E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Huntington's disease (HD) |
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E.1.1.1 | Medical condition in easily understood language |
HD, is a genetically inherited disorder that causes uncontrolled movements (chorea), emotional problems, and the loss of ability to think properly, eventually resulting in death |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10070668 |
E.1.2 | Term | Huntington's disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the efficacy of RO7234292 from baseline compared with placebo on the basis of composite Unified Huntington's Disease Rating Scale (cUHDRS) and total functional capacity scale (TFC) [only for US FDA] score at Week 101
• To evaluate the effects of RO7234292 from baseline compared with placebo on the basis of cerebrospinal fluid (CSF) mutant huntingtin (mHTT) protein level at Week 101 |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of RO7234292 from baseline compared with placebo on basis of cUHDRS [only for US FDA] TFC, TFS total Motor Score (TMS), symbol digit modalities test (SDMT), stroop word reading test (SWR), clinical global impression, severity scale (CGI-S) score at Week 101
•To evaluate the safety and tolerability of RO7234292 compared with placebo on basis of adverse events, Montreal cognitive assessment (MoCA), vital signs, electrocardiograms parameters, clinical laboratory results and by Columbia-suicide severity rating scale (C-SSRS) score
•To characterize the RO7234292 PK profile in plasma and trough CSF on basis of concentration of RO7234292 in plasma and trough concentration of RO7234292 in CSF at specified timepoints
•To evaluate the immune response to RO7234292 on basis of Incidence of anti-drug antibodies
•To evaluate the effects of RO7234292 compared with placebo on basis of whole and regional brain volumes, CSF neurofilament light chain (NfL) protein Level |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age 25 to 65 years at the time of first dose administration
- Manifest HD diagnosis (defined as DCL score of 4)
- Independence Scale (IS) score >= 70
- Genetically confirmed disease by direct DNA testing with a CAP score > 400 (Age x [CAG repeat length – 33.66])
- Ability to read the words "red," "blue," and "green" in native language
- Ability to walk unassisted without a cane or walker and move about without a wheelchair on a daily basis as determined at screening and baseline visit
- Body mass index 16-32 kg/m2; total body weight > 40 kg
- Ability to undergo and tolerate MRI scans
- Ability to tolerate blood draws and lumbar punctures
- Estimated glomerular filtration rate >= 60 mL/min (Cockcroft Gault formula)
- Ability and willingness, in the investigator's judgment, to comply with all aspects of the protocol including completion of interviews and questionnaires for the duration of the study and to carry a smartphone, wear a digital monitoring device, and complete smartphone-based tasks
- Stable medical, psychiatric, and neurological status for at least 12 weeks prior to screening and at the time of enrollment
- Signed study companion consent for participation if a study companion is available who fulfills all of the following criteria:
o Age >= 18 years
o Reliable and competent, in the investigator's judgment
o Sufficiently knowledgeable of the patient's condition to complete study companion assessments of the patient, and likely to remain sufficiently knowledgeable throughout the study, in the investigator's judgment
o Able to comment on study participant's symptoms and functioning experience
o Companions must have no cognitive, behavioral or motor change, in the opinion of the investigator, that would question the validity of the acquired observer-reported data
- For women of childbearing potential: agreement to remain abstinent or use contraceptive measures, women must remain abstinent or use two methods of contraception, including at least one method with a failure rate of < 1% per year, during the treatment period and for 5 months after the final dose of study drug
- For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, with a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 5 months after the final dose of study drug to avoid exposing the Embryo |
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E.4 | Principal exclusion criteria |
- History of attempted suidide or suididal ideation with plan (i.e., active suididal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening
- Current active psychosis, confusional state, or violent behavior
- 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
- History known to the investigator or presence of an abnormal ECG that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree atrioventricular heart block, or evidence of prior myocardial infarction
- Clinical diagnosis of chronic migraines
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of study drug
- Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter
- Positive for hepatitis C virus antibody or hepatitis B surface antigen at screening
- Known HIV infection
- Current or previous use of an antisense oligonucleotide
- Current or previous use of anti-psychotics prescribed for a primary independent psychotic disorder, cholinesterase inhibitors, memantine, amantadine, or riluzole within 12 weeks from initiation of study treatment
- Current use of antipsychotics for motor symptoms or mood stabilization and/or tetrabenazine, valbenazine, or deutetrabenazine at a dose that has not been stable for at least 12 weeks prior to screening or is anticipated to change between screening and treatment initiation
- Current use of supplements at a dose that has not been stable for at least 6 weeks prior to screening or is anticipated to change during the study
- Current use of an antidepressant or benzodiazepine at a dose that has not been stable for at least 12 weeks prior to screening or is anticipated to change between screening and treatment initiation
- Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives prior to screening, whichever is longer
- Antiplatelet or anticoagulant therapy within 14 days prior to screening or anticipated use during the study, including, but not limited to, aspirin, clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban
- History of bleeding diathesis or coagulopathy
- Platelet count less than the lower limit of normal
- History of gene therapy, cell transplantation, or any experimental brain surgery
- Concurrent or planned participation in any interventional clinical study, including explicit pharmacological and non-pharmacological interventions
- Drug and/or alcohol abuse or psychological or physiological dependency within 12 months prior to screening, as per the investigator's judgment
- Poor peripheral venous access
- Scoliosis or spinal deformity or surgery making IT injection not feasible in an outpatient Setting and potentially interfering with distribution of RO7234292 up the neuraxis
- Serious infection requiring oral or IV antibiotics within 14 days prior to screening
- Antiretroviral medications, including antiretroviral medication taken as prophylaxis
- Malignancy within 5 years prior to screening, except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
- Preexisting structural brain lesion as assessed by a centrally read MRI scan during the screening period |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Change from baseline in the cUHDRS score at Week 101
2. Change from baseline in the TFC score at Week 101 (For US FDA)
3. Change from baseline in CSF mHTT protein level at Week 101 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3. Baseline (Week 1) and Week 101 |
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E.5.2 | Secondary end point(s) |
1. Change from baseline in the cUHDRS score at Week 101 (For US FDA)
2. Change from baseline in scores for TFC at Week 101
3. Change from baseline in scores for TMS at Week 101
4. Change from baseline in scores for SDMT at Week 101
5. Change from baseline in scores for SWR at Week 101
6. Change from baseline in the CGI-S score at Week 101
7. Proportion of patients with a decrease from baseline of >= 1 point on the TFC at Week 101
8. Proportion of patients with a decline from baseline of >= 1.2 points on the cUHDRS at Week 101
9. Proportion of patients with an unchanged or improved score on the CGI-C score from baseline at Week 101
10. Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale
11. Change from baseline in MoCA
12. Change from baseline in vital signs, electrocardiograms parameters, and clinical laboratory results
13. Proportion of patients with suicidal ideation or behavior, as assessed by C-SSRS score at each visit, including detailed focus on any individual cases identified as having severe ideation or behavior during the study conduct
14. CSF and plasma concentration of RO7234292
15. Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline
16. Titer and antibody subtype, determined if ADAs are identified
17. Change from baseline in whole and regional brain volumes (caudate, whole brain, and ventricular), as determined by structural MRI, at Week 101
18. Change from baseline in CSF NfL protein level at Week 101 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-9. Baseline and Week 101
10. Up to 101 weeks (25 Months)
11. Baseline, Week 5, 21, 37, 53, 69, 85, 101
12. Baseline to 101 weeks
13. At screening (Week -4 to -1), baseline, Week 5-101, end of treatment for early treatment termination and at early treatment termination
14. Baseline, Week 13, 21, 37, 53, 69, 85, 101 and at early treatment termination
15-16Baseline, Week 13, 21, 37, 53, 69, 85, 101 and at early treatment termination, safety follow up visit
17-18. Baseline and Week 101 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
New Zealand |
Russian Federation |
United States |
Austria |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
Switzerland |
United Kingdom |
Argentina |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |