A Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO7234292 (RG6042) in CSF and Plasma, and Safety and Tolerability Following Intrathecal Administration in Patients With Huntington's Disease

An Open-Label Adaptive Multiple-Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO7234292 in CSF and Plasma, and Safety and Tolerability Following Intrathecal Administration in Patients With Huntington's Disease

Study BP40410 is an open-label, adaptive multiple-dose clinical study designed to characterize the PK of RO7234292 (RG6042) in plasma and CSF as well as the acute time course and recovery profile of CSF mHTT lowering in response to RO7234292 (RG6042) treatment after intrathecal (IT) administration of RO7234292 (RG6042) to patients with manifest Hungtington's disease (HD).

Study Overview

• Status: Completed
• Conditions: Huntingtons Disease
• Intervention / Treatment: Drug: RO7234292 (RG6042)

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333
    • Centre For Human Drug Research; Research
• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • Leonard Wolfson Experimental Neurology Centre
  • Manchester, United Kingdom, M13 9WL
    • Manchester University NHS Foundation Trust (MFT)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Manifest HD diagnosis
• Independence Scale score of >=70.
• Genetically confirmed disease by direct deoxyribonucleic acid testing with a cytosine, adenine, and guanine base sequence found in DNA which is translated into glutamine (CAG) age product (CAP) score > 400.
• Ability to read the words "red," "blue," and "green" in the patient's native language.
• Ability to walk unassisted without a cane or walker and move about without a wheelchair on a daily basis as reviewed at screening and baseline visit.
• Ability to undergo and tolerate MRI scans.

Exclusion Criteria:

• 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.
• Current active psychosis, confusional state, or violent behavior.
• Any serious medical condition or clinically significant laboratory, vital signs, or ECG abnormalities at screening that, in the Investigator's judgment, precludes the patient's safe participation in and completion of the study.
• Clinical diagnosis of chronic migraines or history of low pressure headache after lumbar puncture requiring hospitalization or blood patch.
• Treatment with investigational therapy within 4 weeks prior to screening or 5 drug elimination half-lives of investigational therapy, whichever is longer.
• Concurrent or planned concurrent participation in any interventional clinical study, including explicit pharmacological and non-pharmacological interventions. Observational studies are acceptable.
• Unable or unsafe to perform lumbar puncture on the patient.
• Previous lumbar surgery that is likely, in the opinion of the Investigator or surgical team, to make IT catheter insertion or IT injection unduly difficult or hazardous.
• Poor peripheral venous access.
• Scoliosis or spinal deformity making IT injection not feasible in the outpatient setting.
• Preexisting intra-axial or extra-axial lesions as assessed by a centrally read MRI scan during the screening period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose level 1 of RO7234292 (RG6042); Participants will receive dose level 1 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29.	Drug: RO7234292 (RG6042); RO7234292 (RG6042) will be administered in two IT doses of the same dose level at an interval of 28 days during the treatment period (Day 1 and Day 29). Each dose of RO7234292 (RG6042) will be administered as a single IT bolus injection.; Other Names: Tominersen
Experimental: Dose level 2 of RO7234292 (RG6042); Participants will receive dose level 2 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29.	Drug: RO7234292 (RG6042); RO7234292 (RG6042) will be administered in two IT doses of the same dose level at an interval of 28 days during the treatment period (Day 1 and Day 29). Each dose of RO7234292 (RG6042) will be administered as a single IT bolus injection.; Other Names: Tominersen
Experimental: Dose level 3 of RO7234292 (RG6042); Participants will receive dose level 3 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29.	Drug: RO7234292 (RG6042); RO7234292 (RG6042) will be administered in two IT doses of the same dose level at an interval of 28 days during the treatment period (Day 1 and Day 29). Each dose of RO7234292 (RG6042) will be administered as a single IT bolus injection.; Other Names: Tominersen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentrations of RO7234292 in CSF (Cerebrospinal Fluid)	NA represents: insufficient number of participants with events.	Day 1, 2, 3, 4, 29, 43, 71, 127, and follow-up visit (6 months after last study drug administration)
Concentrations of RO7234292 in Plasma	NA represents:insufficient number of participants with events	Day 1, 2, 3, 4, 5, 28, 29, 30, 43, 71, 127, and follow-up visit (6 months after last study drug administration)
mHTT (Mutant Huntingtin) Concentration in CSF	CSF Mutant Huntingtin Protein (fmol/L) values at time point visits are reported.	Days 1, 2, 3, 29, 43, 71, 127 and follow-up visit (6 months after last study drug administration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Adverse Events According to NCI-CTCAE Grading System	Severity levels levels: 1 = mild; 2 = moderate; 3 = severe used according to NCI-CTCAE grading system. Percentage of participants with 1-3 levels of severities are reported.	Up to 6 months
Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score	The Columbia-Suicide Severity Rating Scale (C-SSRS) is a structured tool to assess suicidal ideation and behavior. 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. Scores 1-10 is used, 1 being less and to 10 being severity increasing. Only one time frame was used per score category: from screening to follow-up visit.	From Screening Day Up To Follow-up Visit (6 months after the last Dosing Day-Day 127)
Incidence of Anti-Drug Antibodies (ADAs)	Percentage of participants who have negative or positive anti-drug antibody affects are reported.	Day 1, Day 28, and follow-up visit (6 months after last study drug administration)
Titer and Antibody Subtype, Determined if ADAs Are Identified	The data cannot be reported and the outcome measure is not applicable as no ADA sample was positive. As no ADA, titer and subtype could not be identified	Day 1, Day 28, and follow-up visit (6 months after last study drug administration)
Amount of RO7234292 in Urine Ae (Micrograms)		Up to 72 hours

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2019
• Primary Completion (Actual): January 18, 2022
• Study Completion (Actual): January 18, 2022

Study Registration Dates

• First Submitted: June 26, 2019
• First Submitted That Met QC Criteria: June 26, 2019
• First Posted (Actual): June 27, 2019

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: June 18, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: BP40410; GEN-PEAK (Other Identifier: Hoffmann-La Roche)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No