Huntington's Disease
Conditions
Brief summary
This study will test the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7234292 administered intrathecally to adult patients with Huntington's Disease.
Interventions
Intrathecal injection
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have completed dosing in ISIS 443139-CS1 Key
Exclusion criteria
* Any new condition or worsening of existing condition that could make the patient unsuitable for participation or interfere with the patient participating in and/or completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | From baseline up to 18 months | Adverse Events include Adverse Events that started at or after Date/Time of First Exposure to Treatment and procedure-related Adverse Events occurring before the start of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | From Baseline to Day 421 | The results of the planned analysis related to mHTT protein levels in CSF are reported |
| Mean Percentage Change in Ventricular Volume Boundary Shift Integral From Baseline to 15 Months | Baseline up to 15 months | — |
| Mean Percentage Change in Caudate Volume Boundary Shift Integral From Baseline to 15 Months | Baseline up to 15 months | — |
| RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | From baseline to Day 421 | — |
| EEG Parameters: Mean Change From Baseline to 15 Months in Absolute Power [8-12Hz] | Baseline to 15 Months | — |
| Mean Change From Baseline in Huntington's Disease Cognitive Assessment Battery Composite Score | Baseline to 15 Months | HD Cognitive Assessment Battery (HD-CAB) was developed to assess cognitive dysfunction in late premanifest and early manifest HD patients. HD-CAB combines scores from six cognitive tests: SDMT, Self-Paced Tapping, Emotional Recognition, CANTAB One Touch Stocking, Hopkins Verbal Learning Test - Revised, and Trail-Making Test. A multi-component score is derived by transforming the subject's score on each cognitive test to a z-score. Using z-scores permits the combination of test scores with different scales. Unlike other measures that use an external reference population to create z-scores, HD-CAB uses the baseline data of the study. Individually, for each of the six cognitive tests, the study baseline mean is subtracted from the subject's score, and this value is divided by the study baseline standard deviation. The six z-scores are averaged to produce the HD-CAB score. A positive change from baseline indicates improvement in cognitive function; a negative change indicates worsening. |
| Mean Percentage Change in Whole Brain Volume Boundary Shift Integral From Baseline to 15 Months | Baseline up to 15 months | — |
Countries
Canada, Germany, United Kingdom
Participant flow
Recruitment details
Participant eligibility for the study was determined within 4 weeks prior to participant entry into the Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| RO7234292 Monthly RO7234292 was administered intrathecally every 28 days for 14 months. | 23 |
| RO7234292 Bimonthly RO7234292 was administered intrathecally every 56 days for 14 months following 2 monthly doses to serve as a loading dose. | 23 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | RO7234292 Monthly | RO7234292 Bimonthly | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 3 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 20 Participants | 43 Participants |
| Age, Continuous | 47.7 Years STANDARD_DEVIATION 9.3 | 49.5 Years STANDARD_DEVIATION 11.3 | 48.6 Years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 23 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 22 Participants | 23 Participants | 45 Participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 18 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 23 | 0 / 23 |
| other Total, other adverse events | 22 / 23 | 22 / 23 |
| serious Total, serious adverse events | 4 / 23 | 3 / 23 |
Outcome results
Primary
Percentage of Participants With Adverse Events
Adverse Events include Adverse Events that started at or after Date/Time of First Exposure to Treatment and procedure-related Adverse Events occurring before the start of treatment.
Time frame: From baseline up to 18 months
Population: Safety population comprising all participants that were randomized and received at least one dose of RO7234292.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RO7234292 Monthly | Percentage of Participants With Adverse Events | 100 Percentage of participants |
| RO7234292 Bimonthly | Percentage of Participants With Adverse Events | 95.7 Percentage of participants |
Secondary
CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline
The results of the planned analysis related to mHTT protein levels in CSF are reported
Time frame: From Baseline to Day 421
Population: ITT Population. The data for Bi-monthly arm was not collected on days 113, 169, 225, 281, 337, 393. Here Number Analyzed represents number of participants from whom samples were collected and analyzed
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 29 | -27.95 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 197 | -40.79 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 225 | -47.01 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 253 | -43.63 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 281 | -40.29 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 309 | -36.67 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 337 | -42.71 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 365 | -49.55 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 393 | -41.55 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 421 | -45.45 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 57 | -26.90 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 85 | -50.30 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 113 | -49.11 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 141 | -54.02 Log (10) fmol/L |
| RO7234292 Monthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 169 | -42.33 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 29 | -21.84 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 365 | -55.07 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 57 | 10.11 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 197 | -36.48 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 85 | -32.63 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 421 | -41.51 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 309 | -40.82 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 141 | -41.76 Log (10) fmol/L |
| RO7234292 Bimonthly | CSF mHTT Protein Concentration Logarithmic Value Change in Geometric Mean (95%CI) From Baseline | Day 253 | -41.06 Log (10) fmol/L |
Secondary
EEG Parameters: Mean Change From Baseline to 15 Months in Absolute Power [8-12Hz]
Time frame: Baseline to 15 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RO7234292 Monthly | EEG Parameters: Mean Change From Baseline to 15 Months in Absolute Power [8-12Hz] | 0.11 log10(mircrovolts^2) | Standard Deviation 0.18 |
| RO7234292 Bimonthly | EEG Parameters: Mean Change From Baseline to 15 Months in Absolute Power [8-12Hz] | 0.02 log10(mircrovolts^2) | Standard Deviation 0.21 |
Secondary
Mean Change From Baseline in Huntington's Disease Cognitive Assessment Battery Composite Score
HD Cognitive Assessment Battery (HD-CAB) was developed to assess cognitive dysfunction in late premanifest and early manifest HD patients. HD-CAB combines scores from six cognitive tests: SDMT, Self-Paced Tapping, Emotional Recognition, CANTAB One Touch Stocking, Hopkins Verbal Learning Test - Revised, and Trail-Making Test. A multi-component score is derived by transforming the subject's score on each cognitive test to a z-score. Using z-scores permits the combination of test scores with different scales. Unlike other measures that use an external reference population to create z-scores, HD-CAB uses the baseline data of the study. Individually, for each of the six cognitive tests, the study baseline mean is subtracted from the subject's score, and this value is divided by the study baseline standard deviation. The six z-scores are averaged to produce the HD-CAB score. A positive change from baseline indicates improvement in cognitive function; a negative change indicates worsening.
