Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
Conditions
Interventions
Product Name: Recombinant AAV-9 vector expressing the human progranulin protein
Product Code: AVB-101
Pharmaceutical Form: Solution for infusion
Current Sponsor code: AVB-101
Other descriptive name:
Sponsors
AviadoBio Ltd
Eligibility
Sex/Gender
All
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 granulin (GRN) mutation as confirmed by a Sponsor approved genetic test; 3. Have frontotemporal dementia (FTD) as evidenced by Clinical Dementia Rating (CDR) + National Alzheimer’s Coordinating Center (NACC) frontotemporal lobar degeneration (FTLD) global score of 0.5, 1.0, or 2.0; 4. Have presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or primary progressive aphasia; 5. Have a thalamic volume of ?5.0 cm3 on each side on Screening magnetic resonance imaging (MRI); 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. Are willing to practice a highly effective birth control method as outlined in the Protocol if the subject or partner is of childbearing potential; 8. Able and willing to comply with all procedures and the study visit schedule as outlined in the Protocol; 9. 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; and 10. Have an identified, informed study partner who is able and willing to support the subject’s participation in the study and to provide assessments of the subject during the study (separate, written informed consent to be obtained from the study partner for their participation, where required to do so by the relevant country’s competent authorities). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 5 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 4
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”; 2. Have 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; 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 in the determination of the neurosurgeon 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 medications 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 as either a suicide attempt within 6 months prior to Screening or have a significant risk of suicide as judged by the Investigator; or 21. Have a known or suspected intolerance or hypersensitivity to the study drug or any of the stated ingredients.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.;Secondary Objective: To evaluate the preliminary clinical and biomarker measures of efficacy of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.;Primary end point(s): Over a 26-week initial and 5year total follow up period: • Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities; • Change from baseline in vital signs, ECG parameters, and physical and neurological examinations, and MMSEChange from baseline in mini-mental state examination (MMSE);; • Change from baseline in clinical chemistry and hematology safety laboratory tests; • Time to achieve clearance of vector genomes in plasma and semen (male only) • Incidence of treatment emergent suicidal ideation or behavior as measured using the C-SSRS. • Change from baseline in MRI including oedema, inflammation, asymptomatic/symptomatic hemorrhage and other structural changes;Timepoint(s) of evaluation of this end point: 26 weeks and 5 years | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Over a 26-week initial and 5-year total follow up period: • Change from baseline in PGRN protein levels in CSF and blood; Over a 26-week initial and 5-year total follow up period: • Change from baseline in NfL levels in CSF and blood Over a 5-year follow up period: • Change from baseline in CDR+NACC FTLD-SB score; • Change in CGI C, PGI-C, CaGI-C;Timepoint(s) of evaluation of this end point: 26 weeks and 5 years | — |
Countries
Belgium, France, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinical Trial Management
Medpace
Outcome results
None listed