Gene Therapy in Patients With Mucopolysaccharidosis Disease

November 22, 2021 updated by: Fondazione Telethon

A Phase I/II Open Label, Dose Escalation, Safety Study in Subjects With Mucopolysaccharidosis Type VI (MPS VI) Using Adeno-Associated Viral Vector 8 to Deliver the Human ARSB Gene to Liver

This study investigated the safety and efficacy of gene therapy approaches for Mucopolysaccharidosis type VI disease caused by the deficiency of arylsulfatase B (ARSB) enzyme. The aim of the study is to evaluate the safety and efficacy of the treatment.

Study Overview

Status

Active, not recruiting

Intervention / Treatment

Detailed Description

Mucopolysaccharidosis type VI disease is involved in Lysosomal Storage Disorder. The MPS VI disease is characterized by growth retardation, corneal clouding, cardiac valve disease, organomegaly, skeletal dysplasia, without central nervous system involvement.

Study Type

Interventional

Enrollment (Actual)

9

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Naples, Italy, 80131
        • Department of Translational Medicine (DISMET) of "Federico II" University, Naples
      • Ankara, Turkey
        • Children's Hospital Hacettepe University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 63 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Documented biochemical and molecular diagnosis of MPS VI. Testing for homozygous or compound heterozygous disease-causing mutations of the ARSB gene must have been performed by an accredited laboratory.
  2. Subjects must be of 4 years of age or older.
  3. Subjects should have received ERT for at least 12 months before enrolment and should continue to receive ERT until 7-14 days before IMP administration.
  4. Documented informed consent; willingness to adhere to protocol and to participate to long-term follow-up, as evidenced by written informed consent.

Exclusion Criteria:

  1. Subjects unable or unwilling to meet requirements of the study.
  2. Participation in a clinical study with an investigational drug in the 6 months prior to enrolment in this trial.
  3. Subjects unable to perform the 6MWT.
  4. History of severe anaphylactoid reaction to Naglazyme in subjects receiving ERT that could affect the safety (severe reaction is meant to be a respiratory impairment event that is life-threatening).
  5. Presence of tracheostomy or need of ventilatory assistance.
  6. Subjects with evidence of progressive myelomalacia that is considered severe enough to require neck surgery in the first six months after enrolment.
  7. Values of AST or ALT above the upper limit of normal range at baseline 2 (at -5days) evaluations.
  8. Co-existence of chronic diseases or clinically relevant abnormal baseline laboratory values; infections with hepatitis B, C, or HIV (Baseline 1).
  9. Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs within 2 months prior to IMP administration.
  10. Female individuals of childbearing age who are pregnant or nursing or unwilling to use effective contraception for at least one year post-IMP administration.
  11. Fertile male individuals who are unwilling to use male barrier contraceptives such as condom.
  12. Any other condition that would not allow the subject to complete follow-up examinations during the course of the study and that, in the opinion of the Investigator, would make the subject unsuitable for the study.
  13. Presence of serum NAB to AAV8 above the limit of detection of the assay (Screening and Baseline 1).
  14. Presence of serum antibodies anti-ARSB above the upper limit of detection of the assay (antibodies anti-ARSB level >31250 or declared positive at the value of serum dilution 1.10 according to the performed assay) at Screening and Baseline 1.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: open label

Adeno-associated viral vector serotype 8 with liver-specific thyroxine-binding globulin (TBG) promoter driving the expression of the human ARSB gene diluted in its final formulation medium [Drug product (DP) diluted in 0.9% saline solution and 0.25% of human serum albumin].

Four dose levels are available:

  • 'Starting dose' is 6x1011 gc of vector per kg of body weight.
  • 'High dose' is 2x1012 gc of vector per kg of body weight.
  • 'Very high dose' is 6x1012 gc of vector per kg of body weight.
  • 'Low dose' is 2x1011 gc of vector per kg of body weight. Intermediate doses are also possible. The administration of the IMP will be performed into a peripheral vein (e.g. median cubital vein) over 2-4 hours using an infusion pump. The IMP final volume to be injected is calculated based on the patient's weight (determined on the day of hospital admission), as 3 mL/kg.

Adeno-associated viral vector serotype 8 with liver-specific thyroxinebinding globulin (TBG) promoter driving the expression of the human ARSB gene. Four dose levels are available:

  • Starting dose is 6x1011 gc of vector per kg of body weight;
  • High dose is 2x1012 gc of vector per kg of body weight and will be administered after at least two subjects at the starting dose have experienced no DLT;
  • Very high dose is 6x1012 vector per kg of body weight and will be administered after three subjects at the high dose have experienced no DLT;
  • Low dose is 2x1011 gc of vector per kg of body weight. Intermediate doses are also possible. The administration of the IMP will be performed into a peripheral vein. The IMP final volume to be injected is calculated based on the patient's weight (determined on the day of hospital admission), as 3 mL/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety and tolerability of the IMP administration
Time Frame: From GT up to 5 years post IMP administration at the following visits: days 1,2,3; weeks 2,3,6,7,8,9,10,11,12,13,14; months 4,9,12; years 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.
Overall safety and tolerability will be determined through monitoring of adverse events, laboratory and clinical investigations and imaging studies (for example complete physical examination with vital signs recording, liver ultrasound, measurement of transaminases, thyroids hormones, creatinine, albumin, total proteins in blood and urine, and urea, C3 and C4 in blood).
From GT up to 5 years post IMP administration at the following visits: days 1,2,3; weeks 2,3,6,7,8,9,10,11,12,13,14; months 4,9,12; years 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.
Primary efficacy outcome - Urinary GAG levels
Time Frame: From GT up to 5 years post IMP administration at the following visits: days 1,2,3; months 4,9,12,15; years 1.5,1.75, 2, 2.5, 3, 4, 5.
To determine the efficacy of gene therapy, post-injection urinary GAG excretion levels will be compared to the average of pre-injection urinary GAG determined at baseline 1 and at visit 1.
From GT up to 5 years post IMP administration at the following visits: days 1,2,3; months 4,9,12,15; years 1.5,1.75, 2, 2.5, 3, 4, 5.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Secondary efficacy outcome - endurance
Time Frame: From GT up to 5 years post IMP administration at the following visits: months 4,9,12; years 1.5, 2, 2.5, 3.
Endurance as measured by 6-minute walk test (6MWT) in walking subjects, 3-minute stair climb test (3MSCT) in walking subjects.
From GT up to 5 years post IMP administration at the following visits: months 4,9,12; years 1.5, 2, 2.5, 3.
Secondary efficacy outcome - lung volumes
Time Frame: From GT up to 5 years post IMP administration at the following visits: months 4,9,12; years 1.5, 2, 2.5, 3.
Forced vital capacity (FVC), and forced expiratory volume at 1 second (FEV1) in cooperative subjects.
From GT up to 5 years post IMP administration at the following visits: months 4,9,12; years 1.5, 2, 2.5, 3.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Nicola Brunetti-Pierri, Department of Translational Medicine (DISMET) of "Federico II" University, Naples

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 17, 2017

Primary Completion (Anticipated)

June 30, 2025

Study Completion (Anticipated)

September 30, 2025

Study Registration Dates

First Submitted

April 12, 2017

First Submitted That Met QC Criteria

May 29, 2017

First Posted (Actual)

June 2, 2017

Study Record Updates

Last Update Posted (Actual)

December 6, 2021

Last Update Submitted That Met QC Criteria

November 22, 2021

Last Verified

November 1, 2021

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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