Clinical trial NCT06064890: 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)
Official title: A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of AVB-101 Administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Frontotemporal Dementia
FTD
FTD-GRN
Dementia, Frontotemporal
Keywords: Gene Therapy
AAV
Intrathalamic
Intraparenchymal
Progranulin
Behavioral Variant FTD
Primary Progressive Aphasia
PGRN
Granulin
Dementia
Dementia Gene Therapy
AAV9
Lead sponsor: AviadoBio Ltd
Sponsor class: INDUSTRY
First posted: 2023-10-03
Enrollment: 9
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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
* 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

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

Primary outcomes:
measure: Number and incidence of AEs and SAEs
timeFrame: Up to week 26
measure: Change from baseline in the Mini-Mental State Examination (MMSE)
timeFrame: Up to week 12
measure: Time to achieve clearance of vector genomes
timeFrame: Up to week 26
measure: Incidence of treatment emergent suicidal ideation or behavior
timeFrame: 26 week initial, 5-year total follow-up period
measure: Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings
timeFrame: 5-year total follow-up period
measure: Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
timeFrame: 5-year total follow-up period
measure: Change from baseline in brain structure
timeFrame: 5-year total follow-up period
Secondary outcomes:
measure: Change from baseline in PGRN protein levels in CSF and blood
timeFrame: 26-week initial and 5-year total follow-up period
measure: Change from baseline in NfL levels in CSF and blood
timeFrame: 26-week initial and 5-year total follow-up period
measure: Change from baseline in CDR + NACC FTLD-SB score
timeFrame: 5-year total follow-up period
measure: Change from baseline in brain volumes
timeFrame: 5-year total follow-up period
measure: Change from baseline in AAV9 immunogenicity in blood
timeFrame: 5-year total follow-up period
measure: Change from baseline in AAV9 immunogenicity in CSF
timeFrame: 5-year total follow-up period
measure: Change from baseline in PGRN immunogenicity in CSF
timeFrame: 5-year total follow-up period
measure: Change from baseline in PGRN immunogenicity in blood
timeFrame: 5-year total follow-up period
measure: Change in Caregiver Global Impression of Change (CaGI-C)
timeFrame: 5-year total follow-up period
measure: Change in Patient Global Impression of Change (PGI-C)
timeFrame: 5-year total follow-up period
measure: Change in Clinical Global Impression of Change (CGI-C)
timeFrame: 5-year total follow-up period
measure: Change from baseline in GRN-specific Genetic Frontotemporal Initiative Cognitive (GENFI-Cog) composite score
timeFrame: 5-year total follow-up period
Other outcomes:
Locations:
city: Columbus
country: United States
facility: The Ohio State University (OSU) Wexner Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Centre
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Katowice
country: Poland
facility: NEURO-CARE Sp. z o.o. Sp. Komandytowa
city: Katowice
country: Poland
facility: Neurologia Slaska Centrum Medyczne
city: Katowice
country: Poland
facility: Uniwersyteckie Centrum Kliniczne, SUM w Katowicach
city: Szczecin
country: Poland
facility: Euromedis Sp. z o.o.
city: Warsaw
country: Poland
facility: Centrum Medyczne NeuroProtect Sp z o.o.
city: Warsaw
country: Poland
facility: Mazowiecki Szpital Brodnowski Sp. z o. o.
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Lund
country: Sweden
facility: Skåne University Hospital
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
Study officials:
References: