dementia frontotemporal dementia
Conditions
Interventions
Eligible subjects will be administered a one-time dose of AVB-101 at ambient
temperature by bilateral, intrathalamic infusion on Study Day 0 (Treatment
Visit). AVB-101 will be mixed with a gadoliniu
Sponsors
AviadoBio Ltd
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Subjects will be eligible to be included in the study if all of the following criteria apply: 1. Are male or female, 30 to 75 years of age, inclusive, at Screening; 2. Are carriers of a pathogenic GRN mutation as confirmed by a Sponsor approved genetic test; 3. Have EITHER symptomatic FTD OR pre-symptomatic carrier of a pathogenic GRN mutation at risk of conversion based on plasma NfL >20 pg/mL; 4. If symptomatic, presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or PPA; 5. Have an identified, informed study partner able to support the subject for the duration of the study; 6. For women of childbearing potential, must have a negative serum pregnancy test at Screening, a negative urine dipstick, and not be breastfeeding within 2 weeks prior to treatment; 7. For sexually active subjects, must agree to use a highly effective barrier method of contraception until at least 3 consecutive negative blood (or semen for male subjects, where possible) vector shedding samples are collected at least 1 week apart; 8. Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol; and 9. The subject and/or legally authorized representative is able and willing to give written informed consent prior to study participation. If a subject lacks the capacity to consent in the Investigator*s opinion, the subject*s assent should be obtained, if required in accordance with local laws, regulations, and customs, plus the written informed consent of a legal representative should be obtained. In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study, they will not be enrolled.
Exclusion criteria
Exclusion criteria: Subjects will be excluded from the study if any of the following criteria apply: 1. Have a classification of the mutation in the GRN gene as *not pathogenic,* *likely benign variant,* or *benign variant* in the Alzheimer*s Disease and Frontotemporal Dementia Mutation Database; 2. Have severe dementia, defined as Clinical Dementia Rating (CDR)+National Alzheimer*s Coordinating Center (NACC) frontotemporal lobar degeneration (FTLD) global score of 3.0, that precludes the ability to comply with study procedures and/or poses unacceptable safety risk to the subject; 3. Have 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; 4. Have a clinically significant abnormality on MRI at Screening considered to be a contraindication to intrathalamic infusion; 5. Have a surgically significant pattern of brain atrophy on MRI at Screening that interferes with planned neurosurgical trajectory; 6. Have had previous treatment with any gene or cell therapy; 7. Have had previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment; 8. Have had a concomitant disease, any clinically significant laboratory abnormality, or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the subject or interfere with study conduct or the subject's ability to comply with study procedures; 9. Have a malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated; 10. Have any contraindications to MRI as per local guidelines; 11. Have any contraindications to gadolinium-based contrast agents per local guidelines; 12. Have any contraindications to general anesthesia for a period of up to 10 hours and/or cardiopulmonary disorders that would result in higher American Society of Anesthesiology risk classification; 13. Have any contraindications to lumbar puncture as per local guidelines; 14. Have been hospitalized for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned procedure during the study; 15. Are using anticoagulants at Screening, or will have an anticipated need during the period of treatment. Antiplatelet therapies are acceptable concomitant medication if they can be stopped at least 48 hours prior to treatment; 16. Have a history of previous serious or recent Coronavirus Disease 2019 (COVID-19) as defined by (1) any history of hospitalization for severe illness at any time, (2) any history of significant respiratory symptoms at any time, or (3) any pre-symptomatic or mildly symptomatic COVID-19 positivity within 12 weeks prior to planned treatment; 17. Have a positive drug screen for drugs of abuse; 18. Have a history of substance abuse disorder; 19. Have the presence of an implanted deep brain stimulation device, ventriculoperitoneal or other cerebrospinal fluid shunt, or other implanted device; 20. Have evidence of suicide risk, as assessed by the Columbia-Suicide Severity Rating Scale, defined
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Over a 26-week initial and 5-year total follow-up period: o Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities; o Change from baseline in vital signs, ECG parameters, and physical and neurological examinations; o Change from baseline in the MMSE; o Change from baseline in biochemistry and hematology safety laboratory tests; o Time to achieve clearance of vector genomes in plasma and semen (males only); o Incidence of treatment-emergent suicidal ideation or behavior as measured on the C-SSRS; and o Change from baseline in MRI results including edema, inflammation, pre-symptomatic/symptomatic hemorrhage, and other structural changes. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints Over a 26-week initial and 5-year total follow-up period: o Change from baseline in PGRN protein levels in CSF and blood. Over a 52-week initial and 5-year total follow-up period: o Change from baseline in NfL levels in CSF and blood. Over a 5-year follow-up period: o Change from baseline in CDR+NACC FTLD-SB score; and o Change in CGI-C, PGI-C, and CaGI-C. Exploratory Endpoints Over a 5-year follow-up period: o Change from baseline in GFAP levels in CSF and blood; o Change from baseline in GENFI-Cog composite score; o Change from baseline in brain volumes including whole brain, white matter, grey matter, ventricles, thalamus, and hippocampus; cortical thickness; and WM integrity (T1/T2/FLAIR MRI); o Change from baseline in inflammatory and lysosomal markers in CSF; and o Change in the Winterlight Speech Assessment score. o Change from baseline in AAV9 immunogenicity in blood (AAV9 ELISPOT and anti-AAV9 antibody) and CSF (anti-AAV9 antibody); and o Change from baseline in PGRN immunogenicity in blood (hPGRN ELISPOT and anti-hPGRN antibody) and CSF (anti-PGRN antibody). | — |
Countries
Netherlands
Outcome results
None listed