanico de Buenos Aires
• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • WESTMEAD HOSPITAL; Deparment of Neurology
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital; Department of Neurology
• Austria
  • Innsbruck, Austria, 6020
    • Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck; Department fuer Neurologie
  • Salzburg, Austria, 5020
    • Christian-Doppler-Klinik - Universitätsklinikum; Universitätskliniik für Neurologie
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z1
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
      • University of British Columbia Hospital; Division of Neurology
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3S 1N2
      • True North Clinical Research-Halifax
  • Ontario
    • North York, Ontario, Canada, M3B 2S7
      • Centre for Movement Disorders
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H2X 0C2
      • Centre Hospitalier de l?Université de Montréal (CHUM)
• Chile
  • Santiago, Chile, 9120000
    • Centro de Trastornos del Movimiento (CETRAM); CETRAM
• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus Universitetshospital; Neurologisk Afdeling F, Neurogenetisk Afsnit
  • København Ø, Denmark, 2100
    • Rigshospitalet, Hukommelsesklinikken
• France
  • Angers Cedex 9, France, 49933
    • CHU Angers, Batiement Larrey 2, Neurologie
  • Creteil, France, 94010
    • Hopital Henri Mondor; Service de Neurologie
  • Lille, France
    • Hopital Roger Salengro Service de Neurologie
  • Marseille, France, 13005
    • CHU de la Timone - Hopital d Adultes; Service de Neurologie
  • Montpellier, France, 34295
    • Hopital Gui de Chauliac; Neurologie
  • Paris, France, 75651
    • Hôpital Pitié Salpêtrère; Département de Génétique et Cytogénétique
  • Toulouse, France, 31059
    • CHU toulouse - Hôpital Purpan; Departement de Neurologie
• Germany
  • Aachen, Germany, 52074
    • Uniklinik RWTH Aachen; Klinik für Neurologie
  • Berlin, Germany, 10117
    • Charité - Universitätsmed. Berlin, Klinik für Psychiatrie und Psychotherapie; Abt. Neuropsychiatrie
  • Bochum, Germany, 44791
    • St. Josef-Hospital, Neurologische Klinik der Ruhr-Uni; Huntington-Center NRW, Abt. Neurodegeneration
  • 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; Zentrum für Seltene Erkrankungen
  • Münster, Germany, 48149
    • George-Huntington- Institut GmbH; Technologiepark Münster
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm; Klinik für Neurologie
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40139
      • IRCCS Istituto delle Scienze Neurologiche; UOC Clinica Neurologica
  • Lazio
    • Roma, Lazio, Italy, 00189
      • Azienda Ospedaliera Sant'Andrea; UOC Neurologia
  • Liguria
    • Genova, Liguria, Italy, 16132
      • Irccs A.O.U.San Martino Ist; Dinogmi
  • Lombardia
    • Milano, Lombardia, Italy, 20133
      • Fondazione IRCCS Istituto Neurologico Carlo Besta; U.O.C. Genetica Medica-Neurogenetica
  • Puglia
    • San Giovanni Rotondo, Puglia, Italy, 71013
      • IRCCS Casa Sollievo Della Sofferenza; Unità Ricerca e Cura Huntington e Malattie Rare
  • Toscana
    • Firenze, Toscana, Italy
      • A.O.U. Careggi; Diaprtimento Scienze Neurologiche e Psichiatriche
• Japan
  • Mie, Japan, 511-0061
    • Kuwana City Medical Center
  • Niigata, Japan, 945-8585
    • National Hospital Organization Niigata National Hospital
  • Okayama, Japan, 700-8558
    • Okayama University Graduate School of Medicine, Densitry and Pharmaceutical Sciences.
  • Osaka, Japan, 558-8558
    • Osaka General Medical Center
  • Tokyo, Japan, 187-8551
    • National Center of Neurology and Psychiatry
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen
  • Leiden, Netherlands, 2333 ZA
    • LUMC
• New Zealand
  • Auckland, New Zealand
    • Auckland DHB - Neurlogy Department; Neurology Department
  • Christchurch, New Zealand, 8011
    • New Zealand Brain Research Institute
  • Wellington, New Zealand, 6021
    • Wellington Hospital; Department of Neurology
• Poland
  • Gdansk, Poland, 80-462
    • Szpital Sw. Wojciecha; Oddzial Neurologiczny
  • Krakow, Poland, 31-505
    • Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii K
  • Warszawa, Poland, 02-957
    • Instytut Psychiatrii i Neurologii
• Russian Federation
  • Krasnojarsk
    • Krasnoyarsk, Krasnojarsk, Russian Federation, 660037
      • FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency
  • Moskovskaja Oblast
    • Moskva, Moskovskaja Oblast, Russian Federation, 125367
      • Research Center of Neurology; Neurology Department #5
  • Tatarstan
    • Kazan, Tatarstan, Russian Federation, 420061
      • ?linical hospital at Kazan station, Republican Center for Movement Disorders and Botulinum Therapy
• Spain
  • Badajoz, Spain, 06080
    • Hospital Universitario de Badajoz; Servicio de Neurología
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau; Servicio de Neurologia
  • Barcelona, Spain, 08036
    • Hospital Clinic Servicio de Neurologia
  • Burgos, Spain, 09006
    • Hospital Universitario de Burgos. Servicio de Neurología
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal; Servicio de Neurologia
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz; Servicio de Neurología
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena; Servicio de Neurologia
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe; Servicio de Neurologia
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital de Cruces; Servicio de Neurologia
• Switzerland
  • Basel, Switzerland, 4031
    • Universitätsspital Basel; Neurologie
  • Gümligen, Switzerland, 3073
    • Neurozentrum Siloah
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZD
    • Aberdeen Royal Infirmary; Medical Genectics
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital
  • Cambridge, United Kingdom, CB2 0SP
    • Cambridge Centre for Brain Repair; Department of Clinical Nuerosciences, Addenbrookes Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales; Division of Psychological Medicine and Clinical Neurosciences
  • Glasgow, United Kingdom, G51 4TF
    • Queen Elizabeth University Hospital Glasgow
  • Leeds, United Kingdom, LS1 3EX
    • Leeds General Infirmary
  • London, United Kingdom, WC1N 3BG
    • National Hospital For Neurology and Neurosurgery
  • Manchester, United Kingdom, M13 9WL
    • Central Manchester University Hospitals NHS Foundation Trust; Manchester Centre for Genomic Medicine
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital
  • Southhampton, United Kingdom, SO16 6YD
    • University Hospital Southampton NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB Medicine
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
  • California
    • La Jolla, California, United States, 92037-1337
      • University of California San Diego
    • Palo Alto, California, United States, 94304
      • Stanford Univ Medical Center
    • Pasadena, California, United States, 91105
      • SC3 Research Group, Inc
    • 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, District of Columbia, United States, 20007
      • Georgetown University; Research Division, Psychiatry
  • Florida
    • Tampa, Florida, United States, 33613
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurological Institute
    • New York, New York, United States, 10032-3725
      • Columbia University
  • 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; McGovern Medical School
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Clinical Neurosciences Center
  • Washington
    • Kirkland, Washington, United States, 98034
      • Evergreen Health Care Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Manifest HD diagnosis, defined as a DCL score of 4
• Independence Scale (IS) score >= 70
• Genetically confirmed disease by direct DNA testing with a CAP score >400
• Clinical assessment to ensure individual has intact functional independence at baseline to maintain self-care and core activities of daily living (ADLs).

