Ph1/2 study of AVB-101 in Subjects with Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aviadobio Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

8 Feb 2024 → ongoing

Decision date (initial)

2024-04-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AviadoBio Limited

External identifiers

EU CT number

2023-509444-10-00

EudraCT number

2022-002568-62

WHO UTN

U1111-1301-8705

ClinicalTrials.gov

NCT06064890

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the safety and tolerability of a one-time, intrathalamic administration of AVB-101 in subjects with FTD-GRN.

Secondary objectives 1

1. 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.

Conditions and MedDRA coding

Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Are male or female, 30 to 75 years of age, inclusive, at Screening
2. 9. 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).
3. 2. Are carriers of a pathogenic granulin (GRN) mutation (ie, heterozygous loss-of-function mutation causative of FTD) as confirmed by a Sponsor approved genetic test.
4. 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
5. 4. Have presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or primary progressive aphasia
6. 5. 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. 6. 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. 7. Able and willing to comply with all procedures and the study visit schedule as outlined in the Protocol
9. 8. 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

Exclusion criteria 20

1. 1. Have a classification of the mutation in the GRN gene as “not pathogenic,” “likely benign variant,” or “benign variant”
2. 10. Have any contraindications to MRI as per local guidelines
3. 11. Have any contraindications to gadolinium-based contrast agents per local guidelines
4. 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
5. 13. Have any contraindications to lumbar puncture as per local guidelines
6. 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
7. 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
8. 16. Have a positive drug screen for drugs of abuse
9. 17. Have a history of substance abuse disorder
10. 18. Have the presence of an implanted deep brain stimulation device, ventriculoperitoneal or other cerebrospinal fluid (CSF) shunt, or other implanted device
11. 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
12. 19. 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
13. 20. Have a known or suspected intolerance or hypersensitivity to the study drug or any of the stated ingredients.
14. 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
15. 4. Have a clinically significant abnormality on magnetic resonance imaging (MRI) at Screening considered to be a contraindication to intrathalamic infusion
16. 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
17. 6. Have had previous treatment with any gene or cell therapy
18. 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
19. 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
20. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. 1.1. Over a 26-week initial and 5-year total follow-up period: - Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities;
2. 1.2. Over a 26-week initial and 5-year total follow-up period: - Change from baseline in vital signs, ECG parameters, and physical and neurological examinations
3. 1.3. Over a 26-week initial and 5-year total follow-up period: - Change from baseline in the MMSE;
4. 1.4. Over a 26-week initial and 5-year total follow-up period: - Change from baseline in biochemistry and hematology safety laboratory tests
5. 1.5. Over a 26-week initial and 5-year total follow-up period: - Incidence of treatment-emergent suicidal ideation or behavior as measured on the C-SSRS;
6. 1.6. Over a 26-week initial and 5-year total follow-up period: - Change from baseline in MRI results including edema, inflammation, asymptomatic/symptomatic hemorrhage, and other structural changes.

Secondary endpoints 2

1. 1.1. Over a 26-week initial and 5-year total follow-up period: - Change from baseline in PGRN protein levels in CSF and blood.
2. 1.2. Over a 5-year follow-up period: - Change from baseline in CDR + NACC FTLD-SB score; and - Change in CGI-C, PGI-C, and CaGI-C

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aviadobio Limited

Sponsor organisation

Aviadobio Limited

Address

20 Water Street

City

London

Postcode

E14 5GX

Country

United Kingdom

Scientific contact point

Organisation

Aviadobio Limited

Contact name

Technical Operations

Public contact point

Organisation

Aviadobio Limited

Contact name

AviadoBio Clinical Trials

Third parties 9

Locations

6 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 158 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications