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)

Phase 2RecruitingNCT06064890

AviadoBio Ltd9 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Frontotemporal Dementia FTD FTD-GRN

Eligibility

Sex: ALLMin age: 30 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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 * 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 OR If, in the Investigator's opinion, the subject lacks capacity to consent, written informed consent of their legal representative must be obtained in accordance with local laws, regulations, and/or customs. In countries where local laws, regulations, and/or customs do not permit subjects who lack capacity to consent to participate in this study, these subjects will not be enrolled * 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 Exclusion Criteria: * 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

Locations (18)

The Ohio State University (OSU) Wexner Medical Center

Columbus, Ohio, United States

RECRUITING

Vanderbilt University Medical Centre

Nashville, Tennessee, United States

RECRUITING

Houston Methodist Hospital

Houston, Texas, United States

RECRUITING

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

RECRUITING

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Italy

RECRUITING

Amsterdam UMC

Amsterdam, Netherlands

RECRUITING

NEURO-CARE Sp. z o.o. Sp. Komandytowa

Katowice, Poland

RECRUITING

Neurologia Slaska Centrum Medyczne

Katowice, Poland

RECRUITING

Uniwersyteckie Centrum Kliniczne, SUM w Katowicach

Katowice, Poland

RECRUITING

Euromedis Sp. z o.o.

Szczecin, Poland

RECRUITING

...and 8 more locations

Outcomes

Primary Outcomes

Number and incidence of AEs and SAEs

Type and incidence of adverse events

Time frame: Up to week 26

Change from baseline in the Mini-Mental State Examination (MMSE)

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.

Time frame: Up to week 12

Incidence of treatment emergent suicidal ideation or behavior

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.

Time frame: 26 week initial, 5-year total follow-up period

Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings

Time frame: 5-year total follow-up period

Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values

Time frame: 5-year total follow-up period

Change from baseline in brain structure

Assessed by presence of any clinically significant MRI findings at post treatment visits including brain swelling or bleeding

Time frame: 5-year total follow-up period

Secondary Outcomes

Change from baseline in PGRN protein levels in CSF and blood

Change over time in level of PGRN

Time frame: 26-week initial and 5-year total follow-up period

Change from baseline in NfL levels in CSF and blood

Change over time in level of NfL

Time frame: 26-week initial and 5-year total follow-up period

Change from baseline in CDR + NACC FTLD-SB score

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.

Time frame: 5-year total follow-up period

Time to achieve clearance of vector genomes

Measured in plasma and semen (males only)

Time frame: Up to week 26

Change from baseline in brain volumes

Calculation based upon 3DT1 MRI scans

Time frame: 5-year total follow-up period

Change from baseline in AAV9 immunogenicity in blood

Measured by level of antibodies and ELISPOT to AAV9 capsid

Time frame: 5-year total follow-up period

Change from baseline in AAV9 immunogenicity in CSF

Measured by level of antibodies to AAV9 capsid

Time frame: 5-year total follow-up period

Change from baseline in PGRN immunogenicity in CSF

Measured by level of antibodies to PGRN protein

Time frame: 5-year total follow-up period

Change from baseline in PGRN immunogenicity in blood

Measured by level of antibodies and ELISPOT to PGRN protein

Time frame: 5-year total follow-up period

Change in Caregiver Global Impression of Change (CaGI-C)

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.

Time frame: 5-year total follow-up period

Change in Patient Global Impression of Change (PGI-C)

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.

Time frame: 5-year total follow-up period

Change in Clinical Global Impression of Change (CGI-C)

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.

Time frame: 5-year total follow-up period

Change from baseline in GRN-specific Genetic Frontotemporal Initiative Cognitive (GENFI-Cog) composite score

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.

Time frame: 5-year total follow-up period

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)

Overview

Conditions

Interventions

Eligibility

Locations (18)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts