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CAMPSIITE™ RGX-121 Gene Therapy in Subjects With MPS II (Hunter Syndrome)

Primary Purpose

Mucopolysaccharidosis Type II (MPS II)

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

RGX-121

About this trial

This is an interventional treatment trial for Mucopolysaccharidosis Type II (MPS II) focused on measuring MPS II, gene therapy, Hunter Syndrome, Lysosomal Storage Disorder

Eligibility Criteria

4 Months - 5 Years (Child)MaleDoes not accept healthy volunteers

Part 1 Inclusion Criteria:

The subject's legal guardian(s) is (are) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
Is a male ≥4 months to < 5 years of age on Day 1
Must meet any of the following criteria:
- Has a documented diagnosis of MPS II and a has a neurocognitive testing score ≤ 77 (Bayley or Kaufman), OR
- Has a documented diagnosis of MPS II AND has a decline of ≥ 1 standard deviation on serial neurocognitive testing administered between 3 to 36 months apart (Bayley or Kaufman) OR
- Has a relative clinically diagnosed with severe MPS II who has the same IDS mutation as the subject AND in the opinion of a geneticist has inherited a severe form of MPS II OR
- Has documented mutation (s) in IDS that in the opinion of a geneticist is always known to result in a neuronopathic phenotype AND in the opinion of a clinician has a severe form of MPS II

Part 2 Inclusion Criteria:

The subject's legal guardian(s) is (are) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
Is a male ≥4 months to < 5 years of age on Day 1
Has a documented diagnosis of neuronopathic MPS II. Neuronopathic MPS II can be documented with any of the following methods:
- Has a BSID-III Cognitive Composite score at or below -1 SD (85) from normative mean
- Has two consecutive neurodevelopmental assessments that support a decline on MSEL visual receptive, expressive language, or fine motor, or BSID-III cognition, expressive language, or fine motor ≥ 1 SD on serial neurocognitive testing administered between 3 to 36 months apart
- Has a relative clinically diagnosed with neuronopathic MPS II who has the same IDS mutation as the subject AND the subject, in the opinion of a geneticist, has inherited a neuronopathic form of MPS II
- Has documented mutation(s) in IDS known to result in a neuronopathic phenotype

Part 1 Exclusion Criteria:

Has contraindications for intracisternal (IC) injection, intracerebroventricular (ICV) injection or lumbar puncture
Has contraindications for immunosuppressive therapy
Has neurocognitive deficit not attributable to MPS II or diagnosis of a neuropsychiatric condition
Has a (cerebral) ventricular shunt that may impact the proper dosing of the subject
Received hematopoietic stem cell transplantation
Has had prior treatment with an AAV-based gene therapy product
Received ELAPRASE® via intrathecal (IT) administration within 4 months of signing the ICF or experienced a serious hypersensitivity reaction to ELAPRASE®
Has received any investigational product within 30 days of Day 1 or 5 half-lives before signing the ICF, whichever is longer

Part 2 Exclusion Criteria:

Has a contraindication for an IC injection, ICV injection or lumbar puncture
Has contraindications for immunosuppressive therapy
Has neurocognitive deficit not attributable to MPS II or diagnosis of a neuropsychiatric condition
Has a (cerebral) ventricular shunt that may impact the proper dosing of the subject
Received hematopoietic stem cell transplantation
Has had prior treatment with an AAV-based gene therapy product
Is receiving idursulfase (ELAPRASE®) via intrathecal (IT) administration, or a blood brain barrier-crossing enzyme replacement therapy. Subjects receiving IT ELAPRASE® or a blood brain barrier-crossing ERT may enroll if they agree to discontinue these therapies starting at least 3 months prior to dosing with RGX-121, and for the 24 months of follow-up
Has received any investigational product within 30 days of Day 1 or 5 half-lives before signing the ICF, whichever is longer

Sites / Locations

University of California San Francisco, Benioff Children's HospitalRecruiting
St. Peter's University HospitalRecruiting
University of North Carolina Chapel Hill
Children's Hospital of PhiladelphiaRecruiting
Children's Hospital of Pittsburgh - UPMC: Program for Neurodevelopment in Rare Disorders
Hospital de Clinicas de Porto AlegreRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Part 1: RGX-121 Dose 1

Part 1: RGX-121 Dose 2

Part 1: RGX-121 Dose 2 Expanded Cohort

Part 1: RGX-121 Dose 3

Part 1: RGX-121 Dose 3 Expanded Cohort

Part 2: RGX-121 Pivotal Expansion

Arm Description

1.3x10^10 GC/g brain mass of RGX-121

6.5x10^10 GC/g brain mass of RGX-121

2.0x10^11 GC/g brain mass of RGX-121

2.9x10^11 GC/g brain mass of RGX-121 (transgene-specific PCR assay) equivalent to, 2.0x10^11 GC/g brain mass of RGX-121 (Poly-A-specific PCR assay)

2.9x10^11 GC/g brain mass of RGX-121 (transgene-specific PCR assay)

Outcomes

Primary Outcome Measures

Part 1 Safety

Number of participants with treatment-related adverse events and serious adverse events as assessed by CTCAE (Version 4.03).

Part 2 Biomarkers

CSF GAG levels (as measured by D2S6)

Part 2 Biomarkers

CSF GAG levels (as measured by D2S6)

Part 2 Neurodevelopmental parameters

Neurodevelopmental function as measured by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or Mullen Scales of Early Learning (MSEL). The Bayley Scales of Infant Development, or the BSID-III is an individually administered test, designed to evaluate the developmental functioning of infants and small children, between 1 and 42 months of age. The purpose of the test is to identify infants and children with developmental delay. The Mullen Scales of Early Learning (MSEL) is a developmental test to measure cognitive ability, language and motor development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. An increase in raw and age equivalent scores indicates neurodevelopmental skill acquisition. Standard scores compare function to age matched normative data.

Part 2 Neurodevelopmental parameters

Neurodevelopmental function as measured by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or Mullen Scales of Early Learning (MSEL). The Bayley Scales of Infant Development, or the BSID-III is an individually administered test, designed to evaluate the developmental functioning of infants and small children, between 1 and 42 months of age. The purpose of the test is to identify infants and children with developmental delay. The Mullen Scales of Early Learning (MSEL) is a developmental test to measure cognitive ability language and motor development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. An increase in raw and age equivalent scores indicates neurodevelopmental skill acquisition. Standard scores compare function to age matched normative data.

Secondary Outcome Measures

Part 1 Safety

Number of participants with treatment-related adverse events as assessed by CTCAE (Version 4.03)

Part 1 Biomarkers

Glycosaminoglycan levels and iduronate-2-sulfatase activity

Part 1 Neurodevelopmental parameters

Neurodevelopment parameters of cognitive, behavioral & adaptive function as measured by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or Kaufman Assessment Battery for Children, 2nd Edition (KABC-II) and Mullen Scales of Early Learning (MSEL). The BSID-III evaluates the developmental functioning of infants & small children 1 to 42 months old to identify developmental delays. The KABC-II measures cognitive skill & academic knowledge to evaluate knowledge acquired & level of school learning attained. This test evaluates children 2.5 to 12.5 years old in 4 dimensions: mental, sequential and simultaneous processing, & knowledge. The MSEL measures cognitive ability language & motor development & has 5 scales: gross & fine motor, visual reception, & receptive and expressive language. An increase in raw & age equivalent scores indicates neurodevelopmental skill acquisition. Standard scores compare function to age matched normative data.

Part 1 Change in neurodevelopmental parameters

Neurodevelopment parameters of cognitive, behavioral and adaptive function as measured by the Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II), Comprehensive Interview Form. The Vineland Adaptive Behavior Scale II (VABS-II) is a standardized paediatric functional assessment tool. The VABS-II offers a way to measure personal and social self-sufficiency in real-life situations and to observe how these cognitive abilities impact the autonomy management process when put into practice. The VABS-II consists in a semi-structured interview with the parents. Higher scores mean a better outcome.

