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Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C

Primary Purpose

Niemann-Pick Disease, Type C

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
2-Hydroxypropyl-Beta-Cyclodextrin
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Niemann-Pick Disease, Type C

Eligibility Criteria

undefined - 6 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 0 to 6 months of age at time of enrollment, both genders, and any race/ethnicity.

  2. Diagnosis of NPC (either NPC1 or NPC2) based upon meeting any of the two following conditions:

    A. Two NPC1/NPC2 mutations, or B. One NPC1/NPC2 mutation and a positive NPC biochemical marker (oxysterol or bile acid biomarker) test Mutations will be interpreted using the American College of Medical Genetics guidelines for the interpretation of sequence variants (2015) and testing must be performed by a CLIA-certified laboratory.

  3. Subjects with evidence of NPC-related liver disease as defined by direct bilirubin (DB) >2mg/dL or DB/total bilirubin ratio >0.2.
  4. Ability to travel to a research site.
  5. Willing to participate in all aspects of trial design including serial blood collections.
  6. Parent / guardian must provide written informed consent to participate in the study. Because of the age range intended for inclusion, assent will not possible.

Exclusion Criteria:

  1. Age > 6 months at time of enrollment in the trial.
  2. A medical condition (such as clinically significant bleeding diathesis or evidence of immune suppression) that in the opinion of the investigator precludes placement of an intravenous catheter
  3. An absolute neutrophil count (ANC) of less than 1,500 per microliter.
  4. A platelet count less than 75,000 per microliter.
  5. History of severe neonatal encephalopathy, per SIBEN (Score of the Iberoamerican Society of Neonatology) including level of consciousness as stupor/coma, absent spontaneous activity, decerebrate posture, flaccid tone, absent suck, absent moro, diverted/nonreactive pupils, lack of heart rate variability, apnea, and infrequent seizures.
  6. Subjects, who in the opinion of the investigators, are unable to comply with the protocol or have specific health concerns that would potentially increase the risk of participation. Examples of inability to comply include unwillingness to relocate or travel to a study site, suspected noncompliance with study procedures, behavior that jeopardizes the safety or security of the data or study staff, and other causes of inability to comply.
  7. Concurrent participation in another investigational drug trial.
  8. History of renal disease or evidence of acute kidney injury defined as serum creatinine greater than 1.5 mg/dL or an increase of at least 0.2-0.3 mg/dL per day.

Sites / Locations

  • St. Louis Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

IV VTS-270 for NPC1 infants

Arm Description

Phase 1: Dosing frequency will be twice a week administered via a peripherally inserted central catheter (PICC) for six weeks for a total of 12 administrations. Doses 3-12 will occur as an outpatient. Doses to be studied are 500, and 1000 mg/kg. Six subjects will be studied at each dose level. Cohort 1: Subjects 1-6 will receive 500 mg/kg Cohort 2: Subjects 7-12 will receive 1000 mg/kg Subjects who demonstrate significant reduction either in the glycine-conjugated trihydroxycholanic acid biomarker or serum bilirubin (direct bilirubin or direct bilirubin:total bilirubin ratio) will be allowed to crossover into the second phase of the study, an open-label phase of six months duration. In the this phase of the study, dosing frequency will be monthly with IV VTS-270 administered via peripheral IV access for six months for a total of six administrations.

Outcomes

Primary Outcome Measures

Efficacy of VTS-270 to reduce plasma levels of glycine-conjugated trihydroxycholanic acid ("bile acid biomarker"), an NPC-specific pharmacodynamic biomarker.
This bile acid is a metabolite of cholesterol, is elevated >99% of NPC1 subjects, is largely generated in the liver and therefore provides a biochemical measure of oxidizable lysosomal unesterified cholesterol in liver tissue. The outcome measure in phase 1 of the study is the change in bile acid levels from baseline to 6 weeks. The outcome measure in phase 2 of the study is the change in bile acid levels from 6 weeks to the end of the 6 month treatment period.

Secondary Outcome Measures

Effect of drug on serum transaminases
Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) are elevated with liver dysfunction. The outcome measure in phase 1 of the study is the change in ALT and AST levels from baseline to 6 weeks. The outcome measure in phase 2 of the study is the change in ALT and AST levels from 6 weeks to the end of the 6 month treatment period.
Reduction of liver and/or spleen volumes
Abdominal ultrasound. The outcome measure in phase 1 of the study is the change in liver and/or spleen volumes from baseline to 6 weeks. The outcome measure in phase 2 of the study is the change in liver and/or spleen volumes from 6 weeks to the end of the 6 month treatment period.

Full Information

First Posted
March 7, 2018
Last Updated
June 29, 2023
Sponsor
Washington University School of Medicine
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT03471143
Brief Title
Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
Official Title
Phase 1/2a Study of 2-Hydroxypropyl-Beta-Cyclodextrin Therapy for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 22, 2019 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Niemann-Pick disease, type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. NPC results from mutation of either the Niemann-Pick C1 disease (NPC1) (~95% of cases) or NPC2 genes. NPC is characterized by the endolysosomal storage of unesterified cholesterol and lipids in both the central nervous system and peripheral tissues such as the liver. Individuals with NPC demonstrate progressive central nervous system decline including inability to coordinate balance, gait, extremity and eye movements. Acute liver disease in the newborn/infant period is frequently observed, but subsequently resolves. However, chronic, sub-clinical liver disease persists. Intrathecal 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD, VTS-270) has proven effective in reducing the signs and prolonging life in animal models and Phase 1/2a data support efficacy in NPC1 patients. VTS-270 also has been shown to be effective in treating liver disease in the NPC1 cat. This Phase 1/2a, open-label, multiple ascending dose trial will evaluate whether VTS-270 administered intravenously is effective in treating acute liver disease in NPC1 infants.
Detailed Description
In the first phase of the study, infants will be treated for a total of 6 weeks, treated twice weekly. Infants will be admitted to the Neonatal Intensive Care Unit (NICU) for the first week of treatment. Procedures during the first week of the study will include blood draws for genetic testing, clinical and research blood draws, urine collection, abdominal ultrasound, peripheral inserted central catheter (PICC) placement, hearing screening, and the first two IV VTS-270 infusions through the PICC line. Weeks 2-6 will occur on an outpatient basis. During week 2-6, the infant will receive 2 doses per week of VTS-270 with blood draws and urine collection during weeks 2, 4, and 6. PICC line will be removed after final infusion. Subjects who demonstrate significant reduction either in the glycine-conjugated trihydroxycholanic acid biomarker or serum bilirubin (direct bilirubin or direct bilirubin: total bilirubin ratio) will be allowed to crossover into the second phase of the study, an open label phase of six months duration in which IV VTS-270 will be administered monthly for a total of six doses. Month 1-6 procedures will occur on an outpatient basis. Procedures during the second phase include a monthly intravenous line placement. After each monthly visit, the intravenous line will be removed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Niemann-Pick Disease, Type C

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Phase 1/2a, open-label, dose escalation, multi-center study of VTS-270 in subjects with NPC dosed twice a week with IV VTS-270 for six weeks for a total of 12 administrations, followed by a six month open-label extension phase in which the subjects are dosed monthly with IV VTS-270 for six months for a total of six administrations
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IV VTS-270 for NPC1 infants
Arm Type
Experimental
Arm Description
Phase 1: Dosing frequency will be twice a week administered via a peripherally inserted central catheter (PICC) for six weeks for a total of 12 administrations. Doses 3-12 will occur as an outpatient. Doses to be studied are 500, and 1000 mg/kg. Six subjects will be studied at each dose level. Cohort 1: Subjects 1-6 will receive 500 mg/kg Cohort 2: Subjects 7-12 will receive 1000 mg/kg Subjects who demonstrate significant reduction either in the glycine-conjugated trihydroxycholanic acid biomarker or serum bilirubin (direct bilirubin or direct bilirubin:total bilirubin ratio) will be allowed to crossover into the second phase of the study, an open-label phase of six months duration. In the this phase of the study, dosing frequency will be monthly with IV VTS-270 administered via peripheral IV access for six months for a total of six administrations.
Intervention Type
Drug
Intervention Name(s)
2-Hydroxypropyl-Beta-Cyclodextrin
Other Intervention Name(s)
VTS-270, HP-Beta-CD
Intervention Description
VTS-270 (2-Hydroxypropyl-Beta-Cyclodextrin) will be administered intravenously to specifically target liver disease. In the first phase of the study, dosing frequency will be twice a week with IV VTS-270 for six weeks for a total of 12 administrations. Subjects will be evaluated at each study visit for evidence of adverse effects. Doses to be studied are 500, and 1000 mg/kg. Six subjects will be studied at each dose level. Cohort 1: Subjects 1-6, 500 mg/kg Cohort 2: Subjects 7-12, 1000 mg/kg
Primary Outcome Measure Information:
Title
Efficacy of VTS-270 to reduce plasma levels of glycine-conjugated trihydroxycholanic acid ("bile acid biomarker"), an NPC-specific pharmacodynamic biomarker.
Description
This bile acid is a metabolite of cholesterol, is elevated >99% of NPC1 subjects, is largely generated in the liver and therefore provides a biochemical measure of oxidizable lysosomal unesterified cholesterol in liver tissue. The outcome measure in phase 1 of the study is the change in bile acid levels from baseline to 6 weeks. The outcome measure in phase 2 of the study is the change in bile acid levels from 6 weeks to the end of the 6 month treatment period.
Time Frame
Phase 1: 6 weeks; Phase 2: 6 months
Secondary Outcome Measure Information:
Title
Effect of drug on serum transaminases
Description
Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) are elevated with liver dysfunction. The outcome measure in phase 1 of the study is the change in ALT and AST levels from baseline to 6 weeks. The outcome measure in phase 2 of the study is the change in ALT and AST levels from 6 weeks to the end of the 6 month treatment period.
Time Frame
Phase 1: 6 weeks; Phase 2: 6 months
Title
Reduction of liver and/or spleen volumes
Description
Abdominal ultrasound. The outcome measure in phase 1 of the study is the change in liver and/or spleen volumes from baseline to 6 weeks. The outcome measure in phase 2 of the study is the change in liver and/or spleen volumes from 6 weeks to the end of the 6 month treatment period.
Time Frame
Phase 1: 6 weeks; Phase 2: 6 months

10. Eligibility

Sex
All
Maximum Age & Unit of Time
6 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 0 to 6 months of age at time of enrollment, both genders, and any race/ethnicity. Diagnosis of NPC (either NPC1 or NPC2) based upon meeting any of the two following conditions: A. Two NPC1/NPC2 mutations, or B. One NPC1/NPC2 mutation and a positive NPC biochemical marker (oxysterol or bile acid biomarker) test Mutations will be interpreted using the American College of Medical Genetics guidelines for the interpretation of sequence variants (2015) and testing must be performed by a CLIA-certified laboratory. Subjects with evidence of NPC-related liver disease as defined by direct bilirubin (DB) >2mg/dL or DB/total bilirubin ratio >0.2. Ability to travel to a research site. Willing to participate in all aspects of trial design including serial blood collections. Parent / guardian must provide written informed consent to participate in the study. Because of the age range intended for inclusion, assent will not possible. Exclusion Criteria: Age > 6 months at time of enrollment in the trial. A medical condition (such as clinically significant bleeding diathesis or evidence of immune suppression) that in the opinion of the investigator precludes placement of an intravenous catheter An absolute neutrophil count (ANC) of less than 1,500 per microliter. A platelet count less than 75,000 per microliter. History of severe neonatal encephalopathy, per SIBEN (Score of the Iberoamerican Society of Neonatology) including level of consciousness as stupor/coma, absent spontaneous activity, decerebrate posture, flaccid tone, absent suck, absent moro, diverted/nonreactive pupils, lack of heart rate variability, apnea, and infrequent seizures. Subjects, who in the opinion of the investigators, are unable to comply with the protocol or have specific health concerns that would potentially increase the risk of participation. Examples of inability to comply include unwillingness to relocate or travel to a study site, suspected noncompliance with study procedures, behavior that jeopardizes the safety or security of the data or study staff, and other causes of inability to comply. Concurrent participation in another investigational drug trial. History of renal disease or evidence of acute kidney injury defined as serum creatinine greater than 1.5 mg/dL or an increase of at least 0.2-0.3 mg/dL per day.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patricia I Dickson, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Louis Children's Hospital
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28803710
Citation
Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet. 2017 Oct 14;390(10104):1758-1768. doi: 10.1016/S0140-6736(17)31465-4. Epub 2017 Aug 10.
Results Reference
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Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C

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