A Study to Evaluate the Safety and Effect of AVB-101, a Gene Therapy Product, in Subjects With a Genetic Sub-type of Frontotemporal Dementia (FTD-GRN)
- Conditions
- FTDFrontotemporal DementiaFTD-GRNDementia, Frontotemporal
- Interventions
- Procedure: Intrathalamic AAV.PGRN administrationGenetic: Intrathalamic AVB-101
- Registration Number
- NCT06064890
- Lead Sponsor
- AviadoBio Ltd
- Brief Summary
The goal of this clinical study is to learn about an investigational gene therapy product called AVB-101, which is designed to treat a disease called Frontotemporal Dementia with Progranulin Mutations (FTD-GRN). FTD-GRN is an early-onset form of dementia, a progressive brain disorder that affects behavior, language and movement. These symptoms result from below normal levels of a protein called progranulin (PGRN) in the brain, which leads to the death of nerve cells (neurons), affecting the brain's ability to function.
The main questions that the study aims to answer are:
1. Is a one-time treatment with AVB-101 safe for patients with FTD-GRN?
2. Does a one-time treatment with AVB-101 restore PGRN levels to at least normal levels?
3. Could AVB-101 work as a treatment to slow down or stop progression of FTD-GRN?
In this study there is no placebo (a dummy pill or treatment used for comparison purposes), so all participants will receive a one-time treatment of AVB-101 delivered directly to the brain, with follow-up assessments for 5 years.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 9
- Male or female, 30 to 75 years of age
- Carriers of a pathogenic GRN mutation
- FTD as evidenced by CDR + NACC FTLD global score of 0.5, 1.0, or 2.0
- Presence of 1 or more of the criteria for diagnosis of possible bvFTD or PPA
- A protocol defined minimum thalamic volume on each side on Screening MRI
- Able and willing to comply with all procedures and the study visit schedule
- Able and willing to give written informed consent prior to study participation, and agree to designate a legal representative to act on their wishes to continue participation should they lose capacity to consent at some point during the study
- An identified, informed study partner who is able and willing to support the participant in the study and to provide assessments of the participant during the study
- Severe dementia, defined as CDR + NACC FTLD global score of 3.0, or other symptoms that preclude the ability to comply with study procedures and/or pose unacceptable safety risk to the subject
- Any concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency
- Clinically significant abnormality on MRI at Screening considered to be a contraindication to Intrathalamic infusion
- Surgically significant pattern of brain atrophy on MRI at Screening that interferes with planned neurosurgical trajectory
- Previous treatment with any gene or cell therapy
- Previous treatment with any investigational medicinal product (IMP) within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment
- Concomitant disease, any clinically significant laboratory abnormality, or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the participant or interfere with study conduct or the participant's ability to comply with study procedures including neurosurgical administration under anesthesia
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1 (dose 1) Intrathalamic AAV.PGRN administration Initial dose, delivered as a one-time only, intrathalamic administration. Cohort 1 (dose 1) Intrathalamic AVB-101 Initial dose, delivered as a one-time only, intrathalamic administration. Cohort 2 (dose 2) Intrathalamic AVB-101 Escalated dose, delivered as a one-time only, intrathalamic administration. Cohort 2 (dose 2) Intrathalamic AAV.PGRN administration Escalated dose, delivered as a one-time only, intrathalamic administration.
- Primary Outcome Measures
Name Time Method Time to achieve clearance of vector genomes Up to week 26 Measured in plasma and semen (males only)
Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings 5-year total follow-up period Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values 5-year total follow-up period Number and incidence of AEs and SAEs Up to week 26 Type and incidence of adverse events
Change from baseline in the Mini-Mental State Examination (MMSE) Up to week 12 Mini-Mental State Examination (MMSE) is a global assessment of cognitive status. Score range 0-30; higher scores reflect better cognitive function. Change in MMSE score from baseline visit to post-treatment visit will be assessed.
Change from baseline in brain structure 5-year total follow-up period Assessed by presence of any clinically significant MRI findings at post treatment visits including brain swelling or bleeding
Incidence of treatment emergent suicidal ideation or behavior 26 week initial, 5-year total follow-up period The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates suicidal ideation and behavior. C-SSRS will be measured at each visit to assess for absence/presence of suicidal ideation and/or behavior.
- Secondary Outcome Measures
Name Time Method Change in Clinical Global Impression of Change (CGI-C) 5-year total follow-up period Global impression of change as assessed by the investigator (clinician). The CGI-C is a 7 point scale where 1= very much improved, 7= very much worse.
Change from baseline in PGRN protein levels in CSF and blood 26-week initial and 5-year total follow-up period Change over time in level of PGRN
Change from baseline in brain volumes 5-year total follow-up period Calculation based upon 3DT1 MRI scans
Change from baseline in PGRN immunogenicity in CSF 5-year total follow-up period Measured by level of antibodies to PGRN protein
Change in Caregiver Global Impression of Change (CaGI-C) 5-year total follow-up period Global impression of change as assessed by the caregiver. The CaGI-C is a 7 point scale where 1= very much improved, 7= very much worse.
Change in Patient Global Impression of Change (PGI-C) 5-year total follow-up period Global impression of change as assessed by the patient. The PGI-C is a 7 point scale where 1= very much improved, 7= very much worse.
Change from baseline in AAV9 immunogenicity in CSF 5-year total follow-up period Measured by level of antibodies to AAV9 capsid
Change from baseline in NfL levels in CSF and blood 26-week initial and 5-year total follow-up period Change over time in level of NfL
Change from baseline in AAV9 immunogenicity in blood 5-year total follow-up period Measured by level of antibodies and ELISPOT to AAV9 capsid
Change from baseline in PGRN immunogenicity in blood 5-year total follow-up period Measured by level of antibodies and ELISPOT to PGRN protein
Change from baseline in CDR + NACC FTLD-SB score 5-year total follow-up period The Clinical Dementia Staging Instrument (CDR) plus National Alzheimer's Coordinating Center Frontotemporal Degeneration domains (NACC FTLD) was developed as a way to improve characterization of cognitive and global function in patients with FTLD. The CDR+NACC FTLD score will capture patients' disease status. CDR+NACC FTLD Sum of Boxes (SB) score refers to the sum of the scores of each domain (sum of boxes) that ranges from 0 to 24.
Change from baseline in GRN-specific Genetic Frontotemporal Initiative Cognitive (GENFI-Cog) composite score 5-year total follow-up period Calculated from the neuropsychological test battery that assesses various cognitive domains: language, attention/processing speed, executive function, verbal and visuospatial memory and social cognition.
Scores from the neuropsychological test battery are converted using standard statistical methods into the composite score. The GRN specific composite score is expected to be more sensitive to detect changes in cognition that are associated with FTD, and will be compared to the baseline score. Lower scores indicate worse performance.
Trial Locations
- Locations (30)
Euromedis Sp. z o.o.
🇵🇱Szczecin, Poland
Centrum Medyczne NeuroProtect Sp z o.o.
🇵🇱Warsaw, Poland
Mazowiecki Szpital Brodnowski Sp. z o. o.
🇵🇱Warsaw, Poland
Vanderbilt University Medical Centre
🇺🇸Nashville, Tennessee, United States
Houston Methodist Hospital
🇺🇸Houston, Texas, United States
The Ohio State University (OSU) Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Amsterdam UMC
🇳🇱Amsterdam, Netherlands
NEURO-CARE Sp. z o.o. Sp. Komandytowa
🇵🇱Katowice, Poland
Neurologia Slaska Centrum Medyczne
🇵🇱Katowice, Poland
Uniwersyteckie Centrum Kliniczne, SUM w Katowicach
🇵🇱Katowice, Poland
Hospital Clinic Barcelona
🇪🇸Barcelona, Spain
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Skåne University Hospital
🇸🇪Lund, Sweden
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
University Hospital of Wales
🇬🇧Cardiff, United Kingdom
The Ohio State University (OSU) Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Vanderbilt University Medical Centre
🇺🇸Nashville, Tennessee, United States
Amsterdam UMC
🇳🇱Amsterdam, Netherlands
Houston Methodist Hospital
🇺🇸Houston, Texas, United States
NEURO-CARE Sp. z o.o. Sp. Komandytowa
🇵🇱Katowice, Poland
Neurologia Slaska Centrum Medyczne
🇵🇱Katowice, Poland
Uniwersyteckie Centrum Kliniczne, SUM w Katowicach
🇵🇱Katowice, Poland
Euromedis Sp. z o.o.
🇵🇱Szczecin, Poland
Skåne University Hospital
🇸🇪Lund, Sweden
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
University Hospital of Wales
🇬🇧Cardiff, United Kingdom
Centrum Medyczne NeuroProtect Sp z o.o.
🇵🇱Warsaw, Poland
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Mazowiecki Szpital Brodnowski Sp. z o. o.
🇵🇱Warsaw, Poland
Hospital Clinic Barcelona
🇪🇸Barcelona, Spain