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Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease

Primary Purpose

Fabry Disease

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

AVR-RD-01

About this trial

This is an interventional treatment trial for Fabry Disease focused on measuring Fabry disease, Cell therapy, Gene therapy, Lysosomal storage disorder, Lenti-viral

Eligibility Criteria

16 Years - 50 Years (Child, Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Subject is male, 16 years of age or older (18 years of age or older in the US), and postpubertal,(minimum age by region)
Subject has a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity (defined as < 1% of normal).

Exclusion Criteria:

Subject has a GLA gene mutation associated with late-onset cardiac variant Fabry disease.
Subject has previously received ERT and/or chaperone therapy within 3 years for treatment of Fabry disease.
Subject has tested positive for anti-AGA antibodies at the time of screening.
Subject has eGFR < 60 mL/min/1.73 m² (ie, chronic kidney disease [CKD] stage ≥ 3) at Screening.
Subject has a prior history of myocardial infarction (MI).
Subject has 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 has a history of moderate to severe valvular heart disease requiring valve replacement.
Subject has 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 has 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 is allowed].
Subject has a prior history of stroke and/or transient ischemic attack (TIA).
Subject has aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) at Screening.
Subject has a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma.
Subject has previously received treatment with AVR-RD-01 or any other gene therapy.

Other inclusion/exclusion criteria apply.

Sites / Locations

Hackensack University Medical Center
University of Pittsburgh Medical Center
Royal Melbourne Hospital
Royal Perth Hospital
Hospital de Clinicas de Porto Alegre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Assignment AVR-RD-01

Arm Description

AVR-RD-01 Drug Product (autologous CD34+ cell-enriched fraction that contains cells transduced with Lentiviral Vector/alpha-galactosidase A (AGA) encoding for the human AGA complementary deoxyribonucleic acid (cDNA) sequence

Outcomes

Primary Outcome Measures

Incidence of and severity of adverse events (AEs) and serious adverse events (SAEs)

Number of participants with clinically relevant abnormalities, as assessed by clinical laboratory tests

Number of participants with clinically relevant abnormalities, as assessed by vital signs

Number of participants with clinically relevant abnormalities as assessed by electrocardiograms (ECGs)

Evaluation of immunogenicity of AVR-RD-01

Presence of anti-AGA antibodies

Presence of replication competent lentivirus (RCL)

Presence of RCL

Evaluate for the presence of aberrant clonal expansion as assessed by integration site analysis (ISA)

Evaluate the effect of AVR-RD-01 on substrate (ie, globotriaosylceramide [Gb3]) in kidney biopsies

Change in the average number of Gb3 inclusions (ie, myelinosomes) per kidney peritubular capillary (PTC) per subject

Secondary Outcome Measures

Change from baseline in AGA enzyme activity level in plasma and peripheral blood leukocytes (PBLs)

Change from baseline in Globotriaosylceramide (Gb3) biomarkers for Fabry disease in plasma and urine

Change from baseline in substrate (i.e. Gb3) in skin biopsy

Change from baseline in renal function as assessed by measured glomerular filtration rate (mGFR)

Change from baseline in renal function as assessed by estimated glomerular filtration rate (eGFR)

Change from baseline in renal function as assessed by urine total protein levels

Change from baseline in renal function as assessed by urine albumin levels

Change from baseline in left ventricular mass index (LVMI) as assessed by cardiac magnetic resonance imaging (MRI)

Change from baseline in abdominal pain and stool consistency as assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D)

Change from baseline in Brief Pain Inventory-Short Form (BPI-SF) questionnaire scores

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

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)

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)

Full Information

NCT ID

NCT03454893

First Posted

December 20, 2017

Last Updated

November 15, 2022

Sponsor

AVROBIO

1. Study Identification

Unique Protocol Identification Number

NCT03454893

Brief Title

Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease

Official 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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Terminated

Why Stopped

AVROBIO is deprioritizing its Fabry disease program

Study Start Date

February 21, 2018 (Actual)

Primary Completion Date

March 14, 2022 (Actual)

Study Completion Date

March 14, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AVROBIO

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in approximately 8 to 12 male subjects 16 years of age or older and postpubertal with a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity who have not previously received treatment with enzyme replacement therapy (ERT) and/or chaperone therapy within 3 years of the time of Screening.

Detailed Description

The duration of each subject's participation in this study will be approximately 64 weeks (or 1 year, 12 weeks), comprised of a 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) will be obtained and the subject will complete other Screening procedures to confirm study eligibility. Once study eligibility is confirmed, subjects will enter the Baseline Period (up to 3 days) during which time assessments will be performed to establish a pre-transplant baseline. Once baseline assessments are complete, the subject will enter the Pre-transplant Period (approximately 6 weeks) during which time mobilization, apheresis, AVR-RD-01 drug product preparation and testing for release, and conditioning regimen administration to achieve myeloablation will take place. Following completion of the Pre-transplant Period, the subject will enter the Transplant Period (1 day) during which time AVR-RD-01 infusion will take place. After AVR-RD-01 infusion, the subject will enter the Post-transplant Follow-up Period (approximately 48 weeks), during which time periodic safety and efficacy assessments will be performed to assess measures of engraftment, clinical response, and safety post-transplant. After study completion, consenting subjects will continue periodic safety and efficacy assessments for approximately 14 years (for a total of 15 years post-transplant follow-up) in a long-term follow-up study to AVRO-RD-01-201.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Fabry Disease

Keywords

Fabry disease, Cell therapy, Gene therapy, Lysosomal storage disorder, Lenti-viral

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single Assignment AVR-RD-01

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

AVR-RD-01

Intervention Description

The subject will receive a one-time IV infusion of AVR-RD-01.

Primary Outcome Measure Information:

Title

Incidence of and severity of adverse events (AEs) and serious adverse events (SAEs)

Time Frame

Baseline to Week 48 post gene therapy

Title

Number of participants with clinically relevant abnormalities, as assessed by clinical laboratory tests

Time Frame

Baseline to Week 48 post gene therapy

Title

Number of participants with clinically relevant abnormalities, as assessed by vital signs

Time Frame

Baseline to Week 48 post gene therapy

Title

Number of participants with clinically relevant abnormalities as assessed by electrocardiograms (ECGs)

Time Frame

Baseline to Week 48 post gene therapy

Title

Evaluation of immunogenicity of AVR-RD-01

Description

Presence of anti-AGA antibodies

Time Frame

Baseline to Week 48 post gene therapy

Title

Presence of replication competent lentivirus (RCL)

Description

Presence of RCL

Time Frame

Baseline to Week 48 post gene therapy

Title

Evaluate for the presence of aberrant clonal expansion as assessed by integration site analysis (ISA)

Time Frame

Baseline to Week 48 post gene therapy

Title

Evaluate the effect of AVR-RD-01 on substrate (ie, globotriaosylceramide [Gb3]) in kidney biopsies

Description

Change in the average number of Gb3 inclusions (ie, myelinosomes) per kidney peritubular capillary (PTC) per subject

Time Frame

Baseline to Week 48 post gene therapy

Secondary Outcome Measure Information:

Title

Change from baseline in AGA enzyme activity level in plasma and peripheral blood leukocytes (PBLs)

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

Change from baseline in Globotriaosylceramide (Gb3) biomarkers for Fabry disease in plasma and urine

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

Change from baseline in substrate (i.e. Gb3) in skin biopsy

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

Change from baseline in renal function as assessed by measured glomerular filtration rate (mGFR)

Time Frame

Baseline to Week 48 post gene therapy

Title

Change from baseline in renal function as assessed by estimated glomerular filtration rate (eGFR)

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

Change from baseline in renal function as assessed by urine total protein levels

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

Change from baseline in renal function as assessed by urine albumin levels

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

Change from baseline in left ventricular mass index (LVMI) as assessed by cardiac magnetic resonance imaging (MRI)

Time Frame

Baseline to Week 48 post gene therapy

Title

Change from baseline in abdominal pain and stool consistency as assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D)

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

Change from baseline in Brief Pain Inventory-Short Form (BPI-SF) questionnaire scores

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

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

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

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)

Time Frame

Baseline to Week 24 and Week 48 post gene therapy

Title

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)

Time Frame

Baseline to Week 48 post gene therapy

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

16 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject is male, 16 years of age or older (18 years of age or older in the US), and postpubertal,(minimum age by region) Subject has a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity (defined as < 1% of normal). Exclusion Criteria: Subject has a GLA gene mutation associated with late-onset cardiac variant Fabry disease. Subject has previously received ERT and/or chaperone therapy within 3 years for treatment of Fabry disease. Subject has tested positive for anti-AGA antibodies at the time of screening. Subject has eGFR < 60 mL/min/1.73 m² (ie, chronic kidney disease [CKD] stage ≥ 3) at Screening. Subject has a prior history of myocardial infarction (MI). Subject has 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 has a history of moderate to severe valvular heart disease requiring valve replacement. Subject has 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 has 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 is allowed]. Subject has a prior history of stroke and/or transient ischemic attack (TIA). Subject has aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) at Screening. Subject has a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma. Subject has previously received treatment with AVR-RD-01 or any other gene therapy. Other inclusion/exclusion criteria apply.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director, MD

Organizational Affiliation

AVROBIO, Inc

Official's Role

Study Director

Facility Information:

Facility Name

Hackensack University Medical Center

City

Hackensack

State/Province

New Jersey

ZIP/Postal Code

07601

Country

United States

Facility Name

University of Pittsburgh Medical Center

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

Facility Name

Royal Melbourne Hospital

City

Melbourne

State/Province

Parkville VIC

Country

Australia

Facility Name

Royal Perth Hospital

City

Perth

Country

Australia

Facility Name

Hospital de Clinicas de Porto Alegre

City

Porto Alegre

State/Province

Rio Grande Do Sul

Country

Brazil

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease

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