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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03454893
Registration number
NCT03454893
Ethics application status
Date submitted
20/12/2017
Date registered
6/03/2018
Date last updated
5/01/2024
Titles & IDs
Public title
Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease
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Scientific title
An Open-Label, Multinational Study Of The Efficacy And Safety of Ex Vivo, Lentiviral Vector-Mediated Gene Therapy AVR-RD-01 For Treatment-Naive Subjects With Classic Fabry Disease
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Secondary ID [1]
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AVRO-RD-01-201
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Fabry Disease
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Condition category
Condition code
Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Metabolic and Endocrine
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Metabolic disorders
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Metabolic and Endocrine
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Other metabolic disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - AVR-RD-01
Experimental: Single Assignment AVR-RD-01 - AVR-RD-01 is an autologous CD34+-enriched cell fraction transduced with LV/AGA containing an RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into the human genome, encodes for functional human AGA.
Treatment: Drugs: AVR-RD-01
Single IV infusion of between 3 - 20 x 10^6 CD34+ cells/kg.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
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Assessment method [1]
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An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The AE/SAE are also inclusive of any abnormalities in Clinical Laboratory Tests, Vital Signs and in Electrocardiographs (ECGs). Of the 13 serious adverse events, no SAEs reported were considered related to AVR RD 01. Of the 354 adverse events, no AEs were considered related to AVR RD 01. The SAEs and AEs reported in the study were attributed to the conditioning agent used, the underlying disease, comorbid conditions, study procedures and concomitant medications.
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Timepoint [1]
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Baseline to Week 48 post gene therapy
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Primary outcome [2]
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Change From Baseline in Immunogenicity of AVR-RD-01
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Assessment method [2]
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Number of subjects with changes in anti-AGA antibodies from Baseline to post infusion timepoints. Unite of measure: Number of subjects negative at baseline but positive at post-treatment timepoints. A negative or zero result (titer lower or unchanged at post-infusion timepoints compare to Baseline) indicates no immune response to the therapeutic protein.
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Timepoint [2]
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Baseline to Week 48 post gene therapy
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Primary outcome [3]
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Presence of Replication Competent Lentivirus (RCL)
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Assessment method [3]
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The "Presence of RCL" is a theoretical risk of lentiviral gene therapy treatment based on the theory that it may be possible for inadvertent generation of RCL caused either by recombination of the lentiviral vector plasmids during the vector production process or by mobilization of proviral DNA in vivo by infectious retroviruses (HIV). The absence of RCL is a positive indicator of safety.
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Timepoint [3]
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Baseline to Week 48 post gene therapy
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Primary outcome [4]
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Evaluation of Aberrant Clonal Expansion
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Assessment method [4]
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Integration Site Analysis (ISA) uses next generation sequencing to identify junction sites between the integrated therapeutic transgene and the host genome. Samples are analyzed for the emergence of clonality (defined as (a single clone accounting for greater than 20% of the population) and whether any integration site is within or near a known oncogene.
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Timepoint [4]
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Baseline to Week 48 post gene therapy
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Primary outcome [5]
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Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject
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Assessment method [5]
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Globotriaosylceramide (Gb3) Inclusions in Peritubular Capillaries (PTC) on Kidney Biopsy. Electron microscopic images of kidney biopsy samples were taken and read centrally by two independent renal pathologists, each of whom scored the average number of Gb3 inclusions per kidney PTC per subject using a quantification method. Healthy renal tissue would have no Gb3 inclusions. A reduction from baseline is desirable.
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Timepoint [5]
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Baseline to Week 48 post gene therapy
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Secondary outcome [1]
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Average Vector Copy Number (VCN) in Peripheral Blood Leukocytes as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)
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Assessment method [1]
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Vector Copy Number (VCN) is a measurement of the number of copies of the therapeutic transgene found in a sample, relative to copies of a reference gene in the human genome. This is an estimate of the number of integration sites per cell (on average). A VCN of 1 would signify that a sample of cells evaluated contains on average at least one [working] copy of the therapeutic transgene per cell.
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Timepoint [1]
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At Week 24 and Week 48 post gene therapy
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Secondary outcome [2]
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Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs)
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Assessment method [2]
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Treatment-naïve Fabry patients are deficient in alpha-galactosidase A (AGA) enzyme activity due to mutations in the GLA gene. Any therapeutic option offered should aim to increase the amount of available AGA enzyme. This assay measured the AGA enzyme activity levels in plasma and PBLs. It should be noted that the measurement in plasma reflects the amount of "free" AGA enzyme that has been released from cells into the extracellular space and is therefore considered a more indirect measure of AGA enzyme activity, compared to the result in PBLs which is more of a direct measure of enzyme within cells. In both cases, enzyme activity is expected to increase from Baseline to the post-infusion timepoints.
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Timepoint [2]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [3]
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Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma
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Assessment method [3]
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Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in plasma. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of circulating Gb3 in plasma.
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Timepoint [3]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [4]
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Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine
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Assessment method [4]
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Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in urine. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of excreted Gb3 in urine.
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Timepoint [4]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [5]
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Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy
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Assessment method [5]
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Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in tissue samples. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of measured Gb3 in tissues.
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Timepoint [5]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [6]
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Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR)
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Assessment method [6]
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mGFR is a measure of the time the kidney takes to filter products that the body does not naturally produce.
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Timepoint [6]
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Baseline to Week 48 post gene therapy
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Secondary outcome [7]
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Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR)
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Assessment method [7]
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eGFR is the measure to evaluate kidney function. It is the estimated amount of blood that is filtered through all glomeruli in a given time.
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Timepoint [7]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [8]
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Change From Baseline in Renal Function as Assessed by Urine Total Protein Levels
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Assessment method [8]
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Timepoint [8]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [9]
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Change From Baseline in Renal Function as Assessed by Urine Albumin Levels
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Assessment method [9]
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A healthy kidney only allows very small amounts of albumin to pass from the blood into the urine. An increased level of albumin in urine (albuminuria) is a marker of renal damage.
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Timepoint [9]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [10]
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Change From Baseline in Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI)
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Assessment method [10]
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LVMI is a surrogate of left ventricular hypertrophy. An increase in LVMI is an independent risk factor for cardiovascular morbidity and mortality.
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Timepoint [10]
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Baseline to Week 48 post gene therapy
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Secondary outcome [11]
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Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D)
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Assessment method [11]
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DIBSS-D assesses bowel habits and abdominal symptoms over a period of time. It was administered daily for 14 days commencing at each study visit.
Stool Consistency scale has been converted to a numeric rating scale for ease of analysis, where 1=Very hard; 2=Hard; 3=Neither too hard nor too soft; 4=Loose but not lumpy; 5=Very loose and watery. The median of each 14-day period was derived per patient, per visit before deriving the group median. Group median at Baseline (pre-treatment) was 3.540 (n=9). Change from baseline (CFB) is presented below. An increase CFB indicates softening of the stools, and a decrease CFB indicates hardening of the stools. Abdominal Pain measure asked the patient to rate the worst level of pain within the past 24hrs (0=no pain; 10=worst possible pain). A mean score was derived for each 14-day period per patient, per visit, and these means used to derive a group mean. An increase CFB indicates more abdominal pain; a decrease CFB indicates less abdominal pain.
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Timepoint [11]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [12]
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Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores
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Assessment method [12]
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The short version of the BPI (Short form) includes 9 items: Q1 - Q9, Question 9 includes 7 sub-items (Q9a - Q9g). It uses a 0 to 10 numeric rating scales for item rating. The pain severity score is calculated as the average of questions answered: Q3 (worst pain), Q4 (least pain), Q5 (average pain) and Q6 (current pain). The pain interference score is calculated as the average of the answered Q9 sub-items, which represents pain interference with general activity (Q9a), mood (Q9b), walking ability (Q9c), normal work (Q9d), relations with other people (Q9e), sleep (Q9f), and enjoyment of life (Q9g). A reduction in score from baseline indicates less pain.
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Timepoint [12]
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Baseline to Week 24 and Week 48 post gene therapy
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Secondary outcome [13]
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Change From Baseline in Physical and Mental Functioning as Assessed by the Short Form 36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores
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Assessment method [13]
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The original version of the SF-36 was administered to the participants and consisted of eight subscales (Vitality, Physical Functioning, Bodily Pain, General Health Perceptions, Physical Role Functioning, Emotional Role Functioning, Social Role Functioning and Mental Health) each scored from 0 (worst health) to 100 (best heath). These scores were normalized (re-scaled) against mean scores obtained in the US general population (Mean=50, Standard deviation 10). The summary health components PCS and MCS are derived from the eight subscales mentioned above and summarize information from all eight subscales but with different weights. For PCS, highest weights are given to the physical subscales while some mental subscales are given negative weights. For MCS, highest weights are given to the mental subscales while some physical subscales are given negative weights. An increase in the normalized score from baseline indicates improvement in physical and mental functioning.
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Timepoint [13]
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Baseline to Week 48 post gene therapy
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Secondary outcome [14]
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Average Vector Copy Number (VCN) in Bone Marrow / Progenitor Cells as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)
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Assessment method [14]
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VCN is defined as the average number of copies of the therapeutic gene (transgene) in a sample of cells and is a measurement of the number of copies of the vector found in a sample, relative to copies of a reference gene in the human genome. This is an estimate of the number of integration sites per cell (on average). A VCN of 1 would signify that a sample of cells evaluated contains on average at least one [working] copy of the therapeutic transgene per cell. This measurement was for VCN in a sample of Bone marrow progenitor cells obtained from an aspirate.
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Timepoint [14]
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At Week 48 post gene therapy
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Eligibility
Key inclusion criteria
1. Subject was male, 16 years of age or older (18 years of age or older in the US), and
post pubertal,(minimum age by region)
2. Subject had a confirmed diagnosis of classic Fabry disease based on deficient AGA
enzyme activity (defined as < 1% of normal).
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Minimum age
16
Years
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Maximum age
50
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Sex
Males
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Subject had a galactosidase alpha (GLA) gene mutation associated with late-onset
cardiac variant Fabry disease.
2. Subject had previously received ERT and/or chaperone therapy within 3 years for
treatment of Fabry disease.
3. Subject had tested positive for anti-AGA antibodies at the time of screening.
4. Subject had eGFR < 60 mL/min/1.73 m² (ie, chronic kidney disease [CKD] stage = 3) at
Screening.
5. Subject had a prior history of myocardial infarction (MI).
6. Subject had a history of coronary artery disease (CAD) with angina requiring
percutaneous transluminal coronary angioplasty (with or without stent placement)
and/or coronary artery bypass graft (CABG).
7. Subject had a history of moderate to severe valvular heart disease requiring valve
replacement.
8. Subject had a history of heart failure, moderate to severe diastolic dysfunction,
and/or left ventricular ejection fraction (LVEF) = 45% on echocardiogram (ECHO)
performed at rest at Screening.
9. Subject had a history of clinically significant cardiac arrhythmia (eg, heart block
[second or third degree], atrial fibrillation requiring therapy, ventricular
fibrillation, ventricular tachycardia, supraventricular tachycardia, or cardiac
arrest).
Note [history of intermittent atrial fibrillation not requiring treatment was
allowed].
10. Subject had a prior history of stroke and/or transient ischemic attack (TIA).
11. Subject had aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) = 3
times the upper limit of normal (ULN) at Screening.
12. Subject had a prior history of (or current) malignancy; the one exception is a prior
history of resected basal cell carcinoma.
13. Subject had previously received treatment with AVR-RD-01 or any other gene therapy.
Other inclusion/exclusion criteria apply.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
21/02/2018
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
14/03/2022
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Sample size
Target
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Accrual to date
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Final
15
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Recruitment in Australia
Recruitment state(s)
Parkville VI
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Recruitment hospital [1]
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Royal Melbourne Hospital - Melbourne
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Recruitment hospital [2]
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Royal Perth Hospital - Perth
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Recruitment postcode(s) [1]
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- Melbourne
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Recruitment postcode(s) [2]
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- Perth
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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New Jersey
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Country [2]
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United States of America
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State/province [2]
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Pennsylvania
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Country [3]
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Brazil
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State/province [3]
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Rio Grande Do Sul
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
AVROBIO
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This was a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in
approximately 15 male subjects, who were 16 years of age or older and postpubertal with a
confirmed diagnosis of classic Fabry disease based on deficient alpha galactosidase A (AGA)
enzyme activity who were considered treatment naïve, i.e., had not previously received
treatment with enzyme replacement therapy (ERT) and/or chaperone therapy within 3 years of
the time of Screening.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03454893
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Inderpal Panesar, MRPharmS
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Address
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AVROBIO, Inc
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03454893
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