Guard3: An Open-label, Parallel-arm, Randomized, Controlled, Phase 2/Phase 3 Study Evaluating the Efficacy and Safety of Autologous HSC Gene Therapy, AVR-RD-02, Compared to ERT for Gaucher Disease Type 3 in Participants Aged 2 to 25
Overview
- Phase
- Phase 2
- Intervention
- Gene therapy
- Conditions
- Gaucher Disease, Type 3
- Sponsor
- AVROBIO
- Primary Endpoint
- Change from baseline in a multidomain endpoint as assessed by Global Statistical Test (GST)
- Status
- Withdrawn
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of autologous hemotopoietic stem cell (HSC) gene therapy, AVR-RD-02, compared to enzyme replacement therapy, for the treatment of Gaucher disease Type 3 in male and female participants aged 2 to 25 years.
The study will consist of 2 parts - Core (Part 1) followed by the ERT-crossover (Part 2)
Detailed Description
Core (Part 1) Once a participant consents, he/she will complete the screening period within 30 days. Eligible participants will have baseline assessments completed 30 days later and then will be randomized into one of two treatment arms: AVR-RD-02 arm or ERT control arm. If randomized to the AVR-RD-02 arm, the participant will enter the pre-gene therapy infusion period (approximately 15 weeks), which consists of mobilization, apheresis, AVR-RD-02 preparation and testing for release, discontinuation of ERT, and conditioning. The participant will then receive the AVR-RD-02 gene therapy (1 day) followed by a 52-week follow-up period in which periodic safety and efficacy assessments will be performed. Participants will not receive ERT after gene therapy infusion unless indicated by pre-specified laboratory and clinical criteria. If randomized to the ERT Control arm, the participant will remain on their prescribed ERT regimen for 52-week observation period with approximately 4 study visits during this time. ERT-crossover (Part 2) After 52 weeks of observation in Part 1, participants in the ERT Control Arm will have the opportunity to enter Part 2 and receive AVR-RD-02. They will start with baseline assessments and follow a similar schedule to the schedule followed by participants assigned to AVR-RD-02 in the Core Study (Part 1).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participant and/or parent, caregiver, or legal representative must be willing and able to provide written informed consent/assent for the study in accordance with applicable regulations and guidelines and to comply with all study visits and procedures, including the use of any data collection device(s) that may be used to directly record participant data.
- •Participant is ≥2 to ≤ 25 years old, at the time of providing informed consent or assent.
- •Participant has a confirmed diagnosis of Gaucher disease Type 3 based on all of the following:
- •Biallelic GBA1 gene mutation
- •Deficient GCase enzyme activity in blood
- •Clinical phenotype with the presence of gaze palsy, predominantly horizontal and with slow or absent saccades
- •Participant has the presence of one or both of the following within 3 months of screening:
- •Ataxia (score ≥1) based on the modified scale for the assessment and rating of ataxia total score (mSARA)
- •Interstitial lung disease (to be confirmed by radiological imaging)
- •Participant has the presence of one or both of the following within 3 months of screening:
Exclusion Criteria
- •Participant has a diagnosis of Gaucher disease Type 1 or Type
- •Participant has any one of the following:
- •Hemoglobin value of \<9.0 g/dL
- •Platelet count of \<70 × 109/L
- •Pulmonary hypertension
- •Bone crisis attributable to osteonecrosis and/or pathological fractures within 3 months prior to Screening
- •Treatment refractory epilepsy
- •Progressive myoclonic epilepsy
- •Participant has had or is scheduled to undergo a partial or total splenectomy.
- •Participant requires use of invasive ventilatory support.
Arms & Interventions
AVR-RD-02 Arm
Participants will have been on a stable prescribed ERT dose for at least 6 consecutive months at the time of Screening and willing to remain on the same ERT dose until 2 weeks prior to gene therapy infusion.
Intervention: Gene therapy
ERT Control Arm
Participants on stable prescribed ERT dose for at least 6 consecutive months at the time of Screening. Participants will have the opportunity to receive a gene therapy infusion of AVR-RD-02 after week 52 of Part 1.
Intervention: Gene therapy
ERT Control Arm
Participants on stable prescribed ERT dose for at least 6 consecutive months at the time of Screening. Participants will have the opportunity to receive a gene therapy infusion of AVR-RD-02 after week 52 of Part 1.
Intervention: Enzyme Replacement Agent
Outcomes
Primary Outcomes
Change from baseline in a multidomain endpoint as assessed by Global Statistical Test (GST)
Time Frame: Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm)
The multidomain endpoint consists of the following 4 domains: I. Change in modified Scale for Assessment and Rating of Ataxia total score (mSARA) II. Percent change in diffusing capacity of the lung for carbon monoxide (DLco) for the assessment of interstitial lung disease (ILD) III. Percent change in spleen volume by Magnetic Resonance Imaging (MRI) IV. Percent change in a liver volume by MRI
Secondary Outcomes
- Change from Baseline in Lyso-Gb1 level in cerebrospinal fluid (CSF) as assessed by liquid chromatography tandem mass spectrometry (LC/MS/MS)(Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm))
- Vector Copy Number (VCN) - Engraftment of genetically-modified hematopoietic stem cells (HSCs) in bone marrow as assessed by digital droplet polymerase chain reaction (ddPCR)(Baseline to 52 weeks post AVR-RD-02 infusion)
- Number of participants with clinically relevant abnormalities as assessed by clinical laboratory tests(Baseline to 52 weeks post AVR-RD-02 infusion)
- Change from baseline in clinical improvement as assessed by Clinical Global Impression -Improvement (CGI-I scale)(Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm))
- Change from baseline in pain as assessed by Brief Pain Inventory-Short Form (BPI-SF) questionnaire scores(Baseline to 52 weeks post AVR-RD-02 infusion (AVR-RD-02 arm) or Baseline to 52 weeks (ERT arm))
- Vector Copy Number (VCN) - Engraftment of genetically-modified hematopoietic stem cells (HSCs) in peripheral blood leukocytes (PBL) as assessed by droplet digital polymerase chain reaction (ddPCR)(Baseline to 52 weeks post AVR-RD-02 infusion)
- Incidence of clinically significant AEs and SAEs(Baseline to 52 weeks post AVR-RD-02 infusion)
- Number of participants with clinically relevant abnormalities as assessed by vital signs(Baseline to 52 weeks post AVR-RD-02 infusion)
- Number of participants with clinically relevant abnormalities as assessed by electrocardiograms (ECGs)(Baseline to 52 weeks post AVR-RD-02 infusion)
- Number of participants with clinically relevant abnormalities as assessed by physical examinations findings(Baseline to 52 weeks post AVR-RD-02 infusion)