Back to resultsA 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) (ASPIRE-FTD)
Primary Purpose
Frontotemporal Dementia, FTD, FTD-GRN
Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Intrathalamic AAV.PGRN administration
Intrathalamic AVB-101
Sponsored by
About this trial
This is an interventional treatment trial for Frontotemporal Dementia focused on measuring Gene Therapy, AAV, Intrathalamic, Intraparenchymal, Progranulin, Behavioral Variant FTD, Primary Progressive Aphasia, PGRN, Granulin, Dementia, Dementia Gene Therapy, AAV9
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
Sites / Locations
- Wielospecjalistyczna Poradnia Lekarska SYNAPSISRecruiting
- Mazowiecki Szpital Brodnowski Sp. z o. o.Recruiting
- Hospital Clinic BarcelonaRecruiting
- Hospital Universitari i Politecnic La FeRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort 1 (dose 1)
Cohort 2 (dose 2)
Arm Description
Initial dose, delivered as a one-time only, intrathalamic administration.
Escalated dose, delivered as a one-time only, intrathalamic administration.
Outcomes
Primary Outcome Measures
Number and incidence of AEs and SAEs
Type and incidence of adverse events
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 to achieve clearance of vector genomes
Measured in plasma and semen (males only)
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.
Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings
Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
Change from baseline in brain structure
Assessed by presence of any clinically significant MRI findings at post treatment visits including brain swelling or bleeding
Secondary Outcome Measures
Change from baseline in PGRN protein levels in CSF and blood
Change over time in level of PGRN
Change from baseline in NfL levels in CSF and blood
Change over time in level of NfL
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.
Change from baseline in brain volumes
Calculation based upon 3DT1 MRI scans
Change from baseline in AAV9 immunogenicity in blood
Measured by level of antibodies and ELISPOT to AAV9 capsid
Change from baseline in AAV9 immunogenicity in CSF
Measured by level of antibodies to AAV9 capsid
Change from baseline in PGRN immunogenicity in CSF
Measured by level of antibodies to PGRN protein
Change from baseline in PGRN immunogenicity in blood
Measured by level of antibodies and ELISPOT to PGRN protein
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT06064890
Brief Title
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)
Acronym
ASPIRE-FTD
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
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 30, 2023 (Actual)
Primary Completion Date
April 1, 2026 (Anticipated)
Study Completion Date
October 31, 2030 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AviadoBio Ltd
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes
5. Study Description
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:
Is a one-time treatment with AVB-101 safe for patients with FTD-GRN?
Does a one-time treatment with AVB-101 restore PGRN levels to at least normal levels?
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
9 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1 (dose 1)
Arm Type
Experimental
Arm Description
Initial dose, delivered as a one-time only, intrathalamic administration.
Arm Title
Cohort 2 (dose 2)
Arm Type
Experimental
Arm Description
Escalated dose, delivered as a one-time only, intrathalamic administration.
Intervention Type
Procedure
Intervention Name(s)
Intrathalamic AAV.PGRN administration
Intervention Description
One-time MRI-guided stereotaxic infusion of AAV.PGRN into the brain
Intervention Type
Genetic
Intervention Name(s)
Intrathalamic AVB-101
Intervention Description
AVB-101 is made from an adeno-associated virus, serotype 9 (AAV9). AAVs are small viruses that are naturally occurring and do not cause illness or infection on their own. AVB-101 has been modified to contain a copy of the correct (non-mutated) GRN gene, plus some other genetic material to enable the GRN gene to function inside neurons (cells within the brain). AVB-101 has also been modified so that it cannot divide and make new copies of itself (known as 'replication'), which means that it cannot cause disease or a large immune response in your body.
Primary Outcome Measure Information:
Title
Number and incidence of AEs and SAEs
Description
Type and incidence of adverse events
Time Frame
Up to week 26
Title
Change from baseline in the Mini-Mental State Examination (MMSE)
Description
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
Title
Time to achieve clearance of vector genomes
Description
Measured in plasma and semen (males only)
Time Frame
Up to week 26
Title
Incidence of treatment emergent suicidal ideation or behavior
Description
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
Title
Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings
Time Frame
5-year total follow-up period
Title
Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
Time Frame
5-year total follow-up period
Title
Change from baseline in brain structure
Description
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 Outcome Measure Information:
Title
Change from baseline in PGRN protein levels in CSF and blood
Description
Change over time in level of PGRN
Time Frame
26-week initial and 5-year total follow-up period
Title
Change from baseline in NfL levels in CSF and blood
Description
Change over time in level of NfL
Time Frame
26-week initial and 5-year total follow-up period
Title
Change from baseline in CDR + NACC FTLD-SB score
Description
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
Title
Change from baseline in brain volumes
Description
Calculation based upon 3DT1 MRI scans
Time Frame
5-year total follow-up period
Title
Change from baseline in AAV9 immunogenicity in blood
Description
Measured by level of antibodies and ELISPOT to AAV9 capsid
Time Frame
5-year total follow-up period
Title
Change from baseline in AAV9 immunogenicity in CSF
Description
Measured by level of antibodies to AAV9 capsid
Time Frame
5-year total follow-up period
Title
Change from baseline in PGRN immunogenicity in CSF
Description
Measured by level of antibodies to PGRN protein
Time Frame
5-year total follow-up period
Title
Change from baseline in PGRN immunogenicity in blood
Description
Measured by level of antibodies and ELISPOT to PGRN protein
Time Frame
5-year total follow-up period
Title
Change in Caregiver Global Impression of Change (CaGI-C)
Description
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
Title
Change in Patient Global Impression of Change (PGI-C)
Description
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
Title
Change in Clinical Global Impression of Change (CGI-C)
Description
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
Title
Change from baseline in GRN-specific Genetic Frontotemporal Initiative Cognitive (GENFI-Cog) composite score
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
AviadoBio Clinical Trials
Phone
+44 203-089-7917
Email
clinicaltrials@aviadobio.com
Facility Information:
Facility Name
Wielospecjalistyczna Poradnia Lekarska SYNAPSIS
City
Katowice
Country
Poland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aneta Pasko
Phone
+48 602-643-900
Email
aneta.pasko@op.pl
Facility Name
Mazowiecki Szpital Brodnowski Sp. z o. o.
City
Warsaw
Country
Poland
Individual Site Status
Recruiting
Facility Name
Hospital Clinic Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Beatriz Bosch
Phone
934 518 240
Email
BBOSCH@recerca.clinic.cat
Facility Name
Hospital Universitari i Politecnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Individual Site Status
Recruiting
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
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)
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