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Niemann-Pick Disease, Type C1Phase 1/2NCT03887533

Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1

A Phase 1/2 study testing VTS-270 in people with Niemann-Pick Disease, Type C1, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Background: For people who have Niemann-Pick disease, type C1 (NPC1), cholesterol and other fats have trouble moving out of liver and other tissue cells. This makes the cells sick. Researchers want to find out if a drug called VTS-270 can help. Read more about this study

Who is it for?
Ages 3 to 60 years
Conditions the study is for
Niemann-Pick Disease, Type C1
What is being tested?
VTS-270
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteUnited States
Study dates
6 Jan 2020to 25 Oct 2021
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 to 60 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

None listed.

Who cannot join

  • Age <3 or > 60 years of age at time of enrollment in the trial.
  • Subjects who have received any form of parenteral cyclodextrin, an HDAC inhibitor, or an experimental therapy for NPC in the prior six months. Prior Intrathecal VTS-270 treatment is allowed.
  • History of hypersensitivity reactions to cyclodextrin or components of the formulation.
  • Pregnancy or breastfeeding. Females of childbearing potential unwilling to utilize a highly effective form of contraception (i.e., barrier method with spermicide, intrauterine device, steroidal contraceptive in conjunction with a barrier method, or abstinence if it is the patient s baseline preference) for the duration of the study and for 30 days after participation.
  • Any systemic infection at the time of enrollment.
  • Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 per microliter. Subjects with benign cyclic/ethnic neutropenia may be enrolled if not clinically symptomatic.
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  • Thrombocytopenia defined as a platelet count less than 75,000 per microliter.
  • Established history of a chronic clotting or bleeding disorder.
  • Use of anticoagulants within 3 months of enrollment
  • Severe or acute liver disease as defined by one of the following:
  • AST or ALT greater than 10-times age-appropriate upper limit of normal
  • Jaundice or right upper quadrant pain
  • International Normalized Ratio (INR) >1.8
  • Individuals with AST and ALT greater than 4-times the age-appropriate upper limit of normal will be excluded if they have a positive NIH Clinical Center Viral Markers Hepatitis Screen (HBsAG, anti-HCV and Anti-HAV IgM). This screening test will not be obtained unless AST and ALT are elevated. An equivalent panel from another laboratory may be used if this elevation is noted on screening. Individuals excluded under this criterion may be rescreened after the acute pathology resolves (e.g. Hepatitis A infection).
  • Presence of anemia defined as two standard deviations below normal for age and gender.
  • Serum creatinine level greater than 1.5 times the age-appropriate upper limit of normal OR FOR INDIVIDUALS >= 6 years of age an eGRF < 60 mL/min 1.73 m squared
  • Hematuria on a single urinalysis, as defined by the American Urological Association (AUA) as five or more red blood cells per high-power field on microscopic evaluation of urinary sediment from a properly collected urinalysis specimen. The patient will not be excluded if two subsequent urine specimens are negative for hematuria as defined by the AUA.
  • Proteinuria (1+ protein on repeat urinalysis) unless evaluated and classified as benign.
  • Active pulmonary disease, oxygen requirement or clinically significant history of decreased blood oxygen saturation (SaO2 <95% on room air), pulmonary therapy, daily use of a cough assist device or pulmonary vest, requiring active suction, or with a tracheostomy.
  • Patients with uncontrolled seizures per either of the criteria below.
  • Unstable frequency, type or duration of seizures. Quantified by a seizure log over one month prior to enrollment.
  • Subject requiring antiepileptic medication changes (other than dose adjustments for weight) in the month prior to enrollment.
  • Individuals receiving parenteral nutrition will be excluded.
  • Patients, 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.
  • Additional exclusion criteria for intrathecal VTS-270
  • Neurologically asymptomatic. Determination made by the investigators based on history, neurological exam and consultant input.
  • Suspected infection of the central nervous system
  • Spinal deformity that would impact the ability to perform a lumbar puncture
  • Skin infection in the lumbar region
  • Prior use of anticoagulants or a bleeding disorder with increased risk of clinical bleeding.
  • Patients unable to complete a behavioral audiological evaluation including pure-tone threshold assessment (500 Hz to 8000 Hz). In consultation with the medical monitor and audiologists, a sedated ABR may be utilized to monitor ototoxicity if the participant is being sedated to receive IT VTS-270.
  • Patients, 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.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Background:

For people who have Niemann-Pick disease, type C1 (NPC1), cholesterol and other fats have trouble moving out of liver and other tissue cells. This makes the cells sick. Researchers want to find out if a drug called VTS-270 can help.

Read more

Objective:

To test if VTS-270 is safe and effective in treating chronic liver disease associated with NPC1.

Eligibility:

People ages 3-60 with NPC1

Design:

Participants may be screened by phone or under another protocol.

Participants will have visits once a month for 12 months. If they have intrathecal injections, the study may last 15 months or more. The first visit will last about 5 days. Others will last 2-3 days.

Participants will get VTS-270 injected into a vein at each visit. They can also choose to have intrathecal injections. These are like spinal taps.

Some visits will also include:

Physical exam

Urine tests

Blood tests. A small tube or needle will be inserted into the participants vein to collect blood. The small tube will also be used to give the VTS-270.

Hearing tests: For one test, participants will have electrodes taped to their head. These will record brain waves.

Breathing tests

Ultrasound of abdomen: Sounds waves will take pictures of the participant s body.

