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

Huntingtons Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03761849
• Other study ID #: BN40423
• Secondary ID: GENERATION HD1
• Status: Completed
• Phase: Phase 3
• Start date: January 23, 2019
• Est. completion date: March 24, 2022

Study information

• Verified date: February 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 899
• Est. completion date: March 24, 2022
• Est. primary completion date: March 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Huntington Disease
• Huntingtons Disease

Intervention

Drug:
• RO7234292
Intrathecal injection
• Placebo
Intrathecal injection

Locations

Country	Name	City	State
Argentina	Hospital Ramos Mejía	Caba
Argentina	INEBA	Capital Federal
Argentina	Hospital Britanico de Buenos Aires	Ciudad Autonoma Buenos Aires
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Royal Melbourne Hospital; Department of Neurology	Parkville	Victoria
Australia	WESTMEAD HOSPITAL; Deparment of Neurology	Westmead	New South Wales
Austria	Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck; Department fuer Neurologie	Innsbruck
Austria	Christian-Doppler-Klinik - Universitätsklinikum; Universitätskliniik für Neurologie	Salzburg
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	True North Clinical Research-Halifax	Halifax	Nova Scotia
Canada	Centre Hospitalier de l?Université de Montréal (CHUM)	Montreal	Quebec
Canada	Centre for Movement Disorders	North York	Ontario
Canada	Ottawa Hospital Research Institute	Ottawa	Ontario
Canada	University of British Columbia Hospital; Division of Neurology	Vancouver	British Columbia
Chile	Centro de Trastornos del Movimiento (CETRAM); CETRAM	Santiago
Denmark	Aarhus Universitetshospital; Neurologisk Afdeling F, Neurogenetisk Afsnit	Aarhus N
Denmark	Rigshospitalet, Hukommelsesklinikken	København Ø
France	CHU Angers, Batiement Larrey 2, Neurologie	Angers Cedex 9
France	Hopital Henri Mondor; Service de Neurologie	Creteil
France	Hopital Roger Salengro Service de Neurologie	Lille
France	CHU de la Timone - Hopital d Adultes; Service de Neurologie	Marseille
France	Hopital Gui de Chauliac; Neurologie	Montpellier
France	Hôpital Pitié Salpêtrère; Département de Génétique et Cytogénétique	Paris
France	CHU toulouse - Hôpital Purpan; Departement de Neurologie	Toulouse
Germany	Uniklinik RWTH Aachen; Klinik für Neurologie	Aachen
Germany	Charité - Universitätsmed. Berlin, Klinik für Psychiatrie und Psychotherapie; Abt. Neuropsychiatrie	Berlin
Germany	St. Josef-Hospital, Neurologische Klinik der Ruhr-Uni; Huntington-Center NRW, Abt. Neurodegeneration	Bochum
Germany	German Center for Neurodegenerative Diseases (DZNE)	Bonn
Germany	Universitätsklinikum Erlangen, Abteilung Molekulare Neurologie	Erlangen
Germany	Universitätsklinikum Schleswig-Holstein / Campus Lübeck; Zentrum für Seltene Erkrankungen	Lübeck
Germany	George-Huntington- Institut GmbH; Technologiepark Münster	Münster
Germany	Universitätsklinikum Ulm; Klinik für Neurologie	Ulm
Italy	IRCCS Istituto delle Scienze Neurologiche; UOC Clinica Neurologica	Bologna	Emilia-Romagna
Italy	A.O.U. Careggi; Diaprtimento Scienze Neurologiche e Psichiatriche	Firenze	Toscana
Italy	Irccs A.O.U.San Martino Ist; Dinogmi	Genova	Liguria
Italy	Fondazione IRCCS Istituto Neurologico Carlo Besta; U.O.C. Genetica Medica-Neurogenetica	Milano	Lombardia
Italy	Azienda Ospedaliera Sant'Andrea; UOC Neurologia	Roma	Lazio
Italy	IRCCS Casa Sollievo Della Sofferenza; Unità Ricerca e Cura Huntington e Malattie Rare	San Giovanni Rotondo	Puglia
Japan	Kuwana City Medical Center	Mie
Japan	National Hospital Organization Niigata National Hospital	Niigata
Japan	Okayama University Graduate School of Medicine, Densitry and Pharmaceutical Sciences.	Okayama
Japan	Osaka General Medical Center	Osaka
Japan	National Center of Neurology and Psychiatry	Tokyo
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	LUMC	Leiden
New Zealand	Auckland DHB - Neurlogy Department; Neurology Department	Auckland
New Zealand	New Zealand Brain Research Institute	Christchurch
New Zealand	Wellington Hospital; Department of Neurology	Wellington
Poland	Szpital Sw. Wojciecha; Oddzial Neurologiczny	Gdansk
Poland	Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii K	Krakow
Poland	Instytut Psychiatrii i Neurologii	Warszawa
Russian Federation	?linical hospital at Kazan station, Republican Center for Movement Disorders and Botulinum Therapy	Kazan	Tatarstan
Russian Federation	FSBHI Siberian Clinical Center of the Federal Medical and Biological Agency	Krasnoyarsk	Krasnojarsk
Russian Federation	Research Center of Neurology; Neurology Department #5	Moskva	Moskovskaja Oblast
Spain	Hospital Universitario de Badajoz; Servicio de Neurología	Badajoz
Spain	Hospital de Cruces; Servicio de Neurologia	Barakaldo	Vizcaya
Spain	Hospital Clinic Servicio de Neurologia	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau; Servicio de Neurologia	Barcelona
Spain	Hospital Universitario de Burgos. Servicio de Neurología	Burgos
Spain	Fundacion Jimenez Diaz; Servicio de Neurología	Madrid
Spain	Hospital Ramon y Cajal; Servicio de Neurologia	Madrid
Spain	Hospital Universitario Virgen Macarena; Servicio de Neurologia	Sevilla
Spain	Hospital Universitario la Fe; Servicio de Neurologia	Valencia
Switzerland	Universitätsspital Basel; Neurologie	Basel
Switzerland	Neurozentrum Siloah	Gümligen
United Kingdom	Aberdeen Royal Infirmary; Medical Genectics	Aberdeen
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Cambridge Centre for Brain Repair; Department of Clinical Nuerosciences, Addenbrookes Hospital	Cambridge
United Kingdom	University Hospital of Wales; Division of Psychological Medicine and Clinical Neurosciences	Cardiff
United Kingdom	Queen Elizabeth University Hospital Glasgow	Glasgow
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	National Hospital For Neurology and Neurosurgery	London
United Kingdom	Central Manchester University Hospitals NHS Foundation Trust; Manchester Centre for Genomic Medicine	Manchester
United Kingdom	John Radcliffe Hospital	Oxford
United Kingdom	Royal Hallamshire Hospital	Sheffield
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southhampton
United States	Dent Neurological Institute	Amherst	New York
United States	John Hopkins University School of Medicine	Baltimore	Maryland
United States	Uab Medicine	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	CenExel Rocky Mountain Clinical Research, LLC	Englewood	Colorado
United States	The University of Texas Health Science Center at Houston; McGovern Medical School	Houston	Texas
United States	Evergreen Health Care Center	Kirkland	Washington
United States	University of California San Diego	La Jolla	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University	New York	New York
United States	Stanford Univ Medical Center	Palo Alto	California
United States	SC3 Research Group, Inc	Pasadena	California
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of California Davis Medical System	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah Clinical Neurosciences Center	Salt Lake City	Utah
United States	University of South Florida	Tampa	Florida
United States	Georgetown University; Research Division, Psychiatry	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Canada,  Chile,  Denmark,  France,  Germany,  Italy,  Japan,  Netherlands,  New Zealand,  Poland,  Russian Federation,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of Participants With Adverse Events		Up to 117 Weeks (29 months)
Secondary	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
Secondary	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
Secondary	Concentration of RO7234292 in Plasma	Concentration of tominersen in plasma reported	Week 21 for ODC and Week 69 for NDC
Secondary	Trough Concentration of RO7234292 in Cerebrospinal Fluid (CSF)	Tominersen concentrations in cerebrospinal fluid	Week 21 for ODC and Week 69 for NDC
Secondary	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
Secondary	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
Secondary	Change From Baseline in CSF mHTT Protein Level	Data to be reported within 12 months after the primary completion.	Baseline, Week 101
Secondary	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
Secondary	Change From Baseline in CSF Neurofilament Light Chain (NfL) Proteint Level		Week 21 for ODC, Weeks 21 and 69 for NDC