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

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

Official Title
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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

Conditions
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Huntingtons Disease

Intervention / Treatment
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* Drug: RO7234292
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RO7234292 Q8W<br>RO4234292 is administered intrathecally every 8 weeks. | Drug: RO7234292<br>* Intrathecal injection<br>* Other names: Tominersen;|
| Experimental: RO7234292 Q16W<br>RO7234292 is administered intrathecally every 16 weeks. Participants in this arm will also receive placebo at alternate weeks to keep the blind. | Drug: RO7234292<br>* Intrathecal injection<br>* Other names: Tominersen;Drug: Placebo<br>* Intrathecal injection<br>|
| Placebo Comparator: Placebo<br>Placebo will be administered every 8 weeks by IT injection. | Drug: Placebo<br>* Intrathecal injection<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HD, RG6042, intrathecal, ASO, antisense oligonucleotide