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)
- Conditions
- dementiafrontotemporal dementia100276641004225810012272
- Registration Number
- NL-OMON53802
- Lead Sponsor
- AviadoBio Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 3
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.
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Over a 26-week initial and 5-year total follow-up period:<br /><br>o Number and incidence of AEs, SAEs, and clinically meaningful laboratory test<br /><br>abnormalities;<br /><br>o Change from baseline in vital signs, ECG parameters, and physical and<br /><br>neurological examinations;<br /><br>o Change from baseline in the MMSE;<br /><br>o Change from baseline in biochemistry and hematology safety laboratory tests;<br /><br>o Time to achieve clearance of vector genomes in plasma and semen (males only);<br /><br>o Incidence of treatment-emergent suicidal ideation or behavior as measured on<br /><br>the C-SSRS; and<br /><br>o Change from baseline in MRI results including edema, inflammation,<br /><br>pre-symptomatic/symptomatic hemorrhage, and other structural changes. </p><br>
- Secondary Outcome Measures
Name Time Method