Clinical trial NCT05164471: Phase 1/2 Dose Confirmation Study of FLT180a in Hemophilia B
Official title: A Dose Confirmation Study of FLT180a (Adeno-associated Viral Vector Containing the Padua Variant of a Codon-optimized Human Factor IX Gene) in Adult Subjects With Hemophilia B
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Hemophilia B
Lead sponsor: Spur Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-12-20
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: Study of FLT180a gene therapy in adults with Hemophilia B. Up to 9 patients will be enrolled to receive a single dose of FLT180a and be followed for 52 weeks. Results will confirm the dose for a future Phase 3 study.


Eligibility criteria: Key Inclusion Criteria:

* Diagnosis of Hemophilia B with known severe or moderately severe FIX deficiency (≤2% normal circulating FIX activity) for which the subject is on continuous, stable and adequate FIX prophylaxis
* Have acceptable laboratory values of a) Hemoglobin ≥11g/dL; b) Platelets ≥100,000 cells/µL; c) AST, ALT and alkaline phosphatase (ALP) ≤ upper limit of normal (ULN); d) Serum albumin \> lower limit of normal (LLN); e) Total bilirubin ≤1.5 x ULN (except if caused by Gilbert's disease); f) Serum creatinine ≤2.0mg/dL.
* Level of neutralizing anti-AAV-S3 antibodies below the limit of the pre-established clinical cutoff using an in vitro transduction inhibition assay within the 4 weeks prior to FLT180a administration
* Has demonstrated ability to accurately, independently and in a timely manner enter bleed diary data during the lead-in study, as judged by the investigator
* At least 150 exposure days to FIX concentrates
* At least 6 months of satisfactory controlled prospective baseline data for bleeding events and FIX consumption data from the FLT-01 lead-in study (ECLIPSE)

Key Exclusion Criteria:

* Any history of alcohol or drug dependence
* Presence of neutralizing anti human FIX antibodies (inhibitor; determined by the Nijmegen modified Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor
* Subjects at high risk of thromboembolic events
* Evidence of advanced liver fibrosis
* Prior treatment with a gene transfer medicinal product
* Subjects with active hepatitis B or C
* Serological evidence of HIV-1, not controlled with anti-viral therapy and as evidenced by cluster of differentiation 4 (CD4)+ counts ≤200 μL
* Cytomegalovirus (CMV) immunoglobulin G positive subjects who are CMV polymerase chain reaction (PCR) positive at screening
* Known coagulation disorder other than hemophilia B
* High sensitivity (hs) troponin-T ≥14 pg/mL during screening
* History of uncontrolled cardiac failure, unstable angina, or myocardial infarction or other acute cardiac conditions requiring clinical management in the past 6 months
* Planned surgical procedure within the next 12 months requiring prophylactic FIX treatment
* Known active severe infection (including documented coronavirus (COVID)-19 infection), or any other significant concurrent, uncontrolled medical condition

Primary outcomes:
measure: Safety and tolerability of FLT180a as assessed by incidence and severity of AEs and SAEs
timeFrame: Post-dose through week 52
measure: Assessment of FIX activity levels to allow dose confirmation for future Phase 3 study
timeFrame: Assessment at Day 21 post-dose
measure: Assessment of FIX activity levels to allow dose confirmation for future Phase 3 study
timeFrame: Assessment at Day 140 post-dose
measure: Assessment of FIX activity levels to allow dose confirmation for future Phase 3 study
timeFrame: Assessment at Day 182 post-dose
Secondary outcomes:
measure: Assessment of change in annualized bleeding rate (ABR)
timeFrame: Pre-dose and Week 52 post-dose
measure: Assessment of change in annualized FIX concentrate consumption
timeFrame: Pre-dose and Week 52 post-dose
measure: Proportion of subjects achieving FIX activity level above 40%
timeFrame: Week 26
measure: The proportion of subjects remaining free from continuous routine FIX prophylaxis
timeFrame: Post dose through week 52
measure: The proportion of subjects achieving a FIX activity level between 50-150%
timeFrame: Pre-dose and Week 52
measure: Assessment of health-related Quality of Life Questionnaire (measuring physical health, feelings, sport and leisure, dealing with haemophilia treatment) (Haem-A-QoL questionnaire)
timeFrame: Pre-dose and Weeks 26, 52 post-dose
measure: Joint bleeding rates
timeFrame: Pre-dose and Week 52
measure: Spontaneous bleeding rates
timeFrame: Pre-dose and Week 52
measure: Number of target joints
timeFrame: Pre-dose and Week 52
measure: Assessment of Quality of Life Questionnaire (measuring mobility, self-care, usual activities, pain/discomfort & anxiety/depression)(EQ-5D-5L questionnaire).
timeFrame: Pre-dose and Weeks 26, 52 post-dose
measure: Measurement of Anti-AAVS3 antibodies and neutralizing antibodies
timeFrame: Pre-dose, Week 4 and Week 26
measure: Evaluation of AAVS3 capsid-specific T-cell reactions
timeFrame: Pre-dose, Week 4 and Week 26
measure: Abnormal or change from baseline findings for liver ultrasound
timeFrame: Pre-dose and Week 52
measure: Abnormal or change from baseline findings for serum alpha-fetoprotein (AFP) levels.
timeFrame: Pre-dose and Week 52
measure: FIX inhibitor level
timeFrame: Pre-dose through Week 52
measure: Use of immunosuppressants (dose and duration per participant) for the prevention and treatment of increased Liver Enzymes
timeFrame: Pre-dose through Week 52
measure: Clearance of vector genomes in plasma and semen as assessed by PCR test
timeFrame: Pre-dose through Week 52
measure: Assessment of Clinically significant changes in 12-lead ECG
timeFrame: Pre-dose through Week 26
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: London
country: United Kingdom
facility: Guys Hospital
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Tust
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
Study officials:
References: