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In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases (IUERT)

Primary Purpose

MPS I, MPS II, MPS IVA

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Aldurazyme (laronidase)

About this trial

This is an interventional treatment trial for MPS I

Eligibility Criteria

18 Years - 50 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Live male or female fetuses at 18 0/7 weeks to 34 6/7 weeks gestation
Diagnosis of one of the 8 included LSDs in utero by genetic or enzymatic analyses performed on amniotic fluid, fetal blood, placental tissue, or other samples through chorionic villus sampling (CVS), amniocentesis, cordocentesis, cell free fetal DNA, or other procedures. In the event that parents are identified as genetic carriers for a LSD, diagnostic testing for the fetus would be performed to confirm the diagnosis
Pregnant women age 18 years to 50 years, carrying a live male or female fetus at 18 0/7 weeks to 34 6/7 weeks gestation
Identified through the above listed means to be carrying a fetus with an LSD.
Ability to give written informed consent and comply with the requirements of the study.

Exclusion Criteria:

Fetuses with a concurrent severe structural anomaly
Fetuses with an additional pathogenic genetic variant not related to the underlying LSD that contribute a significant risk of morbidity or mortality.

Hydrops fetalis will not be an exclusion criterion because ERT has the possibility of significant benefit in this situation.

Women with one or more significant comorbidities that would preclude fetal intervention including, but not limited to:
1. inability to complete the procedure secondary to maternal body habitus or placental location
2. significant cardiopulmonary disease
3. mirror syndrome
4. end organ failure
5. altered mental status
6. placental abruption
7. active preterm labor
8. preterm premature rupture of membranes.
Mother will require therapeutic dosing of anticoagulation within 24 hours prior to or following the intervention.

Sites / Locations

University of CaliforniaRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental: in utero enzyme replacement therapy

Arm Description

ERT will be delivered in utero. Typically, the target of the procedure to administer in utero ERT will be the umbilical vein near the insertion of the umbilical cord into the placenta. The dose of the ERT will be dependent on the specific disease process and enzyme being replaced, and the estimated weight of the fetus. The dosage will be the same as the recommended weight-based postnatal dosing, adjusted for estimated fetal weight. IUERT will be repeated every 2-4 weeks, which is an interval consistent with the standard of care for IUTs (every 2-4 weeks) to avoid excessive access through the umbilical vein. This interval is also consistent with the half-life of each relevant enzyme.

Outcomes

Primary Outcome Measures

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.

Adverse and serious adverse events including, but not limited to, death within 24 hours after the procedure, stillbirth, death prior to initial hospital discharge,increased response with antibody development above that expected with postnatal ERT, and serious related or serious unexpected adverse events exceeding those expected with the natural history of treated disease during the first five years of life, assessed by CTCAE v5.0.

Number of participants to receive the full initial, weight-based dose of enzyme replacement therapy through the fetal umbilical vein, and subsequent doses throughout the pregnancy.

full dose administration compared to the need to halt the intervention prior to administration of a full dose.

Number of participants with the presence and levels of glycosaminoglycans (GAGs) in urine.

Laboratory analysis of urine for GAG levels.

The number of participants with improvement or resolution of hydrops (if present).

Improvement of hydrops via ultrasound and echocardiogram results (if present).

Secondary Outcome Measures

Number of participants that show measured levels of antibodies against the enzyme.

Laboratory analysis of blood to measure antibody levels.

Full Information

NCT ID

NCT04532047

First Posted

August 19, 2020

Last Updated

September 18, 2023

Sponsor

University of California, San Francisco

Collaborators

Duke University

1. Study Identification

Unique Protocol Identification Number

NCT04532047

Brief Title

In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases

Acronym

IUERT

Official Title

In Utero Enzyme Replacement Therapy (ERT) for Prenatally Diagnosed Lysosomal Storage Disorders (LSDs).

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

July 1, 2021 (Actual)

Primary Completion Date

July 2031 (Anticipated)

Study Completion Date

July 2032 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, San Francisco

Collaborators

Duke University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The investigators aims to determine the the maternal and fetal safety and feasibility of in utero fetal enzyme replacement therapy in fetuses with Lysosomal Storage Diseases.

Detailed Description

Because fetuses with these LSDs are at increased risk of serious perinatal morbidity and mortality, particularly in the setting of Non-Immune Hydrops Fetalis (NIHF), the administration of the approved enzyme therapy in utero has the potential to significantly improve outcomes for affected fetuses. The perinatal death rate associated with NIHF ranges from 30 to 75%, so development of an in utero approach to treatment could be of significant benefit. The in utero period has been shown to be a time of relative fetal tolerance to immune stimuli, and this tolerance may lead to improved response to ERT in situations where postnatal initiation instead leads to antibody development and impaired response to treatment. It is also probable that in some cases, initiation of ERT in utero leads to improved neurodevelopmental outcomes if the replaced enzyme impacts the neurologic system during critical periods of development. This is a phase 1 clinical trial to determine the safety and feasibility of fetal enzyme replacement therapy in fetuses with LSD

6. Conditions and Keywords

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

MPS I, MPS II, MPS IVA, MPS VI, Mps VII, Gaucher Disease, Type 2, Gaucher Disease, Type 3, Pompe Disease Infantile-Onset, Wolman Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Experimental: in utero enzyme replacement therapy

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Aldurazyme (laronidase)

Other Intervention Name(s)

Elaprase (idursulfase), Vimizim (elosulfase alfa), Naglazyme (galsulfase), Mepsevii (vestronidase alfa-vjbk), Lumizyme (alglucosidase alfa), Kanuma (sebelipase alfa)

Intervention Description

Enzyme replacement therapy for lysosomal storage diseases

Primary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.

Description

Time Frame

6 years

Title

Number of participants to receive the full initial, weight-based dose of enzyme replacement therapy through the fetal umbilical vein, and subsequent doses throughout the pregnancy.

Description

full dose administration compared to the need to halt the intervention prior to administration of a full dose.

Time Frame

6 years

Title

Number of participants with the presence and levels of glycosaminoglycans (GAGs) in urine.

Description

Laboratory analysis of urine for GAG levels.

Time Frame

6 years

Title

The number of participants with improvement or resolution of hydrops (if present).

Description

Improvement of hydrops via ultrasound and echocardiogram results (if present).

Time Frame

6 years

Secondary Outcome Measure Information:

Title

Number of participants that show measured levels of antibodies against the enzyme.

Description

Laboratory analysis of blood to measure antibody levels.

Time Frame

6 years

Other Pre-specified Outcome Measures:

Title

Number of participants that show functional cardiac, growth, mobility, and neurocognitive function.

Description

ecogardiogram, skeletal survey, neurocognitve assessments such as Bayley III to assess cardiac, growth, mobility and neurocognitive function.

Time Frame

6 years

10. Eligibility

Sex

Female

Gender Based

Yes

Gender Eligibility Description

Maternal pregnant women of age 18-50, carrying a male or female fetus at 18 0/7 weeks to 34 6/7 weeks.

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Live male or female fetuses at 18 0/7 weeks to 34 6/7 weeks gestation Diagnosis of one of the 8 included LSDs in utero by genetic or enzymatic analyses performed on amniotic fluid, fetal blood, placental tissue, or other samples through chorionic villus sampling (CVS), amniocentesis, cordocentesis, cell free fetal DNA, or other procedures. In the event that parents are identified as genetic carriers for a LSD, diagnostic testing for the fetus would be performed to confirm the diagnosis Pregnant women age 18 years to 50 years, carrying a live male or female fetus at 18 0/7 weeks to 34 6/7 weeks gestation Identified through the above listed means to be carrying a fetus with an LSD. Ability to give written informed consent and comply with the requirements of the study. Exclusion Criteria: Fetuses with a concurrent severe structural anomaly Fetuses with an additional pathogenic genetic variant not related to the underlying LSD that contribute a significant risk of morbidity or mortality. Hydrops fetalis will not be an exclusion criterion because ERT has the possibility of significant benefit in this situation. Women with one or more significant comorbidities that would preclude fetal intervention including, but not limited to: inability to complete the procedure secondary to maternal body habitus or placental location significant cardiopulmonary disease mirror syndrome end organ failure altered mental status placental abruption active preterm labor preterm premature rupture of membranes. Mother will require therapeutic dosing of anticoagulation within 24 hours prior to or following the intervention.

Central Contact Person:

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

Tippi MacKenzie, MD

Phone

415-476-4086

tippi.mackenzie@ucsf.edu

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

Emma Canepa, MS, CCRP

Phone

415-476-7255

Emma.Canepa@ucsf.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tippi MacKenzie, MD

Organizational Affiliation

University of California, San Francisco

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of California

City

San Francisco

State/Province

California

ZIP/Postal Code

94158

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Emma Canepa, MS, CCRP

Phone

415-476-7255

Emma.Canepa@ucsf.edu

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

32102934

Citation

Nguyen QH, Witt RG, Wang B, Eikani C, Shea J, Smith LK, Boyle G, Cadaoas J, Sper R, MacKenzie JD, Villeda S, MacKenzie TC. Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII. Sci Transl Med. 2020 Feb 26;12(532):eaay8980. doi: 10.1126/scitranslmed.aay8980.

Results Reference

result

PubMed Identifier

30337566

Citation

Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Author Correction: Lysosomal storage diseases. Nat Rev Dis Primers. 2018 Oct 18;4(1):36. doi: 10.1038/s41572-018-0037-0.

Results Reference

result

PubMed Identifier

9918480

Citation

Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20;281(3):249-54. doi: 10.1001/jama.281.3.249.

Results Reference

result

PubMed Identifier

15324318

Citation

Azevedo AC, Schwartz IV, Kalakun L, Brustolin S, Burin MG, Beheregaray AP, Leistner S, Giugliani C, Rosa M, Barrios P, Marinho D, Esteves P, Valadares E, Boy R, Horovitz D, Mabe P, da Silva LC, de Souza IC, Ribeiro M, Martins AM, Palhares D, Kim CA, Giugliani R. Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI. Clin Genet. 2004 Sep;66(3):208-13. doi: 10.1111/j.1399-0004.2004.00277.x.

Results Reference

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PubMed Identifier

23510062

Citation

Rosenbloom BE, Weinreb NJ. Gaucher disease: a comprehensive review. Crit Rev Oncog. 2013;18(3):163-75. doi: 10.1615/critrevoncog.2013006060.

Results Reference

result

PubMed Identifier

19948615

Citation

Chien YH, Lee NC, Thurberg BL, Chiang SC, Zhang XK, Keutzer J, Huang AC, Wu MH, Huang PH, Tsai FJ, Chen YT, Hwu WL. Pompe disease in infants: improving the prognosis by newborn screening and early treatment. Pediatrics. 2009 Dec;124(6):e1116-25. doi: 10.1542/peds.2008-3667.

Results Reference

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PubMed Identifier

28374935

Citation

Blitz MJ, Rochelson B, Sood M, Bialer MG, Vohra N. Prenatal sonographic findings in a case of Wolman's disease. J Clin Ultrasound. 2018 Jan;46(1):66-68. doi: 10.1002/jcu.22481. Epub 2017 Apr 4.

Results Reference

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PubMed Identifier

28657663

Citation

Tsai AC, Hung YW, Harding C, Koeller DM, Wang J, Wong LC. Next generation deep sequencing corrects diagnostic pitfalls of traditional molecular approach in a patient with prenatal onset of Pompe disease. Am J Med Genet A. 2017 Sep;173(9):2500-2504. doi: 10.1002/ajmg.a.38333. Epub 2017 Jun 28.

Results Reference

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PubMed Identifier

21637107

Citation

Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, Chen YT, Rosenberg AS, Kishnani PS. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med. 2011 Aug;13(8):729-36. doi: 10.1097/GIM.0b013e3182174703.

Results Reference

result

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In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases

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