A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients with Manifest Huntington's disease

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2018-002987-14-GB
• Date of registration: 08/02/2019
• Prospective Registration: Yes
• Primary sponsor: F.Hoffmann La-Roche Ltd
• Public title: A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients with Manifest Huntington's disease
• 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
• Date of first enrolment: 13/02/2019
• Target sample size: 600
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002987-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Canada, Denmark, France, Germany, Italy, Netherlands, New Zealand, Poland, Russian Federation, Spain, Switzerland, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche LTD

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche LTD

Key inclusion & exclusion criteria

Inclusion criteria:
- Age 25 to 65 years
- 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
- 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 620
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 40

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 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 concurrent participation in any interventional clinical study, including explicit pharmacological and non-pharmacological interventions
- Illicit drug or alcohol abuse 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
- Serious infection requiring oral or IV antibiotics within 14 days prior to screening


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Huntington's disease (HD)
MedDRA version: 20.0 Level: PT Classification code 10070668 Term: Huntington's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Code: Ro 723-4292/F02
Pharmaceutical Form: Solution for injection
INN or Proposed INN: not available
CAS Number: 1709886-74-7
Current Sponsor code: RO7234292
Other descriptive name: RG6042, formerly ISIS 443139, IONIS-HTTRx
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Intrathecal use

Primary Outcome(s)

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

Main Objective: • To evaluate the efficacy of RO7234292 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 compared with placebo on the basis of cerebrospinal fluid (CSF) mutant huntingtin (mHTT) protein level at Week 101

Secondary Objective: •To evaluate the efficacy of RO7234292 compared with placebo on the 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 the 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 the 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 the basis of Incidence of anti-drug antibodies
•To evaluate the effects of RO7234292 compared with placebo on the basis of whole and regional brain volumes,CSF neurofilament light chain (NfL) protein Level

Timepoint(s) of evaluation of this end point: 1-3. Baseline (Week 1) and Week 101

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. At 1 year
2-6. Baseline to 2 years
7-10. Up to 2 years
11-12. Baseline to 2 years
13-15. Up to 2 year
16-18. Day 1, Week 4; Week 28; Week 52; Week 76; Week 100, at early termination visit

Secondary end point(s): 1. Change from baseline in scores for 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 cUHDRS score at Week 101 (for US FDA)
7. Change from baseline in the CGI-S score at Week 101
8. Proportion of patients with a decrease from baseline of >= 1 point on the TFC at Week 101
9. Proportion of patients with a decline from baseline of >= 1.2 points on the cUHDRS at Week 101
10. Proportion of patients with an unchanged or improved score on the CGI-C score from baseline at Week 101
11. Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale
12. Change from baseline in MoCA
13. Change from baseline in vital signs, electrocardiograms parameters, and clinical laboratory results
14. 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
15. CSF and plasma concentration of RO7234292
16. Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline
17. Titer and antibody subtype, determined if ADAs are identified
18. Change from baseline in whole and regional brain volumes (caudate, whole brain, and ventricular), as determined by structural magnetic resonance imaging, at Week 101
19. Change from baseline in CSF NfL protein level at Week 101

Secondary ID(s)

BN40423

Source(s) of Monetary Support

F.Hoffmann La-Roche Ltd - Basel

Ethics review

Status: Approved
Approval date:
Contact: