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出境医 / 临床实验 / 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

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

Study Description
Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Huntingtons Disease Drug: RO7234292 (RG6042) Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 2, 2019
Estimated Primary Completion Date : December 24, 2021
Estimated Study Completion Date : December 24, 2021
Arms and Interventions
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 Name: 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 Name: 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 Name: Tominersen
Outcome Measures
Primary Outcome Measures :
  1. Concentrations of RO7234292 in CSF (cerebrospinal fluid) [ Time Frame: Day 1, 2, 3, 4, 29, 43, 71, 127, and follow-up visit (6 months after last study drug administration) ]
  2. Concentrations of RO7234292 in Plasma [ Time Frame: Day 1, 2, 3, 4, 5, 28, 29, 30, 43, 71, 127, and follow-up visit (6 months after last study drug administration) ]
  3. mHTT (mutant Huntingtin) Concentration in CSF [ Time Frame: Days 1, 2, 3, 29, 43, 71, 127 and follow-up visit (6 months after last study drug administration) ]

Secondary Outcome Measures :
  1. Incidence and Severity of Adverse Events [ Time Frame: Up to 6 months ]
  2. Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Screening, Day -1, Day 28, Day 71, Day 127, and follow-up visit (6 months after last study drug administration) ]

    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.


  3. Incidence of Anti-Drug Antibodies (ADAs) [ Time Frame: Day 1, Day 28, and follow-up visit (6 months after last study drug administration) ]
  4. Titer and Antibody Subtype, determined if ADAs are Identified [ Time Frame: Day 1, Day 28, and follow-up visit (6 months after last study drug administration) ]
  5. Concentrations of RO7234292 in Urine [ Time Frame: Up to 72 hours ]

Eligibility Criteria
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Ages Eligible for Study:   25 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Reference Study ID Number: BP40410 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
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Netherlands
Centre For Human Drug Research; Research Recruiting
Leiden, Netherlands, 2333
United Kingdom
Leonard Wolfson Experimental Neurology Centre Recruiting
London, United Kingdom, WC1N 3BG
Manchester University NHS Foundation Truct (MFT) Recruiting
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Layout table for investigator information
Study Director: Clinical Trials Hoffmann-La Roche
Tracking Information
First Submitted Date  ICMJE June 26, 2019
First Posted Date  ICMJE June 27, 2019
Last Update Posted Date June 4, 2021
Actual Study Start Date  ICMJE September 2, 2019
Estimated Primary Completion Date December 24, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 24, 2020)
  • Concentrations of RO7234292 in CSF (cerebrospinal fluid) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Days 1, 2, 3, 29, 43, 71, 127 and follow-up visit (6 months after last study drug administration) ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • Concentrations of RO7234292 in CSF (cerebrospinal fluid) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Day -1, Day 1, 2, 3, 4, 29, 43, 71, 127, and follow-up visit (6 months after last study drug administration) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 24, 2020)
  • Incidence and Severity of Adverse Events [ Time Frame: Up to 6 months ]
  • Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Screening, Day -1, Day 28, Day 71, Day 127, and follow-up visit (6 months after last study drug administration) ]
    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.
  • Incidence of Anti-Drug Antibodies (ADAs) [ Time Frame: Day 1, Day 28, and follow-up visit (6 months after last study drug administration) ]
  • Titer and Antibody Subtype, determined if ADAs are Identified [ Time Frame: Day 1, Day 28, and follow-up visit (6 months after last study drug administration) ]
  • Concentrations of RO7234292 in Urine [ Time Frame: Up to 72 hours ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • Incidence and Severity of Adverse Events [ Time Frame: Up to 6 months ]
  • Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Screening, Day -1, Day 28, Day 71, Day 127, and follow-up visit (6 months after last study drug administration) ]
    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.
  • Incidence of Anti-Drug Antibodies (ADAs) [ Time Frame: Day 1, Day 28, and follow-up visit (6 months after last study drug administration) ]
  • Titer and Antibody Subtype, determined if ADAs are Identified [ Time Frame: Day 1, Day 28, and follow-up visit (6 months after last study drug administration) ]
  • Concentrations of RO7234292 in Urine [ Time Frame: Up to 96 hours ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary 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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Huntingtons Disease
Intervention  ICMJE 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 Name: Tominersen
Study Arms  ICMJE
  • Experimental: Dose level 1 of RO7234292 (RG6042)
    Participants will receive dose level 1 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29.
    Intervention: Drug: RO7234292 (RG6042)
  • Experimental: Dose level 2 of RO7234292 (RG6042)
    Participants will receive dose level 2 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29.
    Intervention: Drug: RO7234292 (RG6042)
  • Experimental: Dose level 3 of RO7234292 (RG6042)
    Participants will receive dose level 3 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29.
    Intervention: Drug: RO7234292 (RG6042)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 26, 2019) 		20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 24, 2021
Estimated Primary Completion Date December 24, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: BP40410 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04000594
Other Study ID Numbers  ICMJE BP40410
GEN-PEAK ( Other Identifier: Hoffmann-La Roche )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
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).
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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