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.

• ClinicalTrials.gov Identifier: NCT05686551
• Recruitment Status: Recruiting
• First Posted: January 17, 2023
• Last Update Posted: March 16, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Huntington Disease	Drug: Tominersen 60 mg; Drug: Placebo; Drug: Tominersen 100 mg	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 360 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 30, 2023
• Estimated Primary Completion Date: January 3, 2025
• Estimated Study Completion Date: January 4, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tominersen 60 mg	Drug: Tominersen 60 mg; 60 mg tominersen administered intrathecally every 16 weeks
Placebo Comparator: Placebo	Drug: Placebo; Matching placebo administered intrathecally every 16 weeks
Experimental: Tominersen 100 mg	Drug: Tominersen 100 mg; 100 mg tominersen administered intrathecally every 16 weeks

Outcome Measures

Primary Outcome Measures :

1. Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale [ Time Frame: Up to Approximately 24 Months ]
2. Change from baseline in clinical laboratory results - Cerebrospinal fluid (CSF) White Blood Cell (WBC) (1/uL) [ Time Frame: From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 ]
3. Change from baseline in clinical laboratory results Cerebrospinal fluid (CSF) protein (g/L) [ Time Frame: From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 ]
4. Change in baseline in structural MRI assessing any new abnormalities including radiographic features consistent with hydrocephalus and other relevant MRI safety findings [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 36 ]
5. Percentage change from baseline in geometric means of CSF mHTT protein levels at Month 9 [ Time Frame: Baseline and Month 9 ]
6. Change from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores (non-U.S. sites) at 16 months [ Time Frame: Up to Approximately 16 Months ]
   Change in scores on the scale
7. Change from baseline in Total Functional Capacity (TFC) Scores (U.S. sites) at 16 months [ Time Frame: Baseline and 16 Months ]
   Change in scores on the scale

Secondary Outcome Measures :

1. Change from baseline in MoCA Scores [ Time Frame: From Baseline, Months 4, 8, 12, 16 and up to approximately Month 36 ]
2. 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 [ Time Frame: Up to Approximately 24 Months ]
3. Change from baseline at 16 months for the assessments of TFC (non-U.S. sites) Scores [ Time Frame: Baseline to 16 Months ]
4. Change from baseline at 16 months for the assessments of cUHDRS (U.S. sites) Scores [ Time Frame: Baseline to 16 Months ]
5. Change from baseline at 16 months for the assessments of Symbol Digit Modalities Test (SDMT) Scores [ Time Frame: Baseline to 16 Months ]
6. Change from Baseline at 16 Months for the Assessments of Stroop Word Reading (SWR) Scores [ Time Frame: Baseline to 16 Months ]
7. Change from baseline at 16 months for the assessments of Total Motor Score (TMS) [ Time Frame: Baseline to 16 Months ]
8. Change from baseline in CSF Neurofilament light Chain (NfL) levels at 16 months [ Time Frame: Baseline to 16 Months ]
9. Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 36 ]
10. Titers determined if ADAs are identified [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 36 ]

Eligibility Criteria

• Ages Eligible for Study: 25 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria

• Signed study companion consent form. A study companion is required for all participants.
• HD gene expansion mutation carrier status. CAP score of 400-500, inclusive, where CAP is calculated as follows:

Age x (CAG repeat length -33.66)

-Prodromal HD, defined as DCL 2 to 3, Total Motor Score (TMS) >6, Independence Scale (IS) = 100 (broadly equivalent to HD-ISS Stage 2), or early manifest HD, defined as DCL 4, TMS > 6, 100 >IS>/= 70, and TFC >/=8 (broadly equivalent to HD-ISS Stage 3)

Companion Inclusion Criteria

- HD gene expansion mutation carrier status. CAP score of 400-500, inclusive, where CAP is calculated as follows: Age x (CAG repeat length -33.66)

• Prodromal HD, defined as DCL 2 to 3, Total Motor Score (TMS) >6, Independence Scale (IS) = 100 (broadly equivalent to HD-ISS Stage 2), or early manifest HD, defined as DCL 4, TMS > 6, 100 >IS>/= 70, and TFC >/=8 (broadly equivalent to HD-ISS Stage 3)
• Signed study companion consent form. A study companion is required for all participants.

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

Contacts and Locations

Contacts

Contact: Reference Study ID Number: BN42489 https://forpatients.roche.com/; 888-662-6728 (U.S. Only); global-roche-genentech-trials@gene.com

Locations

United States, New York

Dent Neurological Institute; Recruiting

Amherst, New York, United States, 14226

Spain

Hospital de Cruces; Servicio de Neurologia; Recruiting

Barakaldo, Vizcaya, Spain, 48903

Hospital Universitario de Badajoz; Servicio de Neurología; Recruiting

Badajoz, Spain, 06080

Hospital de la Santa Creu i Sant Pau; Servicio de Neurologia; Recruiting

Barcelona, Spain, 08041

Hospital Universitario de Burgos. Servicio de Neurología; Recruiting

Burgos, Spain, 09006

Hospital Ramon y Cajal; Servicio de Neurologia; Recruiting

Madrid, Spain, 28034

Sponsors and Collaborators

Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT05686551
• Other Study ID Numbers: BN42489; Other ( Other Identifier: GENERATION HD2 )
• First Posted: January 17, 2023
• Last Update Posted: March 16, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical 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).
• Supporting Materials: Study Protocol

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hoffmann-La Roche:

Prodromal and Early Manifest Huntington's Disease

Additional relevant MeSH terms:

Huntington Disease; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Cognition Disorders; Neurocognitive Disorders; Mental Disorders