Time frame: Baseline to 15 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RO7234292 Monthly | Mean Change From Baseline in Huntington's Disease Cognitive Assessment Battery Composite Score | -0.33 z-score | Standard Deviation 0.27 |
| RO7234292 Bimonthly | Mean Change From Baseline in Huntington's Disease Cognitive Assessment Battery Composite Score | -0.15 z-score | Standard Deviation 0.23 |
Secondary
Mean Percentage Change in Caudate Volume Boundary Shift Integral From Baseline to 15 Months
Time frame: Baseline up to 15 months
Population: Here Number of Participants Analyzed represents number of participants from whom data were collected and analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RO7234292 Monthly | Mean Percentage Change in Caudate Volume Boundary Shift Integral From Baseline to 15 Months | 8.64 Percentage change | Standard Deviation 6.26 |
| RO7234292 Bimonthly | Mean Percentage Change in Caudate Volume Boundary Shift Integral From Baseline to 15 Months | 5.67 Percentage change | Standard Deviation 2.22 |
Secondary
Mean Percentage Change in Ventricular Volume Boundary Shift Integral From Baseline to 15 Months
Time frame: Baseline up to 15 months
Population: Here Number of Participants Analyzed represents number of participants from whom data were collected and analyzed. Only data that passed the QC imaging process were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RO7234292 Monthly | Mean Percentage Change in Ventricular Volume Boundary Shift Integral From Baseline to 15 Months | 46.09 Percentage change | Standard Deviation 32.14 |
| RO7234292 Bimonthly | Mean Percentage Change in Ventricular Volume Boundary Shift Integral From Baseline to 15 Months | 18.77 Percentage change | Standard Deviation 10.36 |
Secondary
Mean Percentage Change in Whole Brain Volume Boundary Shift Integral From Baseline to 15 Months
Time frame: Baseline up to 15 months
Population: Here Number of Participants Analyzed represents number of participants from whom data were collected and analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RO7234292 Monthly | Mean Percentage Change in Whole Brain Volume Boundary Shift Integral From Baseline to 15 Months | 1.63 Percentage change | Standard Deviation 1.41 |
| RO7234292 Bimonthly | Mean Percentage Change in Whole Brain Volume Boundary Shift Integral From Baseline to 15 Months | 0.89 Percentage change | Standard Deviation 0.92 |
Secondary
RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis)
Time frame: From baseline to Day 421
Population: CSF Trough Concentrations were reported following study drug administration. Data for Bi-monthly arm was not collected on days 57, 113, 169, 225, 281, 337, 393. Here Number Analyzed represents number of participants from whom samples were collected and analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 29 | 2.59 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 225 | 5.21 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 253 | 4.96 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 281 | 4.96 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 309 | 5.53 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 337 | 5.12 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 365 | 4.50 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 393 | 3.10 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 421 | 3.01 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 57 | 3.47 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 85 | 3.70 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 113 | 3.97 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 141 | 4.57 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 169 | 4.47 ng/mL |
| RO7234292 Monthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 197 | 4.58 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 29 | 2.52 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 365 | 1.45 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 197 | 1.26 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 85 | 1.39 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 421 | 1.34 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 309 | 1.35 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 141 | 1.35 ng/mL |
| RO7234292 Bimonthly | RO7234292 CSF Trough Concentrations by Study Day Prior to Monthly and Bimonthly IT Administration of 120 mg RO7234292 (Primary Analysis) | Day 253 | 1.45 ng/mL |