Gene Transfer Clinical Trial for Krabbe Disease (RESKUE)
Primary Purpose
Krabbe Disease
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
FBX-101
Sponsored by
About this trial
This is an interventional treatment trial for Krabbe Disease focused on measuring Lysosomal Storage Disorder, Globoid Cell Leukodystrophy, Leukodystrophy, GALC
Eligibility Criteria
Inclusion Criteria:
Diagnosis of infantile Krabbe disease, characterized by the following criteria outlined below:
- Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of Krabbe disease according to the lab releasing the results; AND AT LEAST ONE OF THE FOLLOWING:
- Elevated psychosine predictive of infantile disease ≥ 9.0 nmol/L; OR
- Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR
- Two predicted pathogenic GALC mutations.
- Age at the time of screening: 1 day to 12 months
- Participant has been deemed eligible for treatment with HSCT (standard of care) or is within two weeks of HSC infusion
- Participant's parents or legal guardian consents to participate in the study and provides informed consent according to IRB guidelines prior to any study procedures being performed
- Parent(s) and/or legal guardian able to comply with the clinical protocol
Participant must have adequate organ function at time of screening as measured by:
- Creatinine ≤ 1.5x upper limit of age appropriate normal and creatinine clearance ≥ 60 mL/min/1.73 m2
- Hepatic transaminases (ALT/AST) ≤ 2x age related upper limit of normal
- Ejection fraction of > 50% by echocardiogram or other appropriate study without evidence of pulmonary hypertension.
- Pulmonary evaluation testing demonstrating resting pulse oximeter > 92% on room air
- Coagulation tests within 110% of normal ranges for age. (PT/INR and PTT)
Exclusion Criteria:
- History of prior treatment with a gene therapy product
- Presence of major congenital anomaly affecting the neurological system
- Presence of any neurocognitive deficit or brain damage not attributable to Krabbe disease
- Active aspiration
- Signs of active infection or disease from cytomegalovirus, adenovirus or other viruses
- HIV positive
- Uncontrolled and progressive bacterial or fungal infection.
- Presence of any contraindication for MRI
- Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions
- Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study
- Ongoing veno-occlusive disease (VOD) as determined by liver ultrasound (moderate ascites and static or retrograde portal vein flow) the day before FBX-101 infusion.
Sites / Locations
- Children's Hospital of Orange County (CHOC)Recruiting
- University of Michigan Hospitals - Michigan Medicine
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC)
Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)
Arm Description
Participants will receive a single infusion at the lower dose (N=3 participants)
Participants will receive a single infusion at the higher dose (N=3 participants)
Outcomes
Primary Outcome Measures
Safety as assessed by incidence and severity of adverse events and serious adverse events that are attributed to FBX-101.
Safety as assessed by HSCT incident of engraftment.
Secondary Outcome Measures
Efficacy as assessed by improvement of probability to achieve independent sitting compared to untreated patients or those receiving HSCT only.
Efficacy as assessed by improvement of gross motor function as measured by Peabody Developmental Motor Scale 2nd Edition (PDMS-2) above a functional age equivalent of 12 months compared to untreated patients or those receiving HSCT only
Full Information
NCT ID
NCT04693598
First Posted
December 30, 2020
Last Updated
September 1, 2023
Sponsor
Forge Biologics, Inc
1. Study Identification
Unique Protocol Identification Number
NCT04693598
Brief Title
Gene Transfer Clinical Trial for Krabbe Disease
Acronym
RESKUE
Official Title
A Phase 1/2 Clinical Study of Intravenous Gene Transfer With an AAVrh10 Vector Expressing GALC in Krabbe Subjects Receiving Hematopoietic Stem Cell Transplantation (RESKUE)
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 5, 2021 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Forge Biologics, Inc
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a nonblinded, non-randomized dose escalation study of intravenous AAVrh10 after hematopoietic stem cell transplantation (HSCT) in which subjects will receive standard of care hematopoietic cell transplantation for Krabbe disease, followed by a single infusion of an adeno-associated virus gene therapy product. Extensive natural history subjects will be used to compare as control group.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Krabbe Disease
Keywords
Lysosomal Storage Disorder, Globoid Cell Leukodystrophy, Leukodystrophy, GALC
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
Dose escalation study from a low dose to a high dose following safety review
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
6 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC)
Arm Type
Experimental
Arm Description
Participants will receive a single infusion at the lower dose (N=3 participants)
Arm Title
Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)
Arm Type
Experimental
Arm Description
Participants will receive a single infusion at the higher dose (N=3 participants)
Intervention Type
Biological
Intervention Name(s)
FBX-101
Other Intervention Name(s)
AAVrh.10-hGALC
Intervention Description
A replication-deficient adeno-associated virus gene transfer vector expressing the human galactocerebrosidase (GALC) cDNA will be delivered one-time through a venous catheter inserted into a peripheral limb vein.
Primary Outcome Measure Information:
Title
Safety as assessed by incidence and severity of adverse events and serious adverse events that are attributed to FBX-101.
Time Frame
24 months
Title
Safety as assessed by HSCT incident of engraftment.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Efficacy as assessed by improvement of probability to achieve independent sitting compared to untreated patients or those receiving HSCT only.
Time Frame
12 months and 24 months
Title
Efficacy as assessed by improvement of gross motor function as measured by Peabody Developmental Motor Scale 2nd Edition (PDMS-2) above a functional age equivalent of 12 months compared to untreated patients or those receiving HSCT only
Time Frame
24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
12 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of infantile Krabbe disease, characterized by the following criteria outlined below:
Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of Krabbe disease; AND AT LEAST ONE OF THE FOLLOWING:
Elevated psychosine levels predictive of infantile disease onset by DBS; OR
Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR
Two GALC mutations predictive to result in infantile onset phenotype.
Age at the time of screening: 1 day to 12 months
Participant has been deemed eligible for treatment with HSCT (standard of care) and a fully myeloablative reduced intensity/toxicity conditioning regimen (RIC/RTC) is/has been used
Participant's parents or legal guardian consents to participate in the study and provides informed consent according to IRB guidelines prior to any study procedures being performed
Parent(s) and/or legal guardian able to comply with the clinical protocol
Participant must have adequate organ function at time of screening as measured by:
Creatinine ≤ 1.5x upper limit of age appropriate normal and creatinine clearance ≥ 60 mL/min/1.73 m2
Hepatic transaminases (ALT/AST) ≤ 2x age related upper limit of normal
Ejection fraction of > 50% by echocardiogram or other appropriate study without evidence of pulmonary hypertension
Pulmonary evaluation testing demonstrating resting pulse oximeter > 95% on room air
Coagulation tests within 110% of normal ranges for age. (PT/INR and PTT)
Exclusion Criteria:
History of prior treatment with a gene therapy product
Presence of major congenital anomaly or any other condition that affects neurodevelopmental function
Presence of any neurocognitive deficit or brain damage not attributable to Krabbe disease
Active aspiration
Signs of active infection or disease from cytomegalovirus, adenovirus or other viruses
HIV positive
Uncontrolled and progressive bacterial or fungal infection
Presence of any contraindication for MRI
Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions
Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study
Ongoing veno-occlusive disease (VOD) as determined by liver ultrasound (moderate ascites and static or retrograde portal vein flow) the day before FBX-101 infusion.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michelle Salvo
Phone
380-239-2013
Email
advocacy@forgebiologics.com
Facility Information:
Facility Name
Children's Hospital of Orange County (CHOC)
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mai Ngo
Phone
714-509-8423
Email
pngo@choc.org
First Name & Middle Initial & Last Name & Degree
David Buchbinder, MD
Phone
310-985-3983
Email
dbuchbinder@choc.org
First Name & Middle Initial & Last Name & Degree
David Buchbinder, MD
Facility Name
University of Michigan Hospitals - Michigan Medicine
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Individual Site Status
Active, not recruiting
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
There is no plan to share data
Links:
URL
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083585/
Description
Bascou, N., DeRenzo, A., Poe, M. & Escolar, M., 2018. A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life. Orphanet Journal of Rare Diseases, pp. 1-17.
URL
https://pubmed.ncbi.nlm.nih.gov/30777126/
Description
Beltran-Quintero, M. et al., 2019. Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months. Orphanet Journal of Rare Diseases, pp. 1-13.
URL
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066194/
Description
Bradbury, A. et al., 2018. AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease). Human Gene Therapy, pp. 785-801.
URL
https://pubmed.ncbi.nlm.nih.gov/15901860/
Description
Escolar, M. et al., 2005. Transplantation of Umbilical-Cord Blood in Babies with Infantile Krabbe's Disease. The New England Journal of Medicine, pp. 2069-2081.
URL
https://pubmed.ncbi.nlm.nih.gov/27638597/
Description
Escolar, M. et al., 2016. Clinical management of Krabbe disease. Journal of Neuroscience Research, pp. 1118-1125.
URL
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186542/
Description
Rafi, M., Luzi, P. & Wenger, D., 2020. Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. BioImpacts, pp. 105-115.
URL
https://ashpublications.org/blood/article/137/13/1719/474073/Long-term-neurodevelopmental-outcomes-of
Description
Yoon, I., et al., 2021. Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease. Blood, pp. 1719-1730
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Gene Transfer Clinical Trial for Krabbe Disease
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