The Guard1 Trial, an Open-Label, Multinational Phase 1/2 Study of the Safety and Efficacy of Ex Vivo, Lentiviral Vector-Mediated Gene Therapy AVR-RD-02 for Subjects With Type 1 Gaucher Disease
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- AVROBIO
- 入组人数
- 8
- 试验地点
- 5
- 主要终点
- Number of Clinically Significant Adverse Events (AEs) and Serious Adverse Events (SAEs) of AVR-RD-02
研究概览
简要总结
This was a multinational, open-label study to assess the safety and efficacy of AVR-RD-02 in approximately 8 to 16 subjects (male or female) who are ≥18 and ≤50 years of age and post pubertal at Screening with a confirmed diagnosis of Type 1 Gaucher disease (based on clinical phenotype, genotyping, and deficient GCase enzyme activity in whole blood).
详细描述
Five study periods (Screening, Baseline, Pre-gene Therapy Infusion, Gene Therapy Infusion, and Post-gene Therapy Infusion Follow-up) comprised the study. During the Screening Period (approximately 60 days), written informed consent was obtained and the subject completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, subjects entered the Baseline Period (up to 7 days) during which time assessments were performed to establish Pre-gene Therapy Infusion baseline. Once baseline assessments were completed, the subject entered the Pre-gene Therapy Infusion Period (approximately 8 to 10 weeks) during which time mobilization, apheresis, AVR-RD-02 investigational product preparation and testing for release, busulfan conditioning regimen administration took place. Enzyme replacement therapy was discontinued at least 2 weeks before the scheduled Gene Therapy Infusion Day. Following completion of the Pre-gene Therapy Infusion Period, the subject entered the Gene Therapy Infusion Period (1 day) during which AVR-RD-02 infusion took place. After AVR-RD-02 Gene Therapy Infusion, the subject entered the Post-gene Therapy Infusion Follow-up Period (approximately 52 weeks) during which time periodic safety and efficacy assessments were performed to assess measures of safety, engraftment, and clinical response following AV-RD-02 infusion.
In August 2023, the study was terminated early by the Sponsor, which was not based on any safety or medical reasons and therefore, one subject did not complete the study (i.e., Week 52). Subsequently, in August 2023, the sponsor's long-term follow-up study (AVRO-RD-02-LTF01), was also terminated early for the same reason as the AVRO-RD-02-201 study, and therefore, no subjects completed the 15-year long-term follow-up study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Switch Stable
Switch-stable arm: Subjects who had undergone ERT ≥15 U/kg and ≤60 U/kg every other week (or equivalent; i.e., any combination of infusions resulting in a total monthly ERT dose of >30 U/kg and <120 U/kg) for ≥24 consecutive months for Type 1 Gaucher disease at the time of Screening. Switch-stable subjects must have discontinued ERT at least 2 weeks before the scheduled AVR-RD-02 infusion. Switch-stable subjects who had been and substrate reduction therapy (SRT) must not have received SRT within 12 months of Screening.
干预措施: AVR-RD-02 (Drug)
Treatment-naïve
Treatment-naïve arm: Subjects with Type 1 Gaucher disease who had never received either ERT or SRT for Gaucher disease or had not received either ERT or SRT for Gaucher disease within 12 months of Screening (i.e., treatment-naïve subjects). Enrollment followed a similar scheme as for the switch-stable subjects.
Note: No subjects enrolled in this arm.
干预措施: AVR-RD-02 (Drug)
结局指标
主要结局
Number of Clinically Significant Adverse Events (AEs) and Serious Adverse Events (SAEs) of AVR-RD-02
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
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). AE/SAE can either be related to AVR-RD-02 infusion or attributed to the conditioning agent, mobilization agent(s), study procedures, and the underlying disease.
Vector Copy Number (VCN) in Bone Marrow as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
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.
Change From Baseline in Spleen Volume Assessed by Abdominal MRI
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Percent change in spleen volume = (\[spleen volume at Week 52 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100. A reduction in the percent change from baseline (%CFB) in spleen volume (mL) is a positive indicator of efficacy.
Change From Baseline in Platelet Count
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Ratio to baseline indicates the percent change in platelet count. The Baseline value is defined as 1 or 100%. A ratio to Baseline \<1 indicates a reduction in platelet count and a ratio to Baseline \>1 indicates an increase in platelet count.
Vector Copy Number (VCN) in Peripheral Blood as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
VCN, defined as the average number of copies of the therapeutic gene (transgene) in a sample of cells, is conventionally reported as the number of vector copies 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 progenitor cells obtained from a peripheral blood sample.
Change From Baseline in Liver Volume Assessed by Abdominal MRI
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Percent change in liver volume = (\[liver volume at Week 52 minus liver volume at baseline\] divided by \[liver volume at baseline\]) multiplied by 100. A reduction in the percent change from baseline (%CFB) in liver volume (mL) is a positive indicator of efficacy.
Change From Baseline in Hemoglobin Concentration
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Ratio to baseline indicates the percent change in hemoglobin concentration. The baseline value is defined as 1 or 100%. A ratio to Baseline \<1 indicates a reduction in hemoglobin concentration and a ratio to Baseline \>1 indicates an increase in hemoglobin concentration.
Change From Baseline in Plasma Lyso-Gb1 Levels by Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS)
时间窗: Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Glucosylsphingosine (lyso-Gb1) is the substrate that accumulates in the lysosomes of patients affected by Gaucher disease as a result of deficiencies in GCase enzyme activity. Treatment with AVR-RD-02 is intended to replace the missing GCase enzymatic activity, which allows degradation of accumulated lyso-Gb1 substrate in the lysosomes. Negative values (decrease from Baseline) are an indicator of efficacy.
次要结局
- Change From Baseline in GCase Enzyme Activity Level in Plasma(Weeks 13, 26, 39, and 52)
- Number of Subjects Who Restarted ERT(Between Week 26 and Week 52 post-AVR-RD-02 treatment)
- Change From Baseline in Bone Mineral Density (BMD) Assessed by Bone Density Scan (DXA)(Baseline to 52 weeks post-AVR-RD-02 treatment follow-up)
- Change From Baseline in Plasma Chitotriosidase Activity Levels Measured by Fluorometric Enzyme Assay(Baseline to 52 weeks post-AVR-RD-02 treatment follow-up)
- Change From Baseline in Bone Marrow Burden (BMB) Score as Assessed by Bone Magnetic Resonance Imaging (MRI)(Baseline to 52 weeks post-AVR-RD-02 treatment follow-up)
- Change From Baseline in GCase Enzyme Activity Level in Peripheral Blood Leukocytes(Weeks 13, 26, 39, and 52)
- Change From Baseline in Presence of Anti-GCase Total Antibodies(At Weeks 5, 13, 26, 39, and 52)