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

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ClinicalTrials.gov Identifier: NCT03471143
Recruitment Status : Active, not recruiting
First Posted : March 20, 2018
Last Update Posted : February 1, 2021
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE March 7, 2018
First Posted Date  ICMJE March 20, 2018
Last Update Posted Date February 1, 2021
Actual Study Start Date  ICMJE February 22, 2019
Estimated Primary Completion Date February 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2018)
Efficacy of VTS-270 to reduce plasma levels of glycine-conjugated trihydroxycholanic acid ("bile acid biomarker"), an NPC-specific pharmacodynamic biomarker. [ Time Frame: Phase 1: 6 weeks; Phase 2: 6 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2018)
  • Effect of drug on serum transaminases [ Time Frame: Phase 1: 6 weeks; Phase 2: 6 months ]
    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 [ Time Frame: Phase 1: 6 weeks; Phase 2: 6 months ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
Official Title  ICMJE Phase 1/2a Study of 2-Hydroxypropyl-Beta-Cyclodextrin Therapy for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Condition  ICMJE Niemann-Pick Disease, Type C
Intervention  ICMJE Drug: 2-Hydroxypropyl-Beta-Cyclodextrin

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

Other Names:
  • VTS-270
  • HP-Beta-CD
Study Arms  ICMJE Experimental: IV VTS-270 for NPC1 infants

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: Drug: 2-Hydroxypropyl-Beta-Cyclodextrin
Publications * 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-β-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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 28, 2021)
3
Original Estimated Enrollment  ICMJE
 (submitted: March 13, 2018)
12
Estimated Study Completion Date  ICMJE February 2022
Estimated Primary Completion Date February 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 6 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03471143
Other Study ID Numbers  ICMJE 201708114
1U01HD090845-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
Principal Investigator: Patricia I Dickson, MD Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP