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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04145037




Registration number
NCT04145037
Ethics application status
Date submitted
27/08/2019
Date registered
30/10/2019
Date last updated
18/01/2024

Titles & IDs
Public title
Lentiviral Vector Gene Therapy - The Guard1 Trial of AVR-RD-02 for Subjects With Type 1 Gaucher Disease
Scientific title
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
Secondary ID [1] 0 0
AVRO-RD-02-201
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AVR-RD-02

Experimental: Switch Stable - Switch-stable arm: Subjects who have undergone ERT =15 U/kg and =60 U/kg every other week (or equivalent; ie, 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 discontinue ERT at least 2 weeks before the scheduled transplant day. Switch-stable subjects who have been on ERT and substrate reduction therapy (SRT) must not have received SRT within 12 months of Screening.

Experimental: Treatment-naïve - Treatment-naïve arm: Subjects with Type 1 Gaucher disease who have never received either ERT or SRT for Gaucher disease or have not received either ERT or SRT for Gaucher disease within 12 months of Screening (ie, treatment-naïve subjects). Enrollment will follow a similar scheme as for the switch-stable subjects.


Treatment: Drugs: AVR-RD-02
AVR-RD-02 Drug product: active substance is autologous CD34+ enriched hematopoietic stem cells (HSCs) that have been genetically modified ex vivo with a lentiviral vector (LV) to contain a ribonucleic acid (RNA) transcript that, after reverse transcription, results in codon-optimized, complementary deoxyribonucleic acid (cDNA) that, upon its integration into human genome, encodes for functional human glucocerebrosidase (GCase).
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of clinically significant Adverse Events and Serious Adverse Events of AVR-RD-02
Timepoint [1] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [2] 0 0
Number of participants with clinically relevant abnormalities, as assessed by clinical laboratory tests
Timepoint [2] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [3] 0 0
Number of participants with clinically relevant abnormalities, as assessed by vital signs
Timepoint [3] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [4] 0 0
Number of participants with clinically relevant abnormalities, as assessed by electrocardiograms (ECGs)
Timepoint [4] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [5] 0 0
Average Vector Copy Number (VCN) in peripheral blood as assessed by quantitative polymerase chain reaction (qPCR) and/or droplet digital polymerase chain reaction (ddPCR)
Timepoint [5] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [6] 0 0
Average Vector Copy Number (VCN) in bone marrow as assessed by quantitative polymerase chain reaction (qPCR) and/or droplet digital polymerase chain reaction (ddPCR)
Timepoint [6] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [7] 0 0
Change from Baseline in spleen volume assessed by abdominal MRI
Timepoint [7] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [8] 0 0
Change from Baseline in liver volume assessed by abdominal MRI
Timepoint [8] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [9] 0 0
Change from Baseline in hemoglobin concentration
Timepoint [9] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [10] 0 0
Change from Baseline in platelet count
Timepoint [10] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Primary outcome [11] 0 0
Change from Baseline in plasma lyso-Gb1 levels by liquid chromatography tandem mass spectrometry (LC/MS/MS)
Timepoint [11] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Secondary outcome [1] 0 0
Change from average of Screening and Baseline over time in glucocerebrosidase (GCase) enzyme activity
Timepoint [1] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Secondary outcome [2] 0 0
Incidence of Enzyme Replacement Therapy (ERT) utilized following treatment with AVR-RD-02
Timepoint [2] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Secondary outcome [3] 0 0
Change from Baseline in anti-GCase total antibodies and subsequent titers by an electrochemiluminescence method
Timepoint [3] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Secondary outcome [4] 0 0
Change from Baseline in Bone Mineral Density (BMD) assessed by Bone Density Scan (DXA)
Timepoint [4] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Secondary outcome [5] 0 0
Change from Baseline in plasma Chitotriosidase activity levels measured by fluorometric enzyme assay
Timepoint [5] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Secondary outcome [6] 0 0
Change from Baseline in Bone Marrow Burden (BMB) Score as assessed by bone Magnetic Resonance Imaging (MRI)
Timepoint [6] 0 0
Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

Eligibility
Key inclusion criteria
INCLUSION CRITERIA for all Enrolled (Switch-stable and Treatment-naïve) Subjects:

Note: No treatment-naïve subjects enrolled in this study.

1. Subject was =18 and =50 years old and post pubertal
2. Subject had a confirmed diagnosis of Type 1 Gaucher disease based on deficient GCase enzyme at Screening.

a. For switch-stable subjects, documentation of GCase enzyme activity prior to having been started on ERT or if GCase levels prior to ERT were not available, deficient trough GCase enzyme activity in peripheral blood at Screening.
3. Female subjects of reproductive potential were counseled regarding the risks, benefits, limitations, and alternatives associated with female fertility preservation. Oocyte harvesting and cryopreservation were offered
4. Male subjects were willing to refrain from donating sperm at any time after receiving conditioning therapy. For subjects planning on (or for whom there is a possibility of) fathering children in the future, sperm cryopreservation before administration of the conditioning regimen was recommended.
5. All subjects who had not undergone successful surgical sterilization (ie, vasectomy, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) agreed to remain sexually abstinent or use two effective methods of contraception while sexually active from the day of conditioning administration until 52 weeks post-gene therapy infusion. Two methods of contraception were required even with documented medical assessment of surgical success of sterilization.

1. For male subjects and for male spouses/partners of female subjects, condoms were an acceptable method of barrier contraception
2. For female subjects and for female spouses/partners of male subjects, acceptable methods of barrier contraception included diaphragm, cervical cap, or contraceptive sponge.
6. Male and female subjects agreed to refrain from donating sperm and eggs, respectively, after undergoing conditioning.
7. Subject was willing to refrain from donating blood, organs, tissues, or cells for gene therapy infusion any time after AVR-RD-02 treatment.
8. Subject was willing and able to provide written informed consent 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 subject data.
9. Subject was willing to receive blood or blood products transfusion to manage adverse events (AEs).

Additional Inclusion Criteria for Switch-stable Subjects (in addition to criteria 1-9 above):
10. Subject had undergone a stable dose (within 75% to125% of the prescribed dose) of ERT = 15 U/kg and = 60 U/kg every other week (or equivalent) for = 24 consecutive months with no significant interruptions, in dosing over the last 6 months, in the opinion of the Investigator, prior to Screening
11. Subject had normal or near-normal hematologic values at Screening defined as one or more of the following:

1. Hemoglobin concentration =10 g/dL
2. Platelet count =80 x 10^9/L
12. Subject had stable Gaucher disease during the 6 months immediately preceding Screening defined by:

1. Stable hemoglobin concentration (i.e., within a range of ±2 g/dL of the Screening value) based on documented historical clinical laboratory results and
2. Stable platelet count (within ±20% of the Screening value) based on documented historical clinical laboratory results
13. Subject had not received SRT for Gaucher disease within 12 months of Screening

Additional Inclusion Criteria for Treatment-naïve Subjects (in addition to inclusion criteria 1 through 9, above, treatment-naïve subjects must meet the following inclusion criteria for participation in this study):
14. Subject had neither received ERT nor SRT for Gaucher disease nor has received neither ERT nor SRT for Gaucher disease within 12 months of Screening.
15. Subject had a hemoglobin level =2 g/dL below the lower limit of normal (LLN) for age and sex at Screening and at least one of the following at Screening:

1. Platelet count <120 x 10^9/L
2. Enlarged liver by palpation, confirmed on abdominal MRI
3. Moderate splenomegaly by palpation, confirmed on abdominal MRI
16. For any subject who was treatment-naïve, ERT peri-procedurally (from the Screening Period throughout 2 weeks prior to Gene Therapy Infusion) was considered in consultation with the PI and Sponsor Medical Monitor.

EXCLUSION CRITERIA:

1. Subject had Type 2 or 3 Gaucher disease, had severe neurological signs and symptoms, defined as complete ocular paralysis, overt myoclonus or history of seizures, characteristic of neuronopathic Gaucher disease, or had a tremor, peripheral neuropathy or symptoms of Parkinson's disease.

Subject had any one of the following:

1. Hemoglobin value <9.0 g/dL, or
2. Platelet count <70 x 10^9/L, or
3. Spleen volume >10 x normal, or
4. Pulmonary hypertension 3. Subject had experienced a prior anaphylactic or anaphylactoid reaction (of any severity) to ERT.

4. Treatment-naïve subject had history of clinically significant (CS) anti-GCase antibodies.

5. Subject had a contraindication to ERT, in the opinion of the Investigator. 6. Subject had a contraindication to HSC transplantation (HSCT), in the opinion of the Investigator.