Chest x-ray: This is a picture of the lungs.

Read the detailed description

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 NPC1 (approximately 95% of cases) or NPC2 genes. Biochemically, 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 cerebellar ataxia and dementia. Acute cholestatic liver disease is frequently observed in the neonatal/infantile period but subsequently resolves. However, chronic, sub-clinical liver disease persists. Intrathecal 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD, VTS-270) has proven effective in reducing signs and prolonging life in NPC1 animal models, and Phase 1/2a data support efficacy in NPC1 patients. Parenteral administration of VTS-270 has also been shown to be effective in treating liver disease in the NPC1 cat.

In this Phase 1/2a, open-label, randomized, parallel dose, single-center study, we will examine whether VTS-270 can be used to treat chronic subacute liver disease in NPC1 patients. Our primary objective is to determine the safety and tolerability of intravenous VTS-270 in NPC1 disease. Secondary objectives will be to evaluate the efficacy of VTS-270 to reduce plasma cholestane-3beta,5alpha,6beta-triol, an NPC1-specific pharmacodynamic biomarker, and to normalize the degree of liver injury. Exploratory testing will include lipid and protein biomarkers. This study will evaluate three dose levels (500, 1000 and 1500 mg/kg) administered monthly for twelve months. Safety will be assessed by adverse event recording, clinical laboratory testing and physical examination. Clinical efficacy will be evaluated by assessment of liver chemistries, determination of liver size; and liver STIFFNESS. Biochemical efficacy will be assessed by measurement of plasma cholestane-3beta,5alpha,6beta-triol and other biomarkers.

Being tested
VTS-270
Keywords
2-Hydroxypropyl-B-Cyclodextrin
Medical subject headings
Niemann-Pick Disease, Type C

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VTS-270Drug

    Intravenous VTS-270 was administered on a monthly dosing schedule for 12 months. Each participant received one of two doses (500 or 1000mg/kg). Participants also received monthly 900 mg intrathecal VTS-270 therapy.

Study groups in NCT03887533
Study groupRoleWhat they receive
VTS-270 at 500 mg/kgExperimentalParticipant received dose of 500 mg/kg of intravenous VTS-270 administered over 2 hours monthly for 12 months. Participant also received 900 mg intrathecal VTS-270 therapy monthly for 18 months.
Receives: Drug: VTS-270
VTS-270 at 1000 mg/kgExperimentalParticipant received 1000 mg/kg of intravenous VTS-270 over 4 hours monthly for 12 months. Participant also received 900 mg intrathecal VTS-270 therapy monthly for 18 months.
Receives: Drug: VTS-270

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Participants With Adverse Events by Grade

    Adverse events (AEs) were used to determine safety and assess safety of intravenous VTS-270 in subjects with Niemann-Pick Disease, type C1. Assessment of safety was made by evaluation of summary statistics of adverse events and unanticipated problems. AEs were assessed using CTCAE version 5.0 grades 1-5.

    Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

    Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL*.

    Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL**.

    Grade 4 Life-threatening consequences; urgent intervention indicated.

    Grade 5 Death related to AE

    Measured: 18 months

  2. Participants With Reduction in Plasma Cholestane-3β

    Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction in plasma cholestane-3β, an NPC1-specific pharmacodynamic biomarker

    Measured: Assessed at baseline and at 52 weeks

  3. Participants With Reduction in Plasma Bile Acid B (5α)

    Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction in bile acid B (5α), an NPC1-specific pharmacodynamic biomarker

    Measured: Assessed at baseline and at 52 weeks

  4. Participants With Reduction in C-Triol (6β-triol)

    Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction in C-Triol (6β-triol), an NPC1-specific pharmacodynamic biomarker

    Measured: Assessed at baseline and at 52 weeks

Secondary outcomes (3)
  1. Participants With Reduction in Liver Stiffness (kPa)

    Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction in liver stiffness (kPa)

    Measured: Assessed at baseline and at 52 weeks

  2. Participants With Reduction in Alanine Aminotransferase Level

    Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction of serum alanine aminotransferase level (ALT)

    Measured: Assessed at baseline and at 52 weeks

  3. Participants With Reduction in Aspartate Aminotransferase

    Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction of serum aspartate aminotransferase (AST) level

    Measured: Assessed at baseline and at 52 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Mar 2019
  2. Study start6 Jan 2020
  3. Primary completion25 Oct 2021
  4. Study completion25 Oct 2021

Why it stopped: Enrollment was poor due to COVID-19 pandemic

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03887533
Sponsor's protocol ID
190028
Other IDs
19-CH-0028
Status last verified
Oct 2021
First submitted
22 Mar 2019
Last updated
30 Aug 2022
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010 Jun 3;5:16. doi: 10.1186/1750-1172-5-16.

    PubMed 20525256
  • Porter FD, Scherrer DE, Lanier MH, Langmade SJ, Molugu V, Gale SE, Olzeski D, Sidhu R, Dietzen DJ, Fu R, Wassif CA, Yanjanin NM, Marso SP, House J, Vite C, Schaffer JE, Ory DS. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. 2010 Nov 3;2(56):56ra81. doi: 10.1126/scitranslmed.3001417.

    PubMed 21048217
  • 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.

    PubMed 28803710

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing VTS-270 in people with Niemann-Pick Disease, Type C1, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 0 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 30 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Participants With Adverse Events by Grade (time frame: 18 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03887533, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Aug 2022.

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