GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease.

Study Overview
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Brief Summary
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This study will evaluate the safety, biomarkers, and efficacy of tominersen compared with placebo in participants with prodromal and early manifest Huntington's Disease.

Official Title
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A Phase II, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen in Individuals With Prodromal and Early Manifest Huntington's Disease

Conditions
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Huntington Disease

Intervention / Treatment
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* Drug: Tominersen 60 mg
* Drug: Placebo
* Drug: Tominersen 100 mg


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria -Huntington's disease (HD) gene expansion mutation carrier status with a CAP score of 400-500 inclusive Either: Prodromal HD (defined as DCL 2 to 3, Independence Scale (IS) ⩾70, and ⩾TFC8); or Early manifest HD (defined as DCL 4, Independence Scale (IS) ⩾70, and ⩾TFC8); Total body weight > 40 kg and a body mass index within the range of 18-32 kg/m2 Study Companion Key Exclusion Criteria Current or previous use of an ASO (including small interfering RNA) or any HTT lowering therapy (including tominersen) Anti-platelet or anticoagulant therapy within 14 days prior to screening or anticipated use during the study, including, but not limited to, aspirin (unless </= 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and heparin History of gene therapy, cell transplantation, or brain surgery Hydrocephalus Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug 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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tominersen 60 mg<br> | Drug: Tominersen 60 mg<br>* 60 mg tominersen administered intrathecally every 16 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Matching placebo administered intrathecally every 16 weeks<br>|
| Experimental: Tominersen 100 mg<br> | Drug: Tominersen 100 mg<br>* 100 mg tominersen administered intrathecally every 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale |  | Up to Approximately 24 Months | 
| Change from baseline in clinical laboratory results - Cerebrospinal fluid (CSF) White Blood Cell (WBC) (1/uL) |  | From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 | 
| Change from baseline in clinical laboratory results Cerebrospinal fluid (CSF) protein (g/L) |  | From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 | 
| Change in baseline in structural MRI assessing any new abnormalities including radiographic features consistent with hydrocephalus and other relevant MRI safety findings |  | From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 24 | 
| Percentage change from baseline in geometric means of CSF mHTT protein levels at Month 9 |  | Baseline and Month 9 | 
| Change from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores (non-U.S. sites) at 16 months | Change in scores on the scale | Baseline to 16 Months | 
| Change from baseline in Total Functional Capacity (TFC) Scores (U.S. sites) at 16 months | Change in scores on the scale | Baseline to 16 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in MoCA Scores |  | From Baseline, Months 4, 8, 12, 16 and up to approximately Month 24 | 
| Percentage of participants 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 |  | Up to Approximately 24 Months | 
| Change from baseline at 16 months for the assessments of TFC (non-U.S. sites) Scores |  | Baseline to 16 Months | 
| Change from baseline at 16 months for the assessments of cUHDRS (U.S. sites) Scores |  | Baseline to 16 Months | 
| Change from baseline at 16 months for the assessments of Symbol Digit Modalities Test (SDMT) Scores |  | Baseline to 16 Months | 
| Change from Baseline at 16 Months for the Assessments of Stroop Word Reading (SWR) Scores |  | Baseline to 16 Months | 
| Change from baseline at 16 months for the assessments of Total Motor Score (TMS) |  | Baseline to 16 Months | 
| Change from baseline in CSF Neurofilament light Chain (NfL) levels at 16 months |  | Baseline to 16 Months | 
| Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline |  | From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 24 | 
| Titers determined if ADAs are identified |  | From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prodromal and Early Manifest Huntington's Disease