Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03471143|
Recruitment Status : Recruiting
First Posted : March 20, 2018
Last Update Posted : July 16, 2019
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|
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.
|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)|
|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|
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.
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
- 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.
- 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.
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
|Contact: Daniel S Ory, MDfirstname.lastname@example.org|
|Contact: F S Cole, MDemail@example.com|
|United States, Missouri|
|St. Louis Children's Hospital||Recruiting|
|Saint Louis, Missouri, United States, 63110|
|Contact: Daniel S Ory, MD 314-362-8737 firstname.lastname@example.org|
|Contact: Laura A Linneman, RN 314-454-4950 email@example.com|
|Principal Investigator: Daniel S Ory, MD|
|Principal Investigator: F S Cole, MD|
|Principal Investigator:||Daniel S Ory, MD||Washington University School of Medicine|