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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 : Recruiting
First Posted : March 20, 2018
Last Update Posted : April 25, 2019
Sponsor:
Collaborators:
Johns Hopkins University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Washington University School of Medicine

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.


Condition or disease Intervention/treatment Phase
Niemann-Pick Disease, Type C Drug: 2-Hydroxypropyl-Beta-Cyclodextrin Phase 1 Phase 2

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 statistically 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
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
Official Title: Phase 1/2a Study of 2-Hydroxypropyl-Beta-Cyclodextrin Therapy for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
Actual Study Start Date : February 22, 2019
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2022


Arm Intervention/treatment
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 statistically 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.

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 6 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 three 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

  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.

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03471143


Contacts
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Contact: Daniel S Ory, MD 314-362-8737 dory@wustl.edu
Contact: F S Cole, MD 314-454-4826 fcole@wustl.edu

Locations
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United States, Missouri
St. Louis Children's Hospital Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Daniel S Ory, MD    314-362-8737    dory@wustl.edu   
Contact: Laura A Linneman, RN    314-454-4950    llinneman@wustl.edu   
Principal Investigator: Daniel S Ory, MD         
Principal Investigator: F S Cole, MD         
Sponsors and Collaborators
Washington University School of Medicine
Johns Hopkins University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Daniel S Ory, MD Washington University School of Medicine

Publications:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03471143     History of Changes
Other Study ID Numbers: 201708114
1U01HD090845-01 ( U.S. NIH Grant/Contract )
First Posted: March 20, 2018    Key Record Dates
Last Update Posted: April 25, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Pick Disease of the Brain
Niemann-Pick Diseases
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type C
Liver Diseases
Aphasia, Primary Progressive
Frontotemporal Dementia
Digestive System Diseases
Frontotemporal Lobar Degeneration
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Aphasia
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
TDP-43 Proteinopathies
Neurodegenerative Diseases
Proteostasis Deficiencies
Metabolic Diseases
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic