RECRUITING

A Study of PBFT02 in Participants With FTD and Mutations in the Granulin Precursor (GRN) or C9ORF72 Genes

Conditions

Frontotemporal Dementia FTD FTD-GRN Dementia Frontotemporal C9orf72 Progranulin Mutations Gene Therapy Dementia Gene Therapy AAV1 Fronto-temporal Dementia

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

PBFT02 is a gene therapy for frontotemporal dementia intended to deliver a functional copy of the GRN gene to the brain. This study will assess the safety, tolerability and efficacy of this treatment in patients with frontotemporal dementia and mutations in the granulin precursor (GRN) or chromosome 9 open reading frame 72 (C9ORF72) genes

Official Title

A Phase 1b Open-Label, Multicenter, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacodynamic Effects of a Single Dose of PBFT02 Delivered Into the ICM of Adults With FTD and Mutations in the GRN or C9ORF72 Genes

Quick Facts

Study Start:2021-09-14

Study Completion:2031-08

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT04747431

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:35 Years to 75 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Documented to be a pathogenic carrier of GRN or C9orf72 mutation 2. Clinical diagnosis of frontotemporal dementia 3. Have a reliable informant / caregiver (and back-up informant / caregiver) who personally speaks with or sees the subject at least weekly 4. Living in the community (i.e., not in a nursing home); assisted living may be permitted at the discretion of the investigator	1. Classification of the GRN mutation as "not pathogenic," "likely benign variant," "benign variant," or "pathogenic nature unclear" (FTD- GRN Cohorts 1-3) or C9orf72 HRE length ≤ 30 (FTD-C9orf72 Cohorts 4-5). 2. Previous treatment with any gene therapy. Any other therapies with the potential to alter PGRN levels must be washed out for at least 5 half-lives prior to entry into this study 3. Homozygous GRN mutation carrier (FTD-GRN Cohorts 1-3) or homozygous C9orf72 mutation carrier (FTD-C9orf72 Cohorts 4-5). 4. Rosen-modified Hachinski Ischemic Scale score \> 7 5. Known presence of a structural brain lesion (eg, tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic subject 6. Known presence of an AD-causing mutation in PSEN1, PSEN2 or APP based on genetic testing history (if performed) 7. Previous history of Korsakoff encephalopathy, severe alcohol or substance dependence (within 5 years of onset of dementia), except where onset of increased alcohol consumption occurs at the time of FTD disease onset 8. History of untreated vitamin B12 deficiency 9. Presence of untreated hypothyroidism (thyroid stimulating hormone \[TSH\] \> ULN and free T4 \< LLN) 10. eGFR ≤ 30 ml/min (as calculated using the CKD-EPI equation) 11. Alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \> 2 × ULN, or total bilirubin \> ULN) 12. Respiratory failure that requires supplemental oxygen, tracheostomy, or reliance on non-invasive ventilation for \>2 hours during waking hours 13. Inability to provide full consent or the lack of a legally authorized caregiver with adequate contact who can provide consent 14. Any contraindication to MRI or lumbar puncture (LP) (eg, local infection, history of thrombocytopenia, coagulopathy) 15. Any contraindication to the ICM administration procedure 16. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from ICM injection, anesthesia, LP, and/or MRI (e.g., fever, hypoxia, tachycardia, or evidence of active infection) 17. Immunocompromised status 18. Peripheral axonal sensory neuropathy 19. Receipt of a vaccine within 14 days of dosing 20. A positive test result for human immunodeficiency virus (HIV), human T cell leukemia virus (HTLV) type 1 or type 2, or Hepatitis B or C; a Mycobacterium tuberculosis positive test within 1 year of or determined at screening 21. Malignant neoplasia (except localized skin cancer) or a documented history of hereditary cancer syndrome 22. Any concurrent disease that, in the opinion of the investigator, may cause cognitive impairment unrelated to GRN or C9orf72 mutations, including other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin deficiency 23. Current or recent history of clinically significant suicidal ideation within the past 6 months 24. For women of childbearing potential, a positive serum pregnancy test at the screening visit, a positive serum result on Day 1 prior to administration of the investigational product, or unwillingness to have additional pregnancy tests during the study. Women of childbearing potential must use a highly effective method of birth control or engage in abstinence until 90 days postdose 25. Women who are breastfeeding 26. For sexually active men, unwillingness to use a medically accepted method of double-barrier contraception (such as a condom/diaphragm used with spermicide) or engage in abstinence from the date of screening until 90 days postdose 27. Any condition (eg, history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would put the subject at undue risk or would interfere with evaluation of the investigational product or interpretation of subject safety or study results 28. Any acute illness requiring hospitalization within 30 days of enrollment 29. Failure to meet the protocol-specified coagulation test criteria: * Platelet count \> 100,000 per uL * INR \< 1.5 * aPTT \< 40 seconds 30. Use of anticoagulants in the 2 weeks prior to screening, or anticipated use of anticoagulants during the study. Antiplatelet therapies may be acceptable 31. Hypersensitivity or contraindications to corticosteroid use 32. Known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds 33. ALSFRS-R \< 35 at screening. 34. ALSFRS-R score declining at a rate \> 0.4 unit/month from diagnosis to the screening assessment. 35. SVC \< 75% of predicted normal adjusted for sex, age, and height (from the sitting position). 36. Bulbar-onset ALS. 37. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period. 38. If taking riluzole or edaravone, participant's dose has not been stable for ≥ 30 days prior to Day 1 and/or dose adjustments are anticipated before the Day 60 study visit.

Inclusion Criteria

Exclusion Criteria

1. Documented to be a pathogenic carrier of GRN or C9orf72 mutation
2. Clinical diagnosis of frontotemporal dementia
3. Have a reliable informant / caregiver (and back-up informant / caregiver) who personally speaks with or sees the subject at least weekly
4. Living in the community (i.e., not in a nursing home); assisted living may be permitted at the discretion of the investigator

1. Classification of the GRN mutation as "not pathogenic," "likely benign variant," "benign variant," or "pathogenic nature unclear" (FTD- GRN Cohorts 1-3) or C9orf72 HRE length ≤ 30 (FTD-C9orf72 Cohorts 4-5).
2. Previous treatment with any gene therapy. Any other therapies with the potential to alter PGRN levels must be washed out for at least 5 half-lives prior to entry into this study
3. Homozygous GRN mutation carrier (FTD-GRN Cohorts 1-3) or homozygous C9orf72 mutation carrier (FTD-C9orf72 Cohorts 4-5).
4. Rosen-modified Hachinski Ischemic Scale score \> 7
5. Known presence of a structural brain lesion (eg, tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic subject
6. Known presence of an AD-causing mutation in PSEN1, PSEN2 or APP based on genetic testing history (if performed)
7. Previous history of Korsakoff encephalopathy, severe alcohol or substance dependence (within 5 years of onset of dementia), except where onset of increased alcohol consumption occurs at the time of FTD disease onset
8. History of untreated vitamin B12 deficiency
9. Presence of untreated hypothyroidism (thyroid stimulating hormone \[TSH\] \> ULN and free T4 \< LLN)
10. eGFR ≤ 30 ml/min (as calculated using the CKD-EPI equation)
11. Alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \> 2 × ULN, or total bilirubin \> ULN)
12. Respiratory failure that requires supplemental oxygen, tracheostomy, or reliance on non-invasive ventilation for \>2 hours during waking hours
13. Inability to provide full consent or the lack of a legally authorized caregiver with adequate contact who can provide consent
14. Any contraindication to MRI or lumbar puncture (LP) (eg, local infection, history of thrombocytopenia, coagulopathy)
15. Any contraindication to the ICM administration procedure
16. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from ICM injection, anesthesia, LP, and/or MRI (e.g., fever, hypoxia, tachycardia, or evidence of active infection)
17. Immunocompromised status
18. Peripheral axonal sensory neuropathy
19. Receipt of a vaccine within 14 days of dosing
20. A positive test result for human immunodeficiency virus (HIV), human T cell leukemia virus (HTLV) type 1 or type 2, or Hepatitis B or C; a Mycobacterium tuberculosis positive test within 1 year of or determined at screening
21. Malignant neoplasia (except localized skin cancer) or a documented history of hereditary cancer syndrome
22. Any concurrent disease that, in the opinion of the investigator, may cause cognitive impairment unrelated to GRN or C9orf72 mutations, including other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin deficiency
23. Current or recent history of clinically significant suicidal ideation within the past 6 months
24. For women of childbearing potential, a positive serum pregnancy test at the screening visit, a positive serum result on Day 1 prior to administration of the investigational product, or unwillingness to have additional pregnancy tests during the study. Women of childbearing potential must use a highly effective method of birth control or engage in abstinence until 90 days postdose
25. Women who are breastfeeding
26. For sexually active men, unwillingness to use a medically accepted method of double-barrier contraception (such as a condom/diaphragm used with spermicide) or engage in abstinence from the date of screening until 90 days postdose
27. Any condition (eg, history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would put the subject at undue risk or would interfere with evaluation of the investigational product or interpretation of subject safety or study results
28. Any acute illness requiring hospitalization within 30 days of enrollment
29. Failure to meet the protocol-specified coagulation test criteria:
* Platelet count \> 100,000 per uL
* INR \< 1.5
* aPTT \< 40 seconds
30. Use of anticoagulants in the 2 weeks prior to screening, or anticipated use of anticoagulants during the study. Antiplatelet therapies may be acceptable
31. Hypersensitivity or contraindications to corticosteroid use
32. Known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds
33. ALSFRS-R \< 35 at screening.
34. ALSFRS-R score declining at a rate \> 0.4 unit/month from diagnosis to the screening assessment.
35. SVC \< 75% of predicted normal adjusted for sex, age, and height (from the sitting position).
36. Bulbar-onset ALS.
37. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.
38. If taking riluzole or edaravone, participant's dose has not been stable for ≥ 30 days prior to Day 1 and/or dose adjustments are anticipated before the Day 60 study visit.

Contacts and Locations

Study Contact

Patient/Family Inquiries

CONTACT

267-866-0113

patientservices@passagebio.com

Physician Inquiries

CONTACT

medinfo@passagebio.com

Principal Investigator

Tiffini Voss, MD, PhD

STUDY_DIRECTOR

Passage Bio, Inc.

Study Locations (Sites)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104

United States

University of Texas at Houston

Houston, Texas, 77030

United States

Collaborators and Investigators

Sponsor: Passage Bio, Inc.

Tiffini Voss, MD, PhD, STUDY_DIRECTOR, Passage Bio, Inc.

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2021-09-14

Study Completion Date2031-08

Study Record Updates

Study Start Date2021-09-14

Study Completion Date2031-08

Terms related to this study

Keywords Provided by Researchers

frontotemporal dementia
Progranulin Mutations
FTD-GRN
Gene Therapy
Dementia Gene Therapy
AAV1
Fronto-temporal Dementia
C9orf72

Additional Relevant MeSH Terms

Frontotemporal Dementia
FTD
FTD-GRN
Dementia Frontotemporal
C9orf72