Exclusion Criteria:

• Any serious medical condition or clinically significant laboratory, or vital sign abnormality or claustrophobia at screening that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of study drug

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: RO7234292 Q8W; RO4234292 is administered intrathecally every 8 weeks.	Drug: RO7234292; Intrathecal injection; Other Names: Tominersen
Experimental: RO7234292 Q16W; RO7234292 is administered intrathecally every 16 weeks. Participants in this arm will also receive placebo at alternate weeks to keep the blind.	Drug: RO7234292; Intrathecal injection; Other Names: Tominersen; Drug: Placebo; Intrathecal injection
Placebo Comparator: Placebo; Placebo will be administered every 8 weeks by IT injection.	Drug: Placebo; Intrathecal injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Composite Unified Huntington's Disease Rating Scale (cUHDRS) Score-Z Score	cUHDRS includes the Total Functional Capacity (range, 0-13; higher score means better functioning), Total Motor Score (range, 0-124; higher score means worse motor severity), Symbol Digit Modality Test (range, 0-110, correctly paired numbers-symbols in 90 seconds; higher score means better cognitive performance), and Stroop Word Reading (range, 0-no max value, correctly read colour words in 45 seconds; higher score means better cognitive performance) scores. A z-score for each test is calculated, which alone can be used to describe relationship between an individual's test score and the mean score of a target population. A z-score of 0 is the mean, and ±1 is 1 standard deviation from the mean. For cUHDRS, z-scores of each test are summed, whereby a higher cUHDRS score is better (score of -3.06-no max value) and a change of ≥1.2 is a meaningful worsening, shown to track functional decline.	Weeks 21 for ODC and 69 for NDC
Change From Baseline in the Total Functional Capacity (TFC) Score	Total Functional Capacity (TFC) Scores are reported at Weeks 21 and 69. Total Functional Capacity Score ranges from 0 to 13, with a higher score representing better functioning.	Weeks 21 for ODC and 69 for NDC

