Huntington's Disease
Conditions
Brief summary
This is a first-in-human (FIH) study of RG6496 that will assess the safety and tolerability of single-ascending doses of RG6496 administered to huntington's disease gene expansion carriers (HDGECs). The study consists of two parts: Part 1 \[single-ascending dose\] followed by Part 2 \[open-label extension (OLE)\].
Interventions
DRUGRG6496
RG6496 will be administered as per the schedule specified in the respective arms.
DRUGPlacebo
RG6496 matching placebo will be administered as per the schedule specified in placebo arm.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Part 1: Investigator & participants will be blinded; Part 2: Open-label
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Part 1 * Confirmation of HDGEC status with cytosine-adenine-guanine (CAG) expansion \> 39. * Confirmation of SNP carrier status of the target SNP * Independence Scale (IS) score of ≥70, total functional capacity (TFC) ≥10, total motor score (TMS) \>6. * Ability to read the words "red," "blue," and "green" and be fluent in the language of the informed consent form (ICF) and the tests used at the study site. * Ability to walk unassisted. * Total body weight \> 40 kilogram (kg) and body mass index (BMI) within the range 18-32 kilogram per square meter (kg/m\^2) (inclusive) at baseline. * Ability to undergo and tolerate MRI scans. Part 2 * Completed the post-dose safety follow-up period in the Part 1 of the study. * In the opinion of the Investigator, the participant has not experienced a worsening in health that precludes their safe continued participation in the study.
Exclusion criteria
Part 1 * Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy or treatment with investigational therapy within 90 days or 5 drug-elimination half-lives, whichever is longer prior to screening * Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required * Malignancy within 5 years prior to screening * Planned brain surgery during the study * Positive HIV test, hepatitis B surface antigen and hepatitis B surface antigen at screening * Active psychosis, confusional state, or violent behavior, including aggression that could cause harm to self or others, over the 12 weeks prior to screening. * Current or previous history of a primary independent psychotic disorder. * Scoliosis or spinal deformity or surgery making IT injection not feasible in an outpatient setting * History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening. Part 2 * Prematurely discontinued from Part 1 for any reason (i.e., before the completion of the postdose safety follow-up period of Part 1). * Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required. * Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy * Received any active investigational treatment other than RG6496 during or since completion of Part 1 of the study. * Had confirmed Dose-Limiting Adverse Event (DLAE)(s) in Part 1 of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Adverse Events (AEs) | Up to approximately 24 months | — |
| Part 1: Change From Baseline in Neurological Assessment | Up to approximately 24 months | A neurologic examination including fundoscopy, will be performed by a neurologist or an ophthalmologist depending on local practice. A neurologic examination will include an assessment of mental status, level of consciousness, cranial nerve function, motor function, sensory function, reflexes, gait, and coordination. |
| Part 1: Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | Up to approximately 24 months | C-SSRS measures 4 constructs as follows: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories. Numeric ratings are provided for intensity of ideation (if present), from 1 to 5, with 1 being the least severe and 5 being the most severe. |
| Part 1: Change from Baseline in Montreal Cognitive Assessment (MoCA) | Up to approximately 24 months | MoCA is a rater-administered, participant completed assessment (PerfO instrument) used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0 to 30, where lower scores indicate greater impairment. |
| Part 2: Number of Participants With AEs | Up to approximately 38 months | — |
| Part 2: Change From Baseline in Neurological Assessment | Up to approximately 38 months | A neurologic examination including fundoscopy, will be performed by a neurologist or an ophthalmologist depending on local practice. A neurologic examination will include an assessment of mental status, level of consciousness, cranial nerve function, motor function, sensory function, reflexes, gait, and coordination. |
| Part 2: Number of Participants With Suicidal Ideation or Behavior, as Assessed by C-SSRS Score | Up to approximately 38 months | C-SSRS measures 4 constructs as follows: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories. Numeric ratings are provided for intensity of ideation (if present), from 1 to 5, with 1 being the least severe and 5 being the most severe. |
| Part 2: Change from Baseline in MoCA | Up to approximately 38 months | MoCA is a rater-administered, participant completed assessment (PerfO instrument) used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0 to 30, where lower scores indicate greater impairment. |
Secondary
| Measure | Time frame |
|---|---|
| Part 1: Plasma Concentration of RG6496 | Up to approximately 24 months |
| Part 1 and Part 2: Number of Participants With Anti-drug Antibody (ADA) in Plasma to RG6496 | Part 1: Up to approximately 24 months; Part 2: Up to approximately 38 months |
| Part 1 and Part 2: Change From Baseline of Mutant Huntingtin Protein (mHTT) Concentrations in Cerebrospinal Fluid (CSF) Over Time | Part 1: Up to approximately 24 months; Part 2: Up to approximately 38 months |
Countries
Argentina, Australia, Canada, New Zealand, United Kingdom
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed