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AVROBIO has deprioritized its Fabry disease program
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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.
The duration of each subject's participation in this study was approximately 64 weeks (or 1 year, 12 weeks), comprised of five study periods (Screening, Baseline, Pre-transplant, Transplant, and Post-transplant Follow-up). During the Screening Period (approximately 8 weeks), written informed consent (and assent, if applicable) was obtained and the subject had completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, the subjects entered the Baseline Period (up to 3 days) during which time assessments would have been performed to establish a pre-transplant baseline. Once baseline assessments were completed, the subject entered the Pre-transplant Period (approximately 6 weeks) during which time mobilization, apheresis, AVR-RD-01 investigational drug product preparation and testing for release, and conditioning regimen administration to achieve myeloablation took place. Following completion of the Pre-transplant Period, the subject entered the Transplant Period (1 day) during which time AVR-RD-01 infusion took place. After AVR-RD-01 infusion, the subject entered the Post-transplant Follow-up Period (approximately 48 weeks), during which time periodic safety and efficacy assessments were performed to assess measures of engraftment, clinical response, and safety post-transplant.
In January 2022, the study was terminated early due to a decision by the study sponsor, to deprioritize its Fabry disease development program, and therefore, some subjects (n=5) did not complete the study (i.e., Week 48). Subsequently, in August 2023, the long-term follow-up study (AVRO-RD-01-LTF01), was also terminated early due to the decision by the sponsor to terminate the development program for Fabry disease, and therefore, no subjects completed the 15-year long-term follow-up study. This decision to terminate was not based on any safety or medical reasons.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Single Assignment AVR-RD-01 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AVR-RD-01 | Drug | Single IV infusion of between 3 - 20 x 10^6 CD34+ cells/kg. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline to Week 48 post gene therapy |
| Change From Baseline in Immunogenicity of AVR-RD-01 | 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. | Baseline to Week 48 post gene therapy |
| Presence of Replication Competent Lentivirus (RCL) | 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. | Baseline to Week 48 post gene therapy |
| Evaluation of Aberrant Clonal Expansion | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | 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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Inclusion Criteria:
Exclusion Criteria:
Subject had a galactosidase alpha (GLA) gene mutation associated with late-onset cardiac variant Fabry disease.
Subject had previously received ERT and/or chaperone therapy within 3 years for treatment of Fabry disease.
Subject had tested positive for anti-AGA antibodies at the time of screening.
Subject had eGFR < 60 mL/min/1.73 m² (ie, chronic kidney disease [CKD] stage ≥ 3) at Screening.
Subject had a prior history of myocardial infarction (MI).
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).
Subject had a history of moderate to severe valvular heart disease requiring valve replacement.
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.
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].
Subject had a prior history of stroke and/or transient ischemic attack (TIA).
Subject had aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) at Screening.
Subject had a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma.
Subject had previously received treatment with AVR-RD-01 or any other gene therapy.
Other inclusion/exclusion criteria apply.
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| Name | Affiliation | Role |
|---|---|---|
| Inderpal Panesar, MRPharmS | AVROBIO, Inc | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hackensack University Medical Center | Hackensack | New Jersey | 07601 | United States | ||
| University of Pittsburgh Medical Center |
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Total number of subjects who signed the ICF was 16 (one subject who re-screened was not considered enrolled initially), as a result there were 15 distinct subjects who signed ICF. There were 4 participants who failed screening and were not rescreened.
The Safety population consists of all 11 enrolled subjects who received any preparatory medication.
The Infused population consists of all 9 enrolled subjects who received all preparatory medications and AVR-RD-01.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. Drug: AVR-RD-01 Single IV infusion of between 3 - 20 x 10^6 CD34+ cells/kg |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety population consists of all enrolled subjects who received any preparatory medication.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. Drug: AVR-RD-01 Single IV infusion of between 3 - 20 x 10^6 CD34+ cells/kg. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | The Safety population consists of all enrolled subjects who received any preparatory medication. | Posted | Number | Number of events | Baseline to Week 48 post gene therapy |
|
Up to week 48
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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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. Drug: AVR-RD-01 Single IV infusion of between 3 - 20 x 10^6 CD34+ cells/kg. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | Systematic Assessment |
SF-36 data at W24 was inadvertently not collected due to omission in the Protocol Schedule of Assessments.
Invasive sampling, such as bone marrow aspirate, was only provided by one subject at Week 48.
Central laboratory only reported albumin levels in urine and not urine total protein data.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| AVROBIO MedInfo | AVROBIO, Inc | 617-914-8419 | medinfo@avrobio.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 1, 2020 | Nov 8, 2023 | Prot_002.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 26, 2023 | Nov 8, 2023 | SAP_003.pdf |
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| ID | Term |
|---|---|
| D000795 | Fabry Disease |
| D016464 | Lysosomal Storage Diseases |
| ID | Term |
|---|---|
| D013106 | Sphingolipidoses |
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
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| Baseline to Week 48 post gene therapy |
| Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject | 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. | Baseline to Week 48 post gene therapy |
| At Week 24 and Week 48 post gene therapy |
| Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs) | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR) | mGFR is a measure of the time the kidney takes to filter products that the body does not naturally produce. | Baseline to Week 48 post gene therapy |
| Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Renal Function as Assessed by Urine Total Protein Levels | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Renal Function as Assessed by Urine Albumin Levels | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI) | LVMI is a surrogate of left ventricular hypertrophy. An increase in LVMI is an independent risk factor for cardiovascular morbidity and mortality. | Baseline to Week 48 post gene therapy |
| Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores | 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. | Baseline to Week 24 and Week 48 post gene therapy |
| 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 | 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. | Baseline to Week 48 post gene therapy |
| 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) | 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. | At Week 48 post gene therapy |
| Pittsburgh |
| Pennsylvania |
| 15213 |
| United States |
| Royal Melbourne Hospital | Melbourne | Parkville VIC | Australia |
| Royal Perth Hospital | Perth | Australia |
| Hospital de Clinicas de Porto Alegre | Porto Alegre | Rio Grande do Sul | Brazil |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Description |
|---|
| OG000 | 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. Drug: AVR-RD-01 Single IV infusion of between 3 - 20 x 10^6 CD34+ cells/kg. |
|
|
| Primary | Change From Baseline in Immunogenicity of AVR-RD-01 | 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. | The infused population includes all enrolled subjects who received preparatory medications and AVR-RD-01. Four tested positive for anti-AGA antibodies post-AVR-RD-01 infusion at Week 48 or Early Termination visit. | Posted | Number | Number of positive subjects | Baseline to Week 48 post gene therapy |
|
|
|
| Primary | Presence of Replication Competent Lentivirus (RCL) | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Number | Number of positive subjects | Baseline to Week 48 post gene therapy |
|
|
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| Primary | Evaluation of Aberrant Clonal Expansion | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Number | number of abnormal clonal proliferations | Baseline to Week 48 post gene therapy |
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| Primary | Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. Of the nine subjects, only 2 subjects had baseline and Week 48 results to measure change from baseline. The remaining seven subjects either did not provide both samples or the samples provided were not evaluable. | Posted | Mean | Full Range | Number of inclusions | Baseline to Week 48 post gene therapy |
|
|
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| Secondary | 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) | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | copies/diploid genome | At Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs) | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | nmol/h/mg | Baseline to Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | nM | Baseline to Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | nmol/mmol creatinine | Baseline to Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | number of myelinosomes | Baseline to Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR) | mGFR is a measure of the time the kidney takes to filter products that the body does not naturally produce. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | mL/min/1.73m^2 | Baseline to Week 48 post gene therapy |
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| Secondary | Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | mL/min/1.73 m^2 | Baseline to Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline in Renal Function as Assessed by Urine Total Protein Levels | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. No data were collected for any subjects since samples were not analyzed in order to produce data (Refer to "Limitations and Caveat" section.") | Posted | Baseline to Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline in Renal Function as Assessed by Urine Albumin Levels | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | mg/dL | Baseline to Week 24 and Week 48 post gene therapy |
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| Secondary | Change From Baseline in Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI) | LVMI is a surrogate of left ventricular hypertrophy. An increase in LVMI is an independent risk factor for cardiovascular morbidity and mortality. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | g/m^2 | Baseline to Week 48 post gene therapy |
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| Secondary | Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | units on a scale | Baseline to Week 24 and Week 48 post gene therapy |
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|
|
| Secondary | Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. | Posted | Mean | Standard Deviation | score on a scale | Baseline to Week 24 and Week 48 post gene therapy |
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|
|
| Secondary | 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 | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. For Week 24 data, please see comment in "Limitations and Caveats" section. | Posted | Mean | Standard Deviation | score on a scale | Baseline to Week 48 post gene therapy |
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| Secondary | 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) | 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. | The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. No analysis performed (refer to "Limitations and Caveats" section) | Posted | Mean | Full Range | copies/diploid genome | At Week 48 post gene therapy |
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|
|
| 0 |
| 11 |
| 8 |
| 11 |
| 11 |
| 11 |
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Odynophagia | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Mucosal inflammation | General disorders | Systematic Assessment |
|
| Pyrexia | General disorders | Systematic Assessment |
|
| Cholelithiasis | Hepatobiliary disorders | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | Systematic Assessment |
|
| Seizure | Nervous system disorders | Systematic Assessment |
|
| Choking | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Lung infiltration | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | Systematic Assessment |
|
| Fabry's disease | Congenital, familial and genetic disorders | Systematic Assessment |
|
| Ear congestion | Ear and labyrinth disorders | Systematic Assessment |
|
| Primary hypogonadism | Endocrine disorders | Systematic Assessment |
|
| Dry eye | Eye disorders | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Anal fissure | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Dental caries | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | Systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | Systematic Assessment |
|
| Haematemesis | Gastrointestinal disorders | Systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | Systematic Assessment |
|
| Hiatus hernia | Gastrointestinal disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Odynophagia | Gastrointestinal disorders | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | Systematic Assessment |
|
| Tooth impacted | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Face oedema | General disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Feeling abnormal | General disorders | Systematic Assessment |
|
| Influenza like illness | General disorders | Systematic Assessment |
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| Injection site induration | General disorders | Systematic Assessment |
|
| Injection site pain | General disorders | Systematic Assessment |
|
| Mucosal inflammation | General disorders | Systematic Assessment |
|
| Nodule | General disorders | Systematic Assessment |
|
| Oedema | General disorders | Systematic Assessment |
|
| Oedema peripheral | General disorders | Systematic Assessment |
|
| Pyrexia | General disorders | Systematic Assessment |
|
| Vaccination site pain | General disorders | Systematic Assessment |
|
| Cholelithiasis | Hepatobiliary disorders | Systematic Assessment |
|
| Hepatic steatosis | Hepatobiliary disorders | Systematic Assessment |
|
| Hypertransaminasaemia | Hepatobiliary disorders | Systematic Assessment |
|
| Immunisation reaction | Immune system disorders | Systematic Assessment |
|
| Escherichia urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Folliculitis | Infections and infestations | Systematic Assessment |
|
| Gingivitis | Infections and infestations | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | Systematic Assessment |
|
| Post-acute COVID-19 syndrome | Infections and infestations | Systematic Assessment |
|
| Postoperative wound infection | Infections and infestations | Systematic Assessment |
|
| Rhinitis | Infections and infestations | Systematic Assessment |
|
| Tinea cruris | Infections and infestations | Systematic Assessment |
|
| Tooth infection | Infections and infestations | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection bacterial | Infections and infestations | Systematic Assessment |
|
| Vascular access site infection | Infections and infestations | Systematic Assessment |
|
| Citrate toxicity | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Meniscus cyst | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Post procedural constipation | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Tooth fracture | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Tooth injury | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Traumatic haematoma | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Vascular access site erythema | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Vascular access site haemorrhage | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Vascular access site pain | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | Systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | Systematic Assessment |
|
| Blood follicle stimulating hormone increased | Investigations | Systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | Systematic Assessment |
|
| Blood phosphorus increased | Investigations | Systematic Assessment |
|
| Blood potassium decreased | Investigations | Systematic Assessment |
|
| CD4 lymphocytes decreased | Investigations | Systematic Assessment |
|
| Cardiac murmur | Investigations | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | Systematic Assessment |
|
| Urine analysis abnormal | Investigations | Systematic Assessment |
|
| Abnormal loss of weight | Metabolism and nutrition disorders | Systematic Assessment |
|
| Abnormal weight gain | Metabolism and nutrition disorders | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperlipidaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypovolaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Vitamin D deficiency | Metabolism and nutrition disorders | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Joint swelling | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Lethargy | Nervous system disorders | Systematic Assessment |
|
| Neuralgia | Nervous system disorders | Systematic Assessment |
|
| Parosmia | Nervous system disorders | Systematic Assessment |
|
| Seizure | Nervous system disorders | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | Systematic Assessment |
|
| Depressed mood | Psychiatric disorders | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| Dysuria | Renal and urinary disorders | Systematic Assessment |
|
| Haematuria | Renal and urinary disorders | Systematic Assessment |
|
| Renal haematoma | Renal and urinary disorders | Systematic Assessment |
|
| Urinary hesitation | Renal and urinary disorders | Systematic Assessment |
|
| Azoospermia | Reproductive system and breast disorders | Systematic Assessment |
|
| Erectile dysfunction | Reproductive system and breast disorders | Systematic Assessment |
|
| Gynaecomastia | Reproductive system and breast disorders | Systematic Assessment |
|
| Oligospermia | Reproductive system and breast disorders | Systematic Assessment |
|
| Scrotal discomfort | Reproductive system and breast disorders | Systematic Assessment |
|
| Scrotal erythema | Reproductive system and breast disorders | Systematic Assessment |
|
| Choking | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Dry throat | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Increased viscosity of upper respiratory secretion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Lung infiltration | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Painful respiration | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pharyngeal inflammation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Dermatosis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hair growth abnormal | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Lichen planus | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Nail ridging | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Neurodermatitis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pain of skin | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pigmentation disorder | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Skin plaque | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Flushing | Vascular disorders | Systematic Assessment |
|
| Hypotension | Vascular disorders | Systematic Assessment |
|
| Orthostatic hypotension | Vascular disorders | Systematic Assessment |
|
Not provided
Not provided
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D059345 | Cerebral Small Vessel Diseases |
| D002561 | Cerebrovascular Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008661 | Metabolism, Inborn Errors |
| D008064 | Lipidoses |
| D008052 | Lipid Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D052439 | Lipid Metabolism Disorders |
|
|
| CFB PBL Week 24 |
|
|
| CFB PBL Week 48 |
|
|
|
|
| Myelinosomes in deep dermal capillary endothelial cells (Week 48) |
|
| Myelinosomes in vascular smooth muscle cells (Week 24) |
|
| Myelinosomes in vascular smooth muscle cells (Week 48) |
|
| Myelinosomes in perineurium (Week 24) |
|
| Myelinosomes in perineurium (Week 48) |
|
| Title | Measurements |
|---|---|
|
| Stool Consistency Week 48 |
|
|
| Week 24 (pain interference) |
|
|
| Week 48 (pain interference) |
|
|