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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04145037




Registration number
NCT04145037
Ethics application status
Date submitted
27/08/2019
Date registered
30/10/2019
Date last updated
23/08/2023

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:

1. Subject is =18 and =50 years old and post pubertal

2. Subject has 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 are not available, deficient
trough GCase enzyme activity in peripheral blood at Screening.

3. Female subjects of reproductive potential will be counseled regarding the risks,
benefits, limitations, and alternatives associated with female fertility preservation.
Oocyte harvesting and cryopreservation will be offered

4. Male subjects must be 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 will be recommended.

5. All subjects who have not undergone successful surgical sterilization (ie, vasectomy,
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) must agree 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 are required even with documented medical
assessment of surgical success of sterilization.

1. For male subjects and for male spouses/partners of female subjects, condoms are
an acceptable method of barrier contraception

2. For female subjects and for female spouses/partners of male subjects, acceptable
methods of barrier contraception include diaphragm, cervical cap, or
contraceptive sponge

6. Male and female subjects must agree to refrain from donating sperm and eggs,
respectively, after undergoing conditioning.

7. Subject must be willing to refrain from donating blood, organs, tissues, or cells for
gene therapy infusion any time after AVR-RD-02 treatment.

8. Subject must be 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 must be 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 has 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 has 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 has 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 has 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 has 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 has 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 is treatment-naïve, ERT peri-procedurally (from the Screening
Period throughout 2 weeks prior to Gene Therapy Infusion) will be considered in
consultation with the PI and Sponsor Medical Monitor.

EXCLUSION CRITERIA:

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

2. Subject has 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 has experienced a prior anaphylactic or anaphylactoid reaction (of any
severity) to ERT.

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

5. Subject has a contraindication to ERT, in the opinion of the Investigator.

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

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

8. Subject has 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 has 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 confound the study results or, in the opinion of the
Investigator, may preclude participation in the study.

10. Subject is a pregnant and/or lactating female.

11. Subject is unable to understand the nature, scope, and possible consequences of the
study.

12. Subject has diabetes mellitus (Type 1 or Type 2).

13. Subject has active, progressive bone necrosis.

14. Subject has an active chronic infection during the Screening, Baseline, or Pre-gene
Therapy Infusion Period of the study.

15. Subject has 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 has a history of (or current) tuberculosis.

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

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

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

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

24. Subject is 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 is treatment with cytotoxic or
immunosuppressive agents required per protocol for stem cell transplant.

25. Subject is 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 has any condition that makes it impossible to perform MRI studies.

27. Subject has medical condition(s) and/or is receiving medication(s) that would
contraindicate ability to undergo mobilization (including contraindication to G-CSF
and/or plerixafor), apheresis, or conditioning.

28. Busulfan is contraindicated for the subject.

29. Subject has previously received treatment with AVR-RD-02 or any other gene therapy.

30. Subject is 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/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
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
7
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 not provided in https://clinicaltrials.gov/ct2/show/NCT04145037