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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03761849
Registration number
NCT03761849
Ethics application status
Date submitted
30/11/2018
Date registered
3/12/2018
Date last updated
1/03/2024
Titles & IDs
Public title
A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Participants With Manifest Huntington's Disease
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Scientific 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
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Secondary ID [1]
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GENERATION HD1
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Secondary ID [2]
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BN40423
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Huntingtons Disease
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0
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - RO7234292
Treatment: Drugs - Placebo
Experimental: RO7234292 Q8W - RO4234292 is administered intrathecally every 8 weeks.
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.
Placebo Comparator: Placebo - Placebo will be administered every 8 weeks by IT injection.
Treatment: Drugs: RO7234292
Intrathecal injection
Treatment: Drugs: Placebo
Intrathecal injection
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline in the Composite Unified Huntington's Disease Rating Scale (cUHDRS) Score-Z Score
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Assessment method [1]
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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.
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Timepoint [1]
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Weeks 21 for ODC and 69 for NDC
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Primary outcome [2]
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Change From Baseline in the Total Functional Capacity (TFC) Score
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Assessment method [2]
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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.
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Timepoint [2]
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Weeks 21 for ODC and 69 for NDC
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Secondary outcome [1]
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Change From Baseline in Total Motor Score (TMS)
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Assessment method [1]
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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.
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Timepoint [1]
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Weeks 21 for ODC and 69 for NDC
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Secondary outcome [2]
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Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores' Least Squares Mean Values
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Assessment method [2]
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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.
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Timepoint [2]
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Weeks 21 for ODC and 69 NDC
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Secondary outcome [3]
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Change From Baseline in Stroop Word Reading (SWR) Test Scores' Least Squares Mean Values
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Assessment method [3]
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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.
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Timepoint [3]
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Weeks 21 for ODC and 69 for NDC
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Secondary outcome [4]
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Change From Baseline in the Clinical Global Impression, Severity Scale (CGI-S) Scores' Least Squares Mean Values
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Assessment method [4]
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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.
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Timepoint [4]
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Week 69 for NDC Only
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Secondary outcome [5]
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Percentage of Patients With a Decrease From Baseline of >=1 Point on the Total Functional Capacity (TFC) Score
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Assessment method [5]
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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.
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Timepoint [5]
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Week 69 for NDC only
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Secondary outcome [6]
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Percentage of Patients With a Decline From Baseline of >=1.2 Points on the Composite Unified Huntington's Disease Rating Scale-cUHDRS Score
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Assessment method [6]
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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.
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Timepoint [6]
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Week 69 for NDC Only
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Secondary outcome [7]
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Percentage of Patients With an Unchanged or Improved Score on the Clinical Global Impression, Change Scale Score
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Assessment method [7]
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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.
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Timepoint [7]
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Weeks 53 and 69 NDC only
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Secondary outcome [8]
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Percentage of Participants With Adverse Events
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Assessment method [8]
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Timepoint [8]
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Up to 117 Weeks (29 months)
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Secondary outcome [9]
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Change From Baseline in Montreal Cognitive Assessment (MoCA)
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Assessment method [9]
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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.
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Timepoint [9]
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Up to Week 21 for ODC, Up to Week 69 for NDC
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Secondary outcome [10]
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Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score
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Assessment method [10]
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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
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Timepoint [10]
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For ODC at 13th Month, for NDC at Week 101
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Secondary outcome [11]
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Concentration of RO7234292 in Plasma
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Assessment method [11]
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Concentration of tominersen in plasma reported
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Timepoint [11]
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Week 21 for ODC and Week 69 for NDC
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Secondary outcome [12]
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Trough Concentration of RO7234292 in Cerebrospinal Fluid (CSF)
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Assessment method [12]
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Tominersen concentrations in cerebrospinal fluid
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Timepoint [12]
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Week 21 for ODC and Week 69 for NDC
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Secondary outcome [13]
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Incidence of Anti-Drug Antibodies (ADAs).
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Assessment method [13]
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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.
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Timepoint [13]
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Week 21 for ODC and Week 69 for NDC
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Secondary outcome [14]
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Titer and Antibody Subtype, Determined if ADAs Are Identified
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Assessment method [14]
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Titer and Antibody Subtype was not analyzed and there is not data to report due to participants' discontinuation
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Timepoint [14]
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Week 21 for ODC and Week 69 for NDC
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Secondary outcome [15]
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Change From Baseline in CSF mHTT Protein Level
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Assessment method [15]
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Data to be reported within 12 months after the primary completion.
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Timepoint [15]
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Baseline, Week 101
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Secondary outcome [16]
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Change From Baseline in Whole and Regional Brain Volumes, as Detrmined by Structural Magnetic Resonance Imaging (MRI)
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Assessment method [16]
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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)
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Timepoint [16]
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Week 13 for ODC
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Secondary outcome [17]
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Change From Baseline in CSF Neurofilament Light Chain (NfL) Proteint Level
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Assessment method [17]
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Timepoint [17]
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Week 21 for ODC, Weeks 21 and 69 for NDC
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Eligibility
Key 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).
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Minimum age
25
Years
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Maximum age
65
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
23/01/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
24/03/2022
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Sample size
Target
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Accrual to date
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Final
899
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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WESTMEAD HOSPITAL; Deparment of Neurology - Westmead
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Recruitment hospital [2]
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Monash Medical Centre - Clayton
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Recruitment hospital [3]
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Royal Melbourne Hospital; Department of Neurology - Parkville
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Recruitment postcode(s) [1]
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2145 - Westmead
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Recruitment postcode(s) [2]
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3168 - Clayton
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Recruitment postcode(s) [3]
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3050 - Parkville
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Recruitment outside Australia
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Alabama
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Arizona
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California
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Colorado
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District of Columbia
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Florida
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Illinois
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Maryland
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Missouri
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Washington
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Argentina
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Caba
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Argentina
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Ciudad Autonoma Buenos Aires
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Innsbruck
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Aarhus N
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Ulm
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Italy
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Lazio
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Italy
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Liguria
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Italy
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Lombardia
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Italy
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Puglia
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Italy
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Mie
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Niigata
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Okayama
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Japan
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Osaka
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Tokyo
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Groningen
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Leiden
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Auckland
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Christchurch
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Wellington
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Poland
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Gdansk
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Poland
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Krakow
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Poland
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Warszawa
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Russian Federation
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Krasnojarsk
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Russian Federation
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Moskovskaja Oblast
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Russian Federation
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Tatarstan
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Spain
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Vizcaya
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Spain
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Badajoz
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Spain
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Barcelona
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Spain
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Burgos
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Spain
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Madrid
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Spain
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Sevilla
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Spain
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Valencia
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Switzerland
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Basel
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Switzerland
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Gümligen
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United Kingdom
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Aberdeen
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United Kingdom
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Birmingham
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United Kingdom
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Cambridge
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United Kingdom
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Cardiff
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United Kingdom
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Glasgow
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United Kingdom
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Leeds
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United Kingdom
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London
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United Kingdom
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Manchester
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Oxford
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United Kingdom
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Sheffield
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United Kingdom
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Southhampton
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Hoffmann-La Roche
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Ethics approval
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Summary
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)
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03761849
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Public notes
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Contacts
Principal investigator
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Clinical Trials
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Hoffmann-La Roche
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03761849
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