Mucopolysaccharidosis Type VIPhase 1/2NCT03173521
Gene Therapy in Patients With Mucopolysaccharidosis Disease
A Phase 1/2 study testing AAV2/8.TBG.hARSB in people with Mucopolysaccharidosis Type VI, run by Fondazione Telethon at 2 sites in 2 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 4 to 65 years
- Conditions the study is for
- Mucopolysaccharidosis Type VI
- What is being tested?
- AAV2/8.TBG.hARSB
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 17 Jul 2017to 16 Jul 2024
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
- Subjects must be of 4 years of age or older.
- 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.
- Documented informed consent; willingness to adhere to protocol and to participate to long-term follow-up, as evidenced by written informed consent.
Who cannot join
- Subjects unable or unwilling to meet requirements of the study.
- Participation in a clinical study with an investigational drug in the 6 months prior to enrolment in this trial.
- Subjects unable to perform the 6MWT.
- 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).
- Presence of tracheostomy or need of ventilatory assistance.
- Subjects with evidence of progressive myelomalacia that is considered severe enough to require neck surgery in the first six months after enrolment.
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- Values of AST or ALT above the upper limit of normal range at baseline 2 (at -5days) evaluations.
- Co-existence of chronic diseases or clinically relevant abnormal baseline laboratory values; infections with hepatitis B, C, or HIV (Baseline 1).
- Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs within 2 months prior to IMP administration.
- Female individuals of childbearing age who are pregnant or nursing or unwilling to use effective contraception for at least one year post-IMP administration.
- Fertile male individuals who are unwilling to use male barrier contraceptives such as condom.
- 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.
- Presence of serum NAB to AAV8 above the limit of detection of the assay (Screening and Baseline 1).
- 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.
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
Italy1 site
Department of Translational Medicine (DISMET) of "Federico II" University, Naples
Naples, 80131
Turkey (Türkiye)1 site
Children's Hospital Hacettepe University
Ankara
About this study
Official title: 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.
Read the 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.
- Conditions
- Mucopolysaccharidosis Type VI
- Being tested
- AAV2/8.TBG.hARSB
- Keywords
- MPSVI
- Medical subject headings
- Mucopolysaccharidosis VI
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AAV2/8.TBG.hARSBBiological
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.
| Study group | Role | What they receive |
|---|---|---|
| open label | Experimental | 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. Receives: Biological: AAV2/8.TBG.hARSB |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and tolerability of the IMP administration
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).
Measured: 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
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.
Measured: 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 outcomes (2)
Secondary efficacy outcome - endurance
Endurance as measured by 6-minute walk test (6MWT) in walking subjects, 3-minute stair climb test (3MSCT) in walking subjects.
Measured: 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
Forced vital capacity (FVC), and forced expiratory volume at 1 second (FEV1) in cooperative subjects.
Measured: From GT up to 5 years post IMP administration at the following visits: months 4,9,12; years 1.5, 2, 2.5, 3.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jun 2017
- Study start17 Jul 2017
- Primary completion30 Jul 2021
- Study completion16 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Mucopolysaccharidosis Type VIStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Open Label
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione Telethon
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Nicola Brunetti-Pierri, Principal investigator, Department of Translational Medicine (DISMET) of "Federico II" University, Naples
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03173521
- Sponsor's protocol ID
- TIGEM1-MPS VI
- Status last verified
- Nov 2024
- First submitted
- 12 Apr 2017
- Last updated
- 22 Nov 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Rossi A, Romano R, Fecarotta S, Dell'Anno M, Pecorella V, Passeggio R, Zancan S, Parenti G, Santamaria F, Borgia F, Deodato F, Funghini S, Rupar CA, Prasad C, O'Callaghan M, Mitchell JJ, Valsecchi MG, la Marca G, Galimberti S, Auricchio A, Brunetti-Pierri N. Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy. Med. 2025 Apr 11;6(4):100544. doi: 10.1016/j.medj.2024.10.021. Epub 2024 Nov 14.
PubMed 39547230Brunetti-Pierri N, Ferla R, Ginocchio VM, Rossi A, Fecarotta S, Romano R, Parenti G, Yildiz Y, Zancan S, Pecorella V, Dell'Anno M, Graziano M, Alliegro M, Andria G, Santamaria F, Brunetti-Pierri R, Simonelli F, Nigro V, Vargas M, Servillo G, Borgia F, Soscia E, Gargaro M, Funghini S, Tedesco N, Le Brun PR, Rupar CA, Prasad C, O'Callaghan M, Mitchell JJ, Danos O, Marteau JB, Galimberti S, Valsecchi MG, Veron P, Mingozzi F, Fallarino F, la Marca G, Sivri HS, Auricchio A. Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI. NEJM Evid. 2022 Jul;1(7):EVIDoa2200052. doi: 10.1056/EVIDoa2200052. Epub 2022 Jun 6.
PubMed 38319253
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03173521
- Acronym / sponsor ID
- TIGEM1-MPS VI
- Conditions
- Mucopolysaccharidosis Type VI
- Keywords
- MPSVI
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Fondazione TelethonUniversity, hospital or other
- Study start
- 17 Jul 2017 (actual)
- Primary completion
- 30 Jul 2021 (actual)
- Study completion
- 16 Jul 2024 (actual)
- First posted
- 2 Jun 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open Label
| Arm | Type | Receives |
|---|---|---|
| open label | Experimental | Biological: AAV2/8.TBG.hARSBAdeno-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. |
Who may qualify
- Ages
- 4 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
- Subjects must be of 4 years of age or older.
- 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.
- Documented informed consent; willingness to adhere to protocol and to participate to long-term follow-up, as evidenced by written informed consent.
Key exclusion criteria (14 listed)
- Subjects unable or unwilling to meet requirements of the study.
- Participation in a clinical study with an investigational drug in the 6 months prior to enrolment in this trial.
- Subjects unable to perform the 6MWT.
- 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).
- Presence of tracheostomy or need of ventilatory assistance.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AAV2/8.TBG.hARSBAdeno-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. | Biological | open label |
Primary outcome
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).
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.
2 secondary outcomes
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.
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2024.
- Derived from this study: PubMed 39547230Rossi A, Romano R, Fecarotta S, Dell'Anno M, Pecorella V, Passeggio R, Zancan S, Parenti G, Santamaria F, Borgia F, Deodato F, Funghini S, Rupar CA, Prasad C, O'Callaghan M, Mitchell JJ, Valsecchi MG, la Marca G, Galimberti S, Auricchio A, Brunetti-Pierri N. Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy. Med. 2025 Apr 11;6(4):100544. doi: 10.1016/j.medj.2024.10.021. Epub 2024 Nov 14.
- Derived from this study: PubMed 38319253Brunetti-Pierri N, Ferla R, Ginocchio VM, Rossi A, Fecarotta S, Romano R, Parenti G, Yildiz Y, Zancan S, Pecorella V, Dell'Anno M, Graziano M, Alliegro M, Andria G, Santamaria F, Brunetti-Pierri R, Simonelli F, Nigro V, Vargas M, Servillo G, Borgia F, Soscia E, Gargaro M, Funghini S, Tedesco N, Le Brun PR, Rupar CA, Prasad C, O'Callaghan M, Mitchell JJ, Danos O, Marteau JB, Galimberti S, Valsecchi MG, Veron P, Mingozzi F, Fallarino F, la Marca G, Sivri HS, Auricchio A. Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI. NEJM Evid. 2022 Jul;1(7):EVIDoa2200052. doi: 10.1056/EVIDoa2200052. Epub 2022 Jun 6.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nicola Brunetti-Pierri principal investigator
Department of Translational Medicine (DISMET) of "Federico II" University, Naples
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing AAV2/8.TBG.hARSB in people with Mucopolysaccharidosis Type VI, run by Fondazione Telethon at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy, Turkey (Türkiye). Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03173521, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2024.