Niemann-Pick Disease, Type C
Conditions
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), also known as adrabetadex, has proven effective in reducing the signs and prolonging life in animal models and Phase 1/2a data support efficacy in NPC1 patients. Adrabetadex (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 adrabetadex (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 adrabetadex (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 adrabetadex (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 adrabetadex (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.
Interventions
DRUGVTS-270
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 adrabetadex (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
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1/2a, open-label, dose escalation, multi-center study of adrabetadex (VTS-270) in subjects with NPC dosed twice a week with IV adrabetadex (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 adrabetadex (VTS-270) for six months for a total of six administrations
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Months
Healthy volunteers
No
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 variants classified as pathogenic or likely pathogenic in NPC1/NPC2 on clinical laboratory testing, or B. One variant classified as pathogenic or likely pathogenic on clinical laboratory testing and a positive NPC biochemical marker (oxysterol or bile acid biomarker or PPCS/Lyso509) test, if acid sphingomyelinase deficiency and cholesterol ester storage disease have been excluded either by clinical molecular testing of the SMPD1 and LIPA genes or by clinical biochemical assay for acid sphingomyelinase and lysosomal acid lipase enzymes (or a combination of enzymatic and molecular testing). Variants 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 modified Sarnat 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. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Adrabetadex (VTS-270) to Reduce Plasma Levels of a Conjugated Bile Acid, Known as 5α-cholanic Acid-3β, 5α, 6β-triol N-(Carboxymethyl)-Amide | Phase 1: 6 weeks; Phase 2: 6 months | This bile acid, 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide, 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 primary outcome measure in phase 1 of the study is the change in plasma levels of 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide measured in nanograms/ml from baseline to 6 weeks. The primary outcome measure in phase 2 of the study is the change in plasma levels of 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide measured in nanograms/ml from 6 weeks to the end of the 6 month treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Drug on Serum Transaminases | 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 | 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. We were only able to collect spleen volume data due to the radiologist reporting they could not accurately obtain liver volume data. The contact radiologist for this protocol has left the institution, stopping any additional work on liver ultrasound volumes. None of the remaining radiology colleagues had time to bring forward. Liver volumes will never be obtained for this measure in the future. |
Countries
United States
Participant flow
Recruitment details
The original enrollment goal was 12 subjects up to maximum of 15 subjects to account for potential study withdrawals, discontinuations or unconfirmed diagnosis of NPC. Six subjects would be studied at each dose level. Cohort 1: Subjects 1-6 500mg/kg Cohort 2: Subjects 7-12 1000mg/kg The four subjects enrolled received 500mg/kg study drug.
Participants by arm
| Arm | Count |
|---|---|
| IV Adrabetadex (VTS-270) for NPC1 Infants IV Adrabetadex (VTS-270) for NPC1 Infants. Will measure plasma level of 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | IV Adrabetadex (VTS-270) for NPC1 Infants |
|---|---|
| Age, Categorical <=18 years | 4 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Alanine transaminase (ALT) | 158.5 U/L |
| Aspartate aminotransferase (AST) | 168 U/L |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Plasma level of 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide | 120.6 ng/ml |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 3 Participants |
| Spleen volume | 86.3 cc |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 4 |
| other Total, other adverse events | 2 / 4 |
| serious Total, serious adverse events | 3 / 4 |
Outcome results
Primary
Efficacy of Adrabetadex (VTS-270) to Reduce Plasma Levels of a Conjugated Bile Acid, Known as 5α-cholanic Acid-3β, 5α, 6β-triol N-(Carboxymethyl)-Amide
This bile acid, 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide, 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 primary outcome measure in phase 1 of the study is the change in plasma levels of 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide measured in nanograms/ml from baseline to 6 weeks. The primary outcome measure in phase 2 of the study is the change in plasma levels of 5α-cholanic acid-3β, 5α, 6β-triol N-(carboxymethyl)-amide measured in nanograms/ml from 6 weeks to the end of the 6 month treatment period.
Time frame: Phase 1: 6 weeks; Phase 2: 6 months
Population: One of the participants only had baseline measurement.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IV Adrabetadex (VTS-270) for NPC1 Infants | Efficacy of Adrabetadex (VTS-270) to Reduce Plasma Levels of a Conjugated Bile Acid, Known as 5α-cholanic Acid-3β, 5α, 6β-triol N-(Carboxymethyl)-Amide | 6 weeks | 32.6 ng/ml |
| IV Adrabetadex (VTS-270) for NPC1 Infants | Efficacy of Adrabetadex (VTS-270) to Reduce Plasma Levels of a Conjugated Bile Acid, Known as 5α-cholanic Acid-3β, 5α, 6β-triol N-(Carboxymethyl)-Amide | 6 months | 87.9 ng/ml |
Secondary
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.
Time frame: Phase 1: 6 weeks; Phase 2: 6 months
Population: One of the participants only had baseline measurement.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IV Adrabetadex (VTS-270) for NPC1 Infants | Effect of Drug on Serum Transaminases | ALT 6 weeks | 87 U/L |
| IV Adrabetadex (VTS-270) for NPC1 Infants | Effect of Drug on Serum Transaminases | AST 6 weeks | 114 U/L |
| IV Adrabetadex (VTS-270) for NPC1 Infants | Effect of Drug on Serum Transaminases | ALT 6 months | 65 U/L |
| IV Adrabetadex (VTS-270) for NPC1 Infants | Effect of Drug on Serum Transaminases | AST 6 months | 77 U/L |
Secondary
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. We were only able to collect spleen volume data due to the radiologist reporting they could not accurately obtain liver volume data. The contact radiologist for this protocol has left the institution, stopping any additional work on liver ultrasound volumes. None of the remaining radiology colleagues had time to bring forward. Liver volumes will never be obtained for this measure in the future.
Time frame: Phase 1: 6 weeks; Phase 2: 6 months
Population: We were only able to collect spleen volume data due to the radiologist reporting they could not accurately obtain liver volume data. The contact radiologist for this protocol has left the institution, stopping any additional work on liver ultrasound volumes. None of the remaining radiology colleagues had time to bring forward. Liver volumes will never be obtained for this measure in the future.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IV Adrabetadex (VTS-270) for NPC1 Infants | Reduction of Liver and/or Spleen Volumes | 6 weeks | 71.8 cc |
| IV Adrabetadex (VTS-270) for NPC1 Infants | Reduction of Liver and/or Spleen Volumes | 6 months | 127 cc |