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

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ClinicalTrials.gov Identifier: NCT03887533
Recruitment Status : Recruiting
First Posted : March 25, 2019
Last Update Posted : August 16, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )

Brief 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.

Objective:

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

Eligibility:

People ages 4 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.


Condition or disease Intervention/treatment Phase
Niemann-Pick Disease, Type C1 Drug: VTS-270 Phase 1 Phase 2

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 changes in liver STIFFNESS. Biochemical efficacy will be assessed by measurement of plasma cholestane-3beta,5alpha,6beta-triol and other biomarkers.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1
Estimated Study Start Date : August 21, 2019
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : January 1, 2022


Arm Intervention/treatment
Experimental: 1000 mg/kg
VTS-270 1000 mg/kg
Drug: VTS-270
Intravenous VTS-270 will be administered on a monthly dosing schedule for 12 months. Each participant will receive one of three doses (500, 1000 or 1500 mg/kg). Participants will have the option of receiving monthly 900 mg intrathecal VTS-270 therapy.

Experimental: 1500 mg/kg
VTS-270 1500 mg/kg
Drug: VTS-270
Intravenous VTS-270 will be administered on a monthly dosing schedule for 12 months. Each participant will receive one of three doses (500, 1000 or 1500 mg/kg). Participants will have the option of receiving monthly 900 mg intrathecal VTS-270 therapy.

Experimental: 500 mg/kg
VTS-270 500 mg/kg
Drug: VTS-270
Intravenous VTS-270 will be administered on a monthly dosing schedule for 12 months. Each participant will receive one of three doses (500, 1000 or 1500 mg/kg). Participants will have the option of receiving monthly 900 mg intrathecal VTS-270 therapy.




Primary Outcome Measures :
  1. Safety and Tolerabilty [ Time Frame: one-year ]
    Adverse events and dose reductions for tolerability


Secondary Outcome Measures :
  1. plasma Cholestane-3B,5a,6B-triol [ Time Frame: one-year ]
    Plasma Cholestane-3B,5a,6Btriol will be measured at intervals through the 12-month treatment period and compared with baseline level.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   4 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Age greater than or equal to 4 and less than or equal to 60 years old at time of enrollment
  2. Diagnosis of NPC1 based upon one of the following:

    A. Two NPC1 mutations

    B. Biochemical Positive for NPC (oxysterol/bile acid and sphingomyelinase levels consistent with a diagnosis of NPC) and one NPC1 mutation

    -NPC1 mutations will be interpreted using standards established for the

    interpretation of sequence variants [33].

    • Oxysterol/Bile Acid testing refers to cholestane-3beta,5 ,6beta-triol [7, 8] or

      3beta,5alpha,6beta-trihydroxycholanic acid and its glycine conjugate [34].

  3. Evidence of NPC1-related liver disease as defined by one of the following:

    A. Abnormal liver chemistries as defined by one of the following:

    i. Plasma aspartate aminotransferase (AST) greater than or equal to 1.5-times age-appropriate upper limit of normal

    ii. Plasma aspartate aminotransferase (AST) greater than or equal to 1.25-times age-appropriate upper limit of normal and plasma alanine aminotransferase (ALT) > 1.25-times age-appropriate upper limit of normal

    iii. Plasma aspartate aminotransferase (AST) greater than or equal to 1.25-times age-appropriate upper limit of normal and AST/ALT ratio greater than or equal to 2.0

    B.Abnormal liver chemistries as defined above at least 8 weeks apart.

  4. Ability to travel to the NIH Clinical Center repeatedly for evaluation and follow-up.
  5. Willingness to discontinue all non-prescription supplements, except for an age-appropriate multivitamin/mineral supplement.
  6. Willingness to discontinue miglustat (Zavesca) one month prior and for the duration of the trial.
  7. Women of reproductive age must be willing to use an effective method of contraception for the duration of the trial if sexually active.
  8. Willingness to participate in all aspects of the IV trial

EXCLUSION CRITERIA:

  • Age <4 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.
  • 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:

A. AST or ALT greater than 10-times age-appropriate upper limit of normal

B. Jaundice or right upper quadrant pain

C. 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.

    1. Unstable frequency, type or duration of seizures. Quantified by a seizure log over one month prior to enrollment.
    2. 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

  1. Neurologically asymptomatic. Determination made by the investigators based on history, neurological exam and consultant input.
  2. Suspected infection of the central nervous system
  3. Spinal deformity that would impact the ability to perform a lumbar puncture
  4. Skin infection in the lumbar region
  5. Prior use of anticoagulants or a bleeding disorder with increased risk of clinical bleeding.
  6. 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.
  7. 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.

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): NCT03887533


Contacts
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Contact: Kisha R Jenkins (301) 594-2005 kisha.jenkins@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Forbes D Porter, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Additional Information:
Publications:
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Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT03887533     History of Changes
Other Study ID Numbers: 190028
19-CH-0028
First Posted: March 25, 2019    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: June 11, 2019

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

Keywords provided by National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) ):
2-hydroxypropyl-beta-cyclodextrin

Additional relevant MeSH terms:
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Nervous System Diseases
Pick Disease of the Brain
Aphasia, Primary Progressive
Frontotemporal Dementia
Niemann-Pick Diseases
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type C
Frontotemporal Lobar Degeneration
Dementia
Brain Diseases
Central 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
Histiocytosis, Non-Langerhans-Cell
Histiocytosis