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Motor Score (TMS)	The TMS score is the sum of the individual motor ratings obtained from administration of the 31-item motor assessment. The score ranges from 0 to 124, with a higher score representing more severe impairment.	Weeks 21 for ODC and 69 for NDC
Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores' Least Squares Mean Values	Symbol Digit Modality Test -SDMT test measures the number of items correctly paired maximum of 110 correct pairs in 90 seconds, more correctly paired items representing less impairment. The differences in LS mean ( +/-SE) change from baseline SDMT score between the active groups compared with the placebo group at Weeks 21 and 69 were reported. A negative change from baseline in the SDMT indicates disease progression. The Least Square Mean values of Symbol Digit Modality Test Scores are reported below. The minimum range for the SDMT scale is 0, indicating highest severity. A max number is not possible as it is a time based task, based on the number of correct answers within a set time frame. There are no validated SDMT score thresholds to indicate the level of HD symptom severity.	Weeks 21 for ODC and 69 NDC
Change From Baseline in Stroop Word Reading (SWR) Test Scores' Least Squares Mean Values	Stroop Word Reading-SWR number of words and colors read correctly is counted, with a higher score indicating better cognitive performance scores. There is no upper limit for SWR as it is a time based task. The lower limit (worst possible) however is 0; higher score is better meaning less severity. The differences in LS mean ( +/-SE) change from baseline SWR score between the active groups compared with the placebo group at Weeks 21 and 69 were reported. A negative change from baseline in the SWR indicates disease progression. The Least Square Mean values of Stroop Word Reading (SWR) Test Scores are reported below.	Weeks 21 for ODC and 69 for NDC
Change From Baseline in the Clinical Global Impression, Severity Scale (CGI-S) Scores' Least Squares Mean Values	The CGI-S is a single-item measure of current global severity and is completed by the clinician at specified clinic visits. The CGI-S is assessed using an 11-point numeric rating scale (NRS), where higher scores indicate greater severity. Only NDC participants data were reported, all other data were not available. CGI-S) Scores range from 0 (not at all severe) to 10 (Extremely severe); lower score is better meaning less severity.	Week 69 for NDC Only
Percentage of Patients With a Decrease From Baseline of >=1 Point on the Total Functional Capacity (TFC) Score	Only NDC participant data are available and reported. Total Functional Capacity-TFC score ranges from 0 to 13, with a higher score representing better functioning. In this outcome measure, participants with 1 or higher point score decrease from the Baseline TFC Total Score was considered. The Percentage of these participants with such a change was calculated.	Week 69 for NDC only
Percentage of Patients With a Decline From Baseline of >=1.2 Points on the Composite Unified Huntington's Disease Rating Scale-cUHDRS Score	Only NDC participant data are available and reported. The cUHDRS is comprised of the sum scores of the subscales, score ranges and severities mentioned in the Outcome Measure Description 1 (please see above). In this outcome measure, participants with 1.2 or higher point score decrease from the Baseline Composite Unified Huntington's Disease Rating Scale- cUHDRS Total Score was considered. The Percentage of these participants with such a change was calculated. cUHDRS lowest (worst) score possible value is -3.06 but no upper limit as it involves SWR; higher score is better meaning less severity.	Week 69 for NDC Only
Percentage of Patients With an Unchanged or Improved Score on the Clinical Global Impression, Change Scale Score	The Clinical Global Impression, Change - CGI-C Scale is a single-item measure of change in global status scale and total scores are summed and reported. The CGI-C has 7 response options: "very much worse," "much worse," "minimally worse," "no change," "minimally improved," "much improved," and "very much improved." "Yes", "No" responses collected and total scores are summed and reported below. Percentage of participants who have unchanged or improved scores from the Baseline CGI-C Scores are calculated and reported here. Total CGI-C scores range from 1 (Very much improved) to 7 (Very much worse); lower score is better meaning less severity. Only NDC Arms data were available. Minimum and maximum values are 1 and 7 respectively.	Weeks 53 and 69 NDC only
Percentage of Participants With Adverse Events		Up to 117 Weeks (29 months)
Change From Baseline in Montreal Cognitive Assessment (MoCA)	ODC Week 21 and NDC Week 69 data were reportable. Total MOCA scores are reported. The MoCA is a patient-completed assessment used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0-30, where lower scores indicate greater impairment.	Up to Week 21 for ODC, Up to Week 69 for NDC
Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score	SI-Suicidal Idealation. For ODC, only Treatment Emergent Suicide-Related Events Based on the Columbia-Suicide Severity Rating Scale (CSSRS) are reported. Four constructs are measured: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories, and composite endpoints based on the categories are followed over time to monitor patient safety (Posner et al. 2011). It maps to the Columbia-Classification Algorithm for Suicide Assessment and meets the criteria listed in the U.S. FDA draft guidance for assessment of suicidality in clinical trials (FDA 2012). The higher scores indicate higher severity	For ODC at 13th Month, for NDC at Week 101
Concentration of RO7234292 in Plasma	Concentration of tominersen in plasma reported	Week 21 for ODC and Week 69 for NDC
Trough Concentration of RO7234292 in Cerebrospinal Fluid (CSF)	Tominersen concentrations in cerebrospinal fluid	Week 21 for ODC and Week 69 for NDC
Incidence of Anti-Drug Antibodies (ADAs).	Data at Weeks 21 and 69 for Old Design and New Design Cohorts are reported respectively. All other timepoints were not evaluable and not meaningful.	Week 21 for ODC and Week 69 for NDC
Titer and Antibody Subtype, Determined if ADAs Are Identified	Titer and Antibody Subtype was not analyzed and there is not data to report due to participants' discontinuation	Week 21 for ODC and Week 69 for NDC
Change From Baseline in CSF mHTT Protein Level	Data to be reported within 12 months after the primary completion.	Baseline, Week 101
Change From Baseline in Whole and Regional Brain Volumes, as Detrmined by Structural Magnetic Resonance Imaging (MRI)	Data reported only for ODC Arms. Analysis of Percent Change from Baseline in Volumetric MRI / BSI at 3 Months reported. Analysis performed using analysis of covariance with covariates of CAP, CAG, Age at Baseline and treatment included. Analysis of Change from Baseline in: Caudate Volume (mL)	Week 13 for ODC
Change From Baseline in CSF Neurofilament Light Chain (NfL) Proteint Level		Week 21 for ODC, Weeks 21 and 69 for NDC

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Rodrigues FB, Ferreira JJ, Wild EJ. Huntington's Disease Clinical Trials Corner: June 2019. J Huntingtons Dis. 2019;8(3):363-371. doi: 10.3233/JHD-199003.
• Rodrigues FB, Quinn L, Wild EJ. Huntington's Disease Clinical Trials Corner: January 2019. J Huntingtons Dis. 2019;8(1):115-125. doi: 10.3233/JHD-190001.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2019
• Primary Completion (Actual): March 24, 2022
• Study Completion (Actual): March 24, 2022

Study Registration Dates

• First Submitted: November 30, 2018
• First Submitted That Met QC Criteria: November 30, 2018
• First Posted (Actual): December 3, 2018

Study Record Updates

• Last Update Posted (Actual): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: HD, RG6042, intrathecal, ASO, antisense oligonucleotide
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: BN40423; GENERATION HD1 (Other Identifier: Hoffmann-La Roche)

Drug and device information, study documents

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