Study to Measure Cerebrospinal Fluid Mutant Huntingtin Protein in Participants With Early Manifest Stage I or Stage II Huntington's Disease

Phase 1

Completed

Conditions: Huntington's Disease

Interventions: Other: No Study Drug was Administered in this Study

Registration Number: NCT03664804

Lead Sponsor: Hoffmann-La Roche

Brief Summary: The study is designed as a multi-site, prospective, 15-month longitudinal, cohort study measuring CSF mHTT in participants with early manifest Stage I or Stage II Huntington's Disease (HD).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 95

Inclusion Criteria

Capacity to consent to participate in the study as assessed using the Evaluation to Sign Consent tool and investigator judgment
Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form
Early manifest, Stage I or Stage II HD (defined as TFC of 7-13, inclusive)
Genetically confirmed disease (CAG repeat length ≥ 36 in huntingtin gene by direct DNA testing)
Body mass index ≥18 and ≤32 kg/m2; total body weight >50 kg
Ability to undergo and tolerate MRI scans
Ability to tolerate blood draws and lumbar puncture
Ability and willingness to comply with all aspects of the protocol, including completion of interviews and questionnaires and carrying/wearing of a digital monitoring device
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
For women of childbearing potential: agreement to remain abstinent or use acceptable contraceptive methods during the observational period

Exclusion Criteria

Any condition, including severe chorea, that would prevent either writing or performing pen and paper or smartphone-based tasks
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 sign, or electrocardiogram abnormalities at screening that, in the investigator's judgement, precludes the participant's safe participation in and completion of the study
Pregnant or breastfeeding, or intending to become pregnant during the study
Positive for hepatitis C virus antibody or hepatitis B surface antigen at screening
Known HIV infection
Current or previous use of an antisense oligonucleotide (including small interfering RNA)
Current use of antipsychotics prescribed for psychosis, cholinesterase inhibitors, memantine, amantadine, or riluzole including use within 12 weeks of enrollment
Treatment with an investigational drug within 30 days prior to screening or 5 half-lives of the investigational drug, whichever is longer
Antiplatelet or anticoagulant therapy within the 14 days prior to screening or anticipated use during the study, including, but not limited, to aspirin (unless ≤81mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban
History of bleeding diathesis or coagulopathy; platelet count < lower limit of normal unless stable and assessed by the Investigator and Sponsor Medical Monitor to be not clinically significant
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
History of gene therapy or cell transplantation or any other experimental brain surgery
Concurrent or planned concurrent participation in any clinical study without approval of the Medical Monitor
Presence of implanted shunt for the drainage of CSF or an implanted CNS catheter
Pre-existing structural brain lesion as assessed by MRI scan

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Participants with Early Manifest Stage I or II HD	No Study Drug was Administered in this Study	No study drug was administered in this study

Primary Outcome Measures

Name	Time	Method
Change From Baseline in the Following Clinical Endpoints at 3, 9, and 15 Months: cUHDRS, TFC, TMS, SDMT, SWR Test and IS	Baseline to 15 Months	The reported data are as follows: cUHDRS = composite Unified Huntington's Disease Rating Scale; TFC = Total Functional; Capacity Scale; TMS = Total Motor; Scale; SDMT = Symbol Digit Modalities Test; SWR = Stroop Word Reading; IS = Independence Scale. cUHDRS: score range from -3.06 (worst) to not defined maximum (best); Stroop Word Reading Test: score range not defined, higher scores indicate better cognitive performance; Symbol Digit Modalities Test: score range from 0 (worst) to 110 (best); Total Functional Capacity: score range from 0 (worst) to 13 (best); Total Motor Scale: score range from 0 (best) to 124 (worst). Data at Month 3, 9, and 15 are reported respectively
Change From Baseline in Biomarkers of Neuronal Injury (CSF NfL and Tau) at 3, 9, and 15 Months	Baseline to 15 Months	The reported date appreciations are as follows: CSF = Cerebrospinal Fluid; NfL = Neurofilament Light Chain. An overview of percentage change from baseline in geometric means for CSF tau and CSF NfL, and CSF YKL-40 are reported
Change From Baseline in Brain Atrophy Endpoints (Whole Brain Volume Decline, Caudate Volume Decline) as Determined by Brain MRI, at 3, 9, and 15 Months	Baseline to 15 Months	Data for Least Square (LS) mean percentage change from baseline to Months 3, 9, and 15 for ventricular volume, caudate volume, and whole brain volume, based on boundary shift integrals (BSIs) are reported

Secondary Outcome Measures

Name	Time	Method
Within-Participant Change From Baseline in CSF mHTT Levels at 3, 9, and 15 Months	Baseline to 15 Months	mHTT=Mutant Huntingtin Protein. New stability information has revealed that all samples for this outcome measure were out of stability, leaving no valid data points. Therefore there is no data to report.
Association of Change From Baseline in Cerebrospinal Fluid (FSF) mHTT With Change From Baseline in Clinical Measure	Baseline to 15 Months	New stability information has revealed that all samples for this outcome measure were out of stability, leaving no valid data points. Therefore there is no data to report.
Association of Change From Baseline in Biomarkers of Neuronal Injury	Baseline to 15 Months	New stability information has revealed that all samples for this outcome measure were out of stability, leaving no valid data points. Therefore there is no data to report.
Association of Change From Baseline in Brain Atrophy Endpoints, as Determined by Brain MRI	Baseline to 15 Months	New stability information has revealed that all samples for this outcome measure were out of stability, leaving no valid data points. Therefore there is no data to report.

Trial Locations

Locations (15): CenExel Rocky Mountain Clinical Research, LLC
🇺🇸
Englewood, Colorado, United States
Georgetown University; Research Division, Psychiatry
🇺🇸
Washington, District of Columbia, United States
Hereditary Neurological Disease Centre (HNDC)
🇺🇸
Wichita, Kansas, United States
John Hopkins University School of Medicine
🇺🇸
Baltimore, Maryland, United States
Columbia University
🇺🇸
New York, New York, United States
The University of Texas Health Science Center at Houston; McGovern Medical School
🇺🇸
Houston, Texas, United States
The University of British Columbia; The Centre for Huntington Disease
🇨🇦
Vancouver, British Columbia, Canada
Centre for Movement Disorders (Neuropharm Consulting Inc.)
🇨🇦
Markham, Ontario, Canada
Charité - Universitätsmedizin Berlin, Campus Charité Mitte; Klinik für Psychiatrie und Psychotherapi
🇩🇪
Berlin, Germany
St. Josef and St. Elisabeth gGmbH ; St. Josef Hospital Bochum; Neurologisches Forschungszentrum
🇩🇪
Bochum, Germany
Universitätsklinikum Ulm; Klinik für Neurologie
🇩🇪
Ulm, Germany
NIHR Welcome Trust Birmingham CRF - University Hospitals Birmingham; Department of Neuropsychiatry
🇬🇧
Birmingham, United Kingdom
Cardiff University School of Medicine; Institute of Psychological Medicine Clinical Neurosciences
🇬🇧
Cardiff, United Kingdom
National Hospital For Neurology and Neurosurgery
🇬🇧
London, United Kingdom
Central Manchester University Hospitals NHS Foundation Trust; Manchester Centre for Genomic Medicine
🇬🇧
Manchester, United Kingdom