7. Subject presented with iron, folic acid, and/or vitamin B12 deficiency sustained anemia during Screening.

8. Subject had idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), thrombocytopenia, anemia, hepatomegaly, splenomegaly, and/or osteoporosis, unrelated to Gaucher disease, in the opinion of the Investigator.

9. Subject had a clinical co-morbidity such as neurologic, cardiovascular, pulmonary, hepatic, gastrointestinal, renal, hematologic, endocrine, metabolic, genetic, immunologic, neoplastic, or psychiatric disease, other medical condition(s), or intercurrent illnesses that may have confounded the study results or, in the opinion of the Investigator, may have precluded participation in the study.

10. Subject was a pregnant and/or lactating female. 11. Subject was unable to understand the nature, scope, and possible consequences of the study.

12. Subject had diabetes mellitus (Type 1 or Type 2). 13. Subject had active, progressive bone necrosis. 14. Subject had an active chronic infection during the Screening, Baseline, or Pre-gene Therapy Infusion Period of the study.

15. Subject had an active uncontrolled acute bacterial, viral, fungal, parasitic, or prion-associated infection during the Screening, Baseline, or Pre-gene Therapy Infusion Period of the study.

16. Subject had a history of (or current) tuberculosis. 17. Subject tested positive for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV, Type 1 or 2), human T-cell lymphotropic virus (HTLV)-1, HTLV-2, and/or syphilis on Venereal Disease Research Laboratory (VDRL) test, chemiluminescent microplate immunoassay (CMIA), or enzyme immunosorbent assay (EIA) at Screening.

18. Subject had a prior history of (or current) cancer or precancerous lesion or has a known genetic predisposition to cancer. The one exception was a prior history of resected squamous cell carcinoma.

19. Subject had any other medical condition that predisposes him/her to (or conveys increased risk of) malignancy, in the opinion of the Investigator - including history of (or current) monoclonal gammopathy of undetermined significance (MGUS).

20. Subject had a history of alcohol or illicit drug abuse, according to the Investigator's judgment.

21. Subject had undergone, or was scheduled to undergo, bone marrow transplant, HSC transplant, and/or solid organ transplant. NOTE: Subjects who were otherwise eligible for the study but were scheduled for bone marrow or HSC transplant to treat Type 1 Gaucher disease may have been enrolled in the study (instead of receiving an allogeneic transplant) and undergo gene therapy infusion with AVR-RD-02.

22. Subject had white blood cell count (WBC) < 3.0 x 10^9/L and/or uncorrected bleeding disorder from enrollment (i.e., signing of informed consent at Screening) through the Gene Therapy Infusion Period of the study (i.e., the day of AVR-RD-02 gene therapy infusion).

23. Subject had clinically significant immunosuppressive disease or condition, in the opinion of the Investigator, at Screening.

24. Subject was on (or requires treatment with) cytotoxic or immunosuppressive agents from 60 days prior to signing informed consent at Screening (i.e., study enrollment) through the Week 52 study visit; the one exception was treatment with cytotoxic or immunosuppressive agents required per protocol for stem cell transplant.

25. Subject was on (or requires treatment with) red blood cell (RBC) growth factor (e.g., erythropoietin) from 6 months prior to enrollment (i.e., signing of informed consent at Screening) through the Week 52 study visit.

26. Subject had any condition that made it impossible to perform MRI studies. 27. Subject had medical condition(s) and/or was receiving medication(s) that would contraindicate ability to undergo mobilization (including contraindication to granulocyte colony-stimulating factor (G-CSF) and/or plerixafor), apheresis, or conditioning.

28. Busulfan was contraindicated for the subject. 29. Subject had previously received treatment with AVR-RD-02 or any other gene therapy.

30. Subject was participating in (or plans to participate in) any other investigational drug trial or plans to be exposed to any other investigational agent, device and/or procedure, from 30 days prior to enrollment (i.e., signing of informed consent at Screening) through study completion.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/05/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/08/2023
Sample size
Target
Accrual to date
Final
8
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Iowa
Country [3] 0 0
United States of America
State/province [3] 0 0
New Jersey
Country [4] 0 0
United States of America
State/province [4] 0 0
Pennsylvania
Country [5] 0 0
Canada
State/province [5] 0 0
Ontario

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AVROBIO
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Milena Veselinovic, MD
Address 0 0
AVROBIO
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT04145037