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)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 34
- 主要终点
- Time to achieve clearance of vector genomes
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 30 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Cohort 4 (dose 4)
Additional dose
干预措施: Intrathalamic AVB-101 (Genetic)
Cohort 2 (dose 2)
Escalated dose
干预措施: Intrathalamic AVB-101 (Genetic)
Cohort 3 (dose 3)
Additional dose
干预措施: Intrathalamic AVB-101 (Genetic)
Cohort 1 (dose 1)
Initial dose
干预措施: Intrathalamic AAV.PGRN administration (Procedure)
Cohort 1 (dose 1)
Initial dose
干预措施: Intrathalamic AVB-101 (Genetic)
Cohort 2 (dose 2)
Escalated dose
干预措施: Intrathalamic AAV.PGRN administration (Procedure)
Cohort 4 (dose 4)
Additional dose
干预措施: Intrathalamic AAV.PGRN administration (Procedure)
Cohort 3 (dose 3)
Additional dose
干预措施: Intrathalamic AAV.PGRN administration (Procedure)
结局指标
主要结局
Time to achieve clearance of vector genomes
时间窗: Up to week 26
Measured in plasma and semen (males only)
Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings
时间窗: 5-year total follow-up period
Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
时间窗: 5-year total follow-up period
Number and incidence of AEs and SAEs
时间窗: Up to week 26
Type and incidence of adverse events
Change from baseline in the Mini-Mental State Examination (MMSE)
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Change in Clinical Global Impression of Change (CGI-C)(5-year total follow-up period)
- Change from baseline in PGRN protein levels in CSF and blood(26-week initial and 5-year total follow-up period)
- Change from baseline in brain volumes(5-year total follow-up period)
- Change from baseline in PGRN immunogenicity in CSF(5-year total follow-up period)
- Change in Caregiver Global Impression of Change (CaGI-C)(5-year total follow-up period)
- Change in Patient Global Impression of Change (PGI-C)(5-year total follow-up period)
- Change from baseline in AAV9 immunogenicity in CSF(5-year total follow-up period)
- Change from baseline in NfL levels in CSF and blood(26-week initial and 5-year total follow-up period)
- Change from baseline in AAV9 immunogenicity in blood(5-year total follow-up period)
- Change from baseline in PGRN immunogenicity in blood(5-year total follow-up period)
- Change from baseline in CDR + NACC FTLD-SB score(5-year total follow-up period)
- Change from baseline in GRN-specific Genetic Frontotemporal Initiative Cognitive (GENFI-Cog) composite score(5-year total follow-up period)
- Time to achieve clearance of vector genomes(Up to week 26)
- Change from baseline in GFAP levels in CSF and blood(5-year total follow-up period)