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

Phase 3

Completed

Conditions: Huntingtons Disease

Interventions: Drug: Placebo
Drug: RO7234292

Registration Number: NCT03761849

Lead Sponsor: Hoffmann-La Roche

Brief 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)

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 899

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo will be administered every 8 weeks by IT injection.
RO7234292 Q16W	RO7234292	RO7234292 is administered intrathecally every 16 weeks. Participants in this arm will also receive placebo at alternate weeks to keep the blind.
RO7234292 Q16W	Placebo	RO7234292 is administered intrathecally every 16 weeks. Participants in this arm will also receive placebo at alternate weeks to keep the blind.
RO7234292 Q8W	RO7234292	RO4234292 is administered intrathecally every 8 weeks.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in the Composite Unified Huntington's Disease Rating Scale (cUHDRS) Score-Z Score	Weeks 21 for ODC and 69 for NDC	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.
Change From Baseline in the Total Functional Capacity (TFC) Score	Weeks 21 for ODC and 69 for NDC	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients With an Unchanged or Improved Score on the Clinical Global Impression, Change Scale Score	Weeks 53 and 69 NDC only	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.
Trough Concentration of RO7234292 in Cerebrospinal Fluid (CSF)	Week 21 for ODC and Week 69 for NDC	Tominersen concentrations in cerebrospinal fluid
Change From Baseline in Whole and Regional Brain Volumes, as Detrmined by Structural Magnetic Resonance Imaging (MRI)	Week 13 for ODC	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)
Change From Baseline in CSF Neurofilament Light Chain (NfL) Proteint Level	Week 21 for ODC, Weeks 21 and 69 for NDC
Change From Baseline in Stroop Word Reading (SWR) Test Scores' Least Squares Mean Values	Weeks 21 for ODC and 69 for NDC	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.
Percentage of Patients With a Decrease From Baseline of >=1 Point on the Total Functional Capacity (TFC) Score	Week 69 for NDC only	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.
Change From Baseline in Total Motor Score (TMS)	Weeks 21 for ODC and 69 for NDC	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.
Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores' Least Squares Mean Values	Weeks 21 for ODC and 69 NDC	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.
Change From Baseline in the Clinical Global Impression, Severity Scale (CGI-S) Scores' Least Squares Mean Values	Week 69 for NDC Only	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.
Incidence of Anti-Drug Antibodies (ADAs).	Week 21 for ODC and Week 69 for NDC	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.
Percentage of Patients With a Decline From Baseline of >=1.2 Points on the Composite Unified Huntington's Disease Rating Scale-cUHDRS Score	Week 69 for NDC Only	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.
Percentage of Participants With Adverse Events	Up to 117 Weeks (29 months)
Change From Baseline in Montreal Cognitive Assessment (MoCA)	Up to Week 21 for ODC, Up to Week 69 for NDC	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.
Concentration of RO7234292 in Plasma	Week 21 for ODC and Week 69 for NDC	Concentration of tominersen in plasma reported
Change From Baseline in CSF mHTT Protein Level	Baseline, Week 101	Data to be reported within 12 months after the primary completion.
Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score	For ODC at 13th Month, for NDC at Week 101	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
Titer and Antibody Subtype, Determined if ADAs Are Identified	Week 21 for ODC and Week 69 for NDC	Titer and Antibody Subtype was not analyzed and there is not data to report due to participants' discontinuation

Trial Locations

Locations (96): Uab Medicine
🇺🇸
Birmingham, Alabama, United States
Barrow Neurological Institute
🇺🇸
Phoenix, Arizona, United States
University of California San Diego
🇺🇸
La Jolla, California, United States
Stanford Univ Medical Center
🇺🇸
Palo Alto, California, United States
SC3 Research Group, Inc
🇺🇸
Pasadena, California, United States
University of California Davis Medical System
🇺🇸
Sacramento, California, United States
CenExel Rocky Mountain Clinical Research, LLC
🇺🇸
Englewood, Colorado, United States
Georgetown University; Research Division, Psychiatry
🇺🇸
Washington, District of Columbia, United States
University of South Florida
🇺🇸
Tampa, Florida, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
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Uab Medicine
🇺🇸Birmingham, Alabama, United States