A clinical study comparing different doses of Tominersen with a placebo in people with prodromal (very early subtle signs) and early manifest Huntington's disease. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II DOSE-FINDING STUDY TO ASSESS THE SAFETY, BIOMARKERS, AND EFFICACY OF TOMINERSEN IN PEOPLE WITH PRODROMAL AND EARLY MANIFEST HUNTINGTON'S DISEASE
Summary description of the study
The purpose of this study is to compare the positive and/or negative effects of Tominersen (RO7234292) with those of placebo (a substance that looks like Tominersen but contains no active ingredient) in participating Huntington patients. This is a globally conducted, randomized, multicenter, placebo-controlled double-blind study. This means that participating patients will be randomly assigned (a random principle) to three treatment groups. Double-blind means that neither the patient nor the responsible investigator knows which treatment the patient is receiving. In this study, the patient will receive either 60 mg of Tominersen at each dosing visit, 100 mg of Tominersen at each dosing visit, or placebo at each dosing visit. The treatment will be administered every 16 weeks as an injection into the spinal canal and will last at least 16 months. During the study, routine general medical and neurological examinations are planned before the administration of the study drug, during which the health status will be assessed. At certain appointments, an imaging study (magnetic resonance imaging) of the brain will also be performed to examine brain structure and function. In addition, the patient will answer questionnaires about their disease, mobility, behavior, and physical and mental abilities at each appointment at the study center. As of April 2023, up to 360 patients worldwide will participate in the study.
(BASEC)
Intervention under investigation
The drug being investigated in this study is called Tominersen. Tominersen is an investigational drug that inhibits the production of the HTT protein. Defective HTT proteins are the cause of Huntington's disease. In an initial clinical study, Tominersen has been shown to reduce the amount of this harmful protein by inhibiting its production. It is hoped that by lowering the amount of mHTT, the progression of the disease can be slowed or completely stopped. Investigational drug means that Tominersen has not yet been approved by health authorities for the treatment of Huntington's disease or other diseases.
Each dose of Tominersen (100 mg or 60 mg) or placebo will be administered as a single injection into the spinal canal in the lower back area. The investigational product then enters the fluid that surrounds the spinal cord and brain (the so-called cerebrospinal fluid). Participants must come to the study center every 16 weeks for the dosing visit so that study staff can monitor the administration and respond to medical emergencies. Each study visit may last up to one day. Overall, participation in the study lasts about 16 to 24 months (double-blind study phase). Following the double-blind study phase, participants may have the opportunity to participate in the open-label extension study.
(BASEC)
Disease under investigation
This clinical study is for patients suffering from Huntington's disease. Huntington's disease is a condition caused by a mutated (defective) huntingtin protein (mHTT) that leads to the death of nerve cells in the brain. It is hoped that a therapy that reduces the production of this defective mHTT protein in the body can address the cause of Huntington's disease. Currently approved therapies aim to alleviate the severity of symptoms, preserve the patient's abilities as much as possible, and improve their quality of life. There are currently no treatment options that delay or completely halt the recognizable progression of Huntington's disease. Therefore, there is a need for therapies that target the underlying cause of Huntington's disease.
(BASEC)
- Age: 25 to 50 years (inclusive) at the time of informed consent - Diagnosis of Huntington's disease defined as a diagnostic certainty degree (DCL score) of 2-3, IS score (Independence Scale; degree of independence) = 100 (patients with prodromal Huntington's disease) or patients with early manifest (recognizable) Huntington's disease defined as a diagnostic certainty degree (DCL score) of 4, IS score (Independence Scale; degree of independence) ≥ 70 - Genetically confirmed disease according to direct DNA testing (CAP score of 400-500) - Ability to read the words "red", "blue", and "green" in the respective native language (BASEC)
Exclusion criteria
- History of attempted suicide or active suicidal thoughts (i.e., including planning the execution) resulting in hospitalization and/or change in care intensity in the last 12 months prior to screening (the preliminary examination for study enrollment) - Currently active psychosis, confusion, or violence - Current or previous treatment with an antisense oligonucleotide (short, artificially created DNA segments that prevent messenger RNA from instructing cells to produce proteins) - Investigator-known history or current presence of clinically significant abnormalities on the ECG (in the investigator's judgment) or signs of a heart attack in the past - Pregnancy or breastfeeding or intention to become pregnant during the study period or within 5 months after the last dose of the study drug (BASEC)
Trial sites
Basel, Bern
(BASEC)