Part 2 Change in neurodevelopmental parameters

Change from baseline in neurodevelopment effect on daily living skills as measured by the Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II), Comprehensive Interview Form. The Vineland Adaptive Behavior Scale II (VABS-II) is a standardized paediatric functional assessment tool. The VABS-II offers a way to measure personal and social self-sufficiency in real-life situations and to observe how these cognitive abilities impact the autonomy management process when put into practice. The VABS-II consists in a semi-structured interview with the parents. Higher scores mean a better outcome.

Part 2 Change in brain magnetic resonance imaging (MRI) parameters

Change from baseline in brain size as measured on MRI

Part 2 Safety

Number of participants with treatment-related adverse events as assessed by CTCAE (Version 4.03)

Part 2 Biomarkers

Change in Glycosaminoglycan levels and iduronate-2-sulfatase activity

Full Information

NCT ID

NCT03566043

First Posted

May 1, 2018

Last Updated

May 8, 2023

Sponsor

REGENXBIO Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03566043

Brief Title

CAMPSIITE™ RGX-121 Gene Therapy in Subjects With MPS II (Hunter Syndrome)

Official Title

A Phase 1/2/3 Multicenter, Open-Label Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacodynamics of RGX-121 in Pediatric Subjects With MPS II (Hunter Syndrome)

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 27, 2018 (Actual)

Primary Completion Date

May 2024 (Anticipated)

Study Completion Date

May 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

REGENXBIO Inc.

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

RGX-121 is a gene therapy which is intended to deliver a functional copy of the iduronate-2-sulfatase gene (IDS) to the central nervous system. This study is a safety and efficacy, dose ranging study to determine whether RGX-121 is safe, effective and well-tolerated by patients with MPS II.

Detailed Description

MPS II (Hunter Syndrome) is a rare X-linked recessive genetic disease caused by mutations in the iduronate-2-sulfatase gene (IDS). Enzyme replacement therapy (ERT) with recombinant idursulfase (ELAPRASE®) is the only approved product for the treatment of Hunter syndrome, however, ERT as currently administered does not cross the blood brain barrier and is therefore unable to address the unmet need in MPS II patients with central nervous system (CNS) (neurocognition and behavior) involvement. RGX-121 is designed to deliver a functional gene to cells in the CNS. Iduronate-2-sulfatase (I2S) may then be secreted by transduced cells, which may then cross-correct non-transduced cells by taking up the functional enzyme. This is a Phase I/II/III study enrolling in two sequential parts. Part 1 is a Phase I/II, first-in-human, multicenter, open-label, single arm dose escalation study of RGX-121. Three one-time doses of RGX-121 will be studied in up to 16 pediatric subjects who have neuronopathic MPS II. Safety will be the primary focus for the initial 24 weeks after treatment (primary study period) whereupon, subjects will continue to be assessed (safety and efficacy) for up to a total of 104 weeks following treatment with RGX-121. Part 2 is a pivotal expansion, multicenter, open-label, single arm study of RGX-121. A single dose of RGX-121 will be studied in up to 30 pediatric patients who have been diagnosed with neuronopathic MPS II. Subjects will be assessed at various timepoints for 24 months after receiving RGX-121. Subjects will be given the opportunity to enroll in a separate 3-year long-term follow-up study in accordance with the US federal government guidelines for the safety follow-up of patients receiving gene therapy.

6. Conditions and Keywords

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

Mucopolysaccharidosis Type II (MPS II)

Keywords

MPS II, gene therapy, Hunter Syndrome, Lysosomal Storage Disorder

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Model Description

Dose escalation

Masking

None (Open Label)

Masking Description

Open Label

Allocation

Non-Randomized

Enrollment

48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Part 1: RGX-121 Dose 1

Arm Type

Experimental

Arm Description

1.3x10^10 GC/g brain mass of RGX-121

Arm Title

Part 1: RGX-121 Dose 2

Arm Type

Experimental

Arm Description

6.5x10^10 GC/g brain mass of RGX-121

Arm Title

Part 1: RGX-121 Dose 2 Expanded Cohort

Arm Type

Experimental

Arm Description

6.5x10^10 GC/g brain mass of RGX-121

Arm Title

Part 1: RGX-121 Dose 3

Arm Type

Experimental

Arm Description

2.0x10^11 GC/g brain mass of RGX-121

Arm Title

Part 1: RGX-121 Dose 3 Expanded Cohort

Arm Type

Experimental

Arm Description

2.9x10^11 GC/g brain mass of RGX-121 (transgene-specific PCR assay) equivalent to, 2.0x10^11 GC/g brain mass of RGX-121 (Poly-A-specific PCR assay)

Arm Title

Part 2: RGX-121 Pivotal Expansion

Arm Type

Experimental

Arm Description

2.9x10^11 GC/g brain mass of RGX-121 (transgene-specific PCR assay)

Intervention Type

Genetic

Intervention Name(s)

RGX-121

Intervention Description

Recombinant adeno-associated virus serotype 9 capsid containing human iduronate-2-sulfatase expression cassette

Primary Outcome Measure Information:

Title

Part 1 Safety

Description

Number of participants with treatment-related adverse events and serious adverse events as assessed by CTCAE (Version 4.03).

Time Frame

24 Weeks

Title

Part 2 Biomarkers

Description

CSF GAG levels (as measured by D2S6)

Time Frame

52 Weeks

Title

Part 2 Biomarkers

Description

CSF GAG levels (as measured by D2S6)

Time Frame

104 weeks

Title

Part 2 Neurodevelopmental parameters

Description

Time Frame

52 Weeks

Title

Part 2 Neurodevelopmental parameters

Description

Neurodevelopmental function as measured by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or Mullen Scales of Early Learning (MSEL). The Bayley Scales of Infant Development, or the BSID-III is an individually administered test, designed to evaluate the developmental functioning of infants and small children, between 1 and 42 months of age. The purpose of the test is to identify infants and children with developmental delay. The Mullen Scales of Early Learning (MSEL) is a developmental test to measure cognitive ability language and motor development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. An increase in raw and age equivalent scores indicates neurodevelopmental skill acquisition. Standard scores compare function to age matched normative data.

Time Frame

104 weeks

Secondary Outcome Measure Information:

Title

Part 1 Safety

Description

Number of participants with treatment-related adverse events as assessed by CTCAE (Version 4.03)

Time Frame

104 Weeks

Title

Part 1 Biomarkers

Description

Glycosaminoglycan levels and iduronate-2-sulfatase activity

Time Frame

104 Weeks

Title

Part 1 Neurodevelopmental parameters

Description

Time Frame

104 Weeks

Title

Part 1 Change in neurodevelopmental parameters

Description

Time Frame

104 Weeks

Title

Part 2 Change in neurodevelopmental parameters

Description

Time Frame

52 Weeks

Title

Part 2 Change in brain magnetic resonance imaging (MRI) parameters

Description

Change from baseline in brain size as measured on MRI

Time Frame

52 Weeks

Title

Part 2 Safety

Description

Number of participants with treatment-related adverse events as assessed by CTCAE (Version 4.03)

Time Frame

24 Months

Title

Part 2 Biomarkers

Description

Change in Glycosaminoglycan levels and iduronate-2-sulfatase activity

Time Frame

24 Months

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

Genetic-based gender identity

Minimum Age & Unit of Time

4 Months

Maximum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

Eligibility Criteria

Part 1 Inclusion Criteria: The subject's legal guardian(s) is (are) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures Is a male ≥4 months to < 5 years of age on Day 1 Must meet any of the following criteria: Has a documented diagnosis of MPS II and a has a neurocognitive testing score ≤ 77 (Bayley or Kaufman), OR Has a documented diagnosis of MPS II AND has a decline of ≥ 1 standard deviation on serial neurocognitive testing administered between 3 to 36 months apart (Bayley or Kaufman) OR Has a relative clinically diagnosed with severe MPS II who has the same IDS mutation as the subject AND in the opinion of a geneticist has inherited a severe form of MPS II OR Has documented mutation (s) in IDS that in the opinion of a geneticist is always known to result in a neuronopathic phenotype AND in the opinion of a clinician has a severe form of MPS II Part 2 Inclusion Criteria: The subject's legal guardian(s) is (are) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures Is a male ≥4 months to < 5 years of age on Day 1 Has a documented diagnosis of neuronopathic MPS II. Neuronopathic MPS II can be documented with any of the following methods: Has a BSID-III Cognitive Composite score at or below -1 SD (85) from normative mean Has two consecutive neurodevelopmental assessments that support a decline on MSEL visual receptive, expressive language, or fine motor, or BSID-III cognition, expressive language, or fine motor ≥ 1 SD on serial neurocognitive testing administered between 3 to 36 months apart Has a relative clinically diagnosed with neuronopathic MPS II who has the same IDS mutation as the subject AND the subject, in the opinion of a geneticist, has inherited a neuronopathic form of MPS II Has documented mutation(s) in IDS known to result in a neuronopathic phenotype Part 1 Exclusion Criteria: Has contraindications for intracisternal (IC) injection, intracerebroventricular (ICV) injection or lumbar puncture Has contraindications for immunosuppressive therapy Has neurocognitive deficit not attributable to MPS II or diagnosis of a neuropsychiatric condition Has a (cerebral) ventricular shunt that may impact the proper dosing of the subject Received hematopoietic stem cell transplantation Has had prior treatment with an AAV-based gene therapy product Received ELAPRASE® via intrathecal (IT) administration within 4 months of signing the ICF or experienced a serious hypersensitivity reaction to ELAPRASE® Has received any investigational product within 30 days of Day 1 or 5 half-lives before signing the ICF, whichever is longer Part 2 Exclusion Criteria: Has a contraindication for an IC injection, ICV injection or lumbar puncture Has contraindications for immunosuppressive therapy Has neurocognitive deficit not attributable to MPS II or diagnosis of a neuropsychiatric condition Has a (cerebral) ventricular shunt that may impact the proper dosing of the subject Received hematopoietic stem cell transplantation Has had prior treatment with an AAV-based gene therapy product Is receiving idursulfase (ELAPRASE®) via intrathecal (IT) administration, or a blood brain barrier-crossing enzyme replacement therapy. Subjects receiving IT ELAPRASE® or a blood brain barrier-crossing ERT may enroll if they agree to discontinue these therapies starting at least 3 months prior to dosing with RGX-121, and for the 24 months of follow-up Has received any investigational product within 30 days of Day 1 or 5 half-lives before signing the ICF, whichever is longer

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Patient Advocacy

Phone

866-860-0117

MPSII@regenxbio.com

Facility Information:

Facility Name

University of California San Francisco, Benioff Children's Hospital

City

Oakland

State/Province

California

ZIP/Postal Code

94609

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Matt Thura

Phone

510-428-3885

Ext

5241

matt.thura@ucsf.edu

First Name & Middle Initial & Last Name & Degree

Dr. Paul Harmatz

Facility Name

St. Peter's University Hospital

City

New Brunswick

State/Province

New Jersey

ZIP/Postal Code

08901

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Alexander Schramm - Director, Office of Research

Phone

732-745-8600

Ext

8628

aschramm@saintpetersuh.com

First Name & Middle Initial & Last Name & Degree

Debra-Lynn Day-Salvatore, MD

Facility Name

University of North Carolina Chapel Hill

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Lindsay Torrice

Phone

919-966-1135

Lindsay_torrice@med.unc.edu

First Name & Middle Initial & Last Name & Degree

Elizabeth Jalazo, MD

Facility Name

Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Genevieve Nesom

Phone

267-426-1368

nesomg@chop.edu

First Name & Middle Initial & Last Name & Degree

Dr. Can Ficicioglu

Facility Name

Children's Hospital of Pittsburgh - UPMC: Program for Neurodevelopment in Rare Disorders

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15224

Country

United States

Individual Site Status

Active, not recruiting

Facility Name

Hospital de Clinicas de Porto Alegre

City

Porto Alegre

State/Province

ZIP/Postal Code

90035-903

Country

Brazil

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marina Zambrano

Phone

55 51 3359-6340

mzambrano@hcpa.edu.br

First Name & Middle Initial & Last Name & Degree

Dr. Roberto Giugliani

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

CAMPSIITE™ RGX-121 Gene Therapy in Subjects With MPS II (Hunter Syndrome)

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