Sponsor
F. Hoffmann-La Roche Ltd.
(BASEC)
Contact
Contact Person Switzerland
Silvia Caviezel-Koster
+41 61 715 43 53
switzerland.clinical-research@clutterroche.comRoche Pharma (Schweiz) AG
(BASEC)
General Information
Hoffmann-La Roche
(ICTRP)
Scientific Information
888-662-6728 (U.S. Only)
switzerland.clinical-research@clutterroche.com(ICTRP)
Name of the authorising ethics committee (for multicentre studies, only the lead committee)
Ethics Committee Bern
(BASEC)
Date of authorisation
01.05.2023
(BASEC)
ICTRP Trial ID
NCT05686551 (ICTRP)
Official title (approved by ethics committee)
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 (BASEC)
Academic 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 (ICTRP)
Public title
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 (ICTRP)
Disease under investigation
Huntington Disease (ICTRP)
Intervention under investigation
Drug: Tominersen 60 mgDrug: PlaceboDrug: Tominersen 100 mg (ICTRP)
Type of trial
Interventional (ICTRP)
Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor). (ICTRP)
Inclusion/Exclusion criteria
Inclusion Criteria
-HD gene expansion mutation carrier status with a cytosine-adenine-guanine-age product
(CAP) score of 400-500 inclusive
Either:
- Prodromal HD (defined as Diagnostic Confidence Level (DCL) 2 to 3, Independence
Scale (IS) ?70, and TFC ?8) or
- Early manifest HD (defined as DCL 4, IS ?70, and TFC ?8)
- Total body weight > 40 kilograms (kg) and a body mass index (BMI) within the range
of 18-32 kilograms per meter square (kg/m2)
- Study companion
Exclusion Criteria
- Current or previous use of an antisense oligonucleotide (ASO) (including small
interfering ribonucleic acid [RNA]) or any huntingtin gene/protein (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 milligrams per day [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 (ICTRP)
not available
Primary and secondary end points
Incidence and Severity of Adverse Events (AEs), With Severity Determined According to the AE Severity Grading Scale;Change From Baseline in Clinical Laboratory Results - Cerebrospinal Fluid (CSF) White Blood Cell (WBC);Change From Baseline in Clinical Laboratory Results CSF Protein;Change From Baseline in Structural Magnetic Resonance Imaging (MRI) Assessing Any New Abnormalities Including Radiographic Features Consistent With Hydrocephalus and Other Relevant MRI Safety Findings;Percentage Change From Baseline in Geometric Means of CSF Mutant Huntingtin (mHTT) Protein Levels at Month 9;Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores (non-U.S. Sites) at 16 Months;Change From Baseline in Total Functional Capacity (TFC) Scores (U.S. Sites) at 16 Months (ICTRP)
Change From Baseline in Montreal Cognitive Assessment (MoCA) Scores;Percentage of Participants With Suicidal Ideation or Behavior (I/B) as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) at Each Visit, Including Detailed Focus on Any Individual Cases Identified as Having Severe I/B During the Study Conduct;Change From Baseline at 16 Months for the Assessments of TFC (non-U.S. Sites) Scores;Change From Baseline at 16 Months for the Assessments of cUHDRS (U.S. Sites) Scores;Change From Baseline at 16 Months for the Assessments of Symbol Digit Modalities Test (SDMT) Scores;Change From Baseline at 16 Months for the Assessments of Stroop Word Reading (SWR) Score;Change From Baseline at 16 Months for the Assessment of Total Motor Score (TMS);Change From Baseline in CSF Neurofilament Light Chain (NfL) Levels at 16 Months;Incidence of Anti-drug Antibodies (ADAs) at Specified Timepoints Relative to the Prevalence of ADAs at Baseline;Titers Determined if ADAs are Identified (ICTRP)
Registration date
16.12.2022 (ICTRP)
Incorporation of the first participant
not available
Secondary sponsors
not available
Additional contacts
Reference Study ID Number: BN42489. https://forpatients.roche.com/, global-roche-genentech-trials@gene.com, 888-662-6728 (U.S. Only) (ICTRP)
Secondary trial IDs
Other, 2022-001991-32, 2023-503928-10-00, BN42489 (ICTRP)
Results-Individual Participant Data (IPD)
not available
Further information on the trial
https://clinicaltrials.gov/ct2/show/NCT05686551 (ICTRP)
Results of the trial
Results summary
not available
Link to the results in the primary register
not available