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Syner-G: Synergistic Enteral Regimen for Treatment of the Gangliosidoses

Sponsor
University of Minnesota (Other)
Overall Status
Terminated
CT.gov ID
NCT02030015
Collaborator
Rare Diseases Clinical Research Network (Other), National Center for Advancing Translational Science (NCATS) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Lysosomal Disease Network (Other)
16
Enrollment
1
Location
1
Arm
43.3
Actual Duration (Months)
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators hypothesize that a combination therapy using miglustat and the ketogenic diet for infantile and juvenile patients with gangliosidoses will create a synergy that 1) improves overall survival for patients with infantile or juvenile gangliosidoses, and 2) improves neurodevelopmental clinical outcomes of therapy, compared to data reported in previous natural history studies. The ketogenic diet is indicated for management of seizures in patients with seizure disorders. In this study, the ketogenic diet will be used to minimize or prevent gastrointestinal side-effects of miglustat. A Sandhoff disease mouse study has shown that the ketogenic diet may also improve central nervous system response to miglustat therapy (see Denny in "Citations" list below). Patients with infantile and juvenile gangliosidoses commonly suffer from seizure disorders, and use of the ketogenic diet in these patients may therefore also improve seizure management.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

The infantile and juvenile forms of GM1 and GM2 gangliosidoses are neurodegenerative conditions that are lethal during childhood. There are no known effective therapies available for treatment of infantile and juvenile gangliosidoses. Studies of monotherapy with miglustat for treatment of these conditions have demonstrated safety, but have not demonstrated notable clinical improvement. To date, combination therapy for the infantile and juvenile gangliosidoses has not been explored. This study will evaluate a multi-targeted combination therapy for treatment of the gangliosidoses, using FDA approved therapies that have demonstrated safety in children. It is the aim of this study to learn if combination therapy using the "Syner-G" regimen (that is, synergistic enteral regimen for treatment of the gangliosidoses) will show improvement in overall survival and clinical benefits in neurodevelopmental abilities in children with gangliosidosis diseases.

This study is planned as a 5-year longitudinal treatment study. Subjects will be started on the treatment regimen when they are enrolled in the study. Data will be collected during yearly evaluations and at completion of study. Investigators may choose to stop therapy at any time, as clinically indicated for individual patients.

The Ketogenic Diet is a special diet that contains higher amounts of fat and lower amounts of carbohydrate compared to an average diet. The purpose of this is to help reduce food-miglustat interactions. The ketogenic diet may also help in management of seizures in these patients. (The ketogenic diet has been used as an anti-seizure treatment in a variety of medical conditions for many decades.) A study in Sandhoff disease mice has shown that the ketogenic diet may also help miglustat be more effective in the central nervous system (see Denny in "Citations" list below).

Miglustat will be used to reduce the amount of ganglioside accumulation in the child's cells. Miglustat is not FDA approved for treatment of the gangliosidoses. It is FDA approved for a different inherited metabolic disease called Gaucher disease type I.

This study has been issued Investigational New Drug (IND) # 127636 by the U.S. Food and Drug Administration (FDA).

Study Design

Study Type:
Interventional
Actual Enrollment :
16 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Synergistic Enteral Regimen for Treatment of the Gangliosidoses (Syner-G)
Actual Study Start Date :
Dec 22, 2015
Actual Primary Completion Date :
Jul 31, 2019
Actual Study Completion Date :
Jul 31, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Syner-G Therapy Regimen

The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet, and daily treatment with orally-administered miglustat, for the duration of the 60-month study.

Drug: miglustat
The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study.
Other Names:
  • Zavesca®

    • Other: Ketogenic Diet
    The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet for the 60-month duration of this study.

    Outcome Measures

    Primary Outcome Measures

    1. The Duration of Survival of Each Research Subject, Measured in Months and Years [From date of enrollment until 60 months thereafter, or the date of subject's death from any cause, whichever comes first, assessed up to 60 months]

      The survival duration of patients with infantile and juvenile forms of gangliosidoses will be assessed, in order to judge the clinical impact of the Syner-G therapy regimen. This will be accomplished by recording the subject's age on the date of enrollment in this study, and the subject's age at the conclusion of this study, or on the date of their death, whichever comes first. The duration of each subject's survival, expressed in months and years, will be compared to available natural history data in order to arrive at an expert assessment of the impact of the Syner-G therapy upon patient longevity.

    Secondary Outcome Measures

    1. Rate of Change in Neurocognitive Functioning [Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment]

      The Bayley Scales of Infant and Toddler Development and the Vineland Adaptive Behavior Scales will be administered upon enrollment and annually thereafter for five years. Changes in these neurodevelopmental assessments will be evaluated over the duration of follow-up. Ability of the child to have these assessments yearly may be subject to patient's insurance coverage for such assessments.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 204 Months
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Subjects must have a documented infantile or juvenile gangliosidosis disease.

    2. Age: 17 years or less at time of enrollment

    3. Subjects and their caregivers must be willing to work with a ketogenic diet team for management of the subject's ketogenic diet.

    Exclusion Criteria:

    1. A desire to not participate

    2. Patients who are older than 17 years will not be enrolled in this study.

    3. Children with severe renal impairment will not be enrolled in this study.

    4. Post-pubertal females who are pregnant, or who are unwilling to use highly-effective methods to prevent pregnancy, will be excluded from this study.

    5. Breast-feeding females will be excluded from this study.

    6. Subjects who have an allergy to miglustat or any of the components within the drug product will be excluded from this study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Minnesota Minneapolis Minnesota United States 55455

    Sponsors and Collaborators

    • University of Minnesota
    • Rare Diseases Clinical Research Network
    • National Center for Advancing Translational Science (NCATS)
    • National Institute of Neurological Disorders and Stroke (NINDS)
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    • Lysosomal Disease Network

    Investigators

    • Principal Investigator: Jeanine R. Jarnes, PharmD, University of Minnesota Fairview Hospital

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT02030015
    Other Study ID Numbers:
    • Syner_G_Regimen
    • U54NS065768
    • 1311M46101
    First Posted:
    Jan 8, 2014
    Last Update Posted:
    Apr 14, 2021
    Last Verified:
    Mar 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by University of Minnesota
    infantile Tay-Sachs disease
    juvenile Tay-Sachs disease
    infantile GM1 gangliosidosis
    juvenile GM1 gangliosidosis
    infantile GM2 gangliosidosis
    juvenile GM2 gangliosidosis
    Sandhoff disease
    gangliosidoses
    miglustat
    ketogenic diet
    SYNER-G regimen
    Syner-G
    Zavesca
    Tay-Sachs disease
    Tay Sachs disease
    Additional relevant MeSH terms:
    Gangliosidoses
    Tay-Sachs Disease
    Gangliosidosis, GM1
    Sandhoff Disease
    Gangliosidoses, GM2
    Miglustat

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Syner-G Therapy Regimen
    Arm/Group Description The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet, and daily treatment with orally-administered miglustat, for the duration of the 60-month study. miglustat: The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study. Ketogenic Diet: The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet for the 60-month duration of this study.
    Period Title: Overall Study
    STARTED 16
    COMPLETED 0
    NOT COMPLETED 16

    Baseline Characteristics

    Arm/Group Title Syner-G Therapy Regimen
    Arm/Group Description The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet, and daily treatment with orally-administered miglustat, for the duration of the 60-month study. miglustat: The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study. Ketogenic Diet: The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet for the 60-month duration of this study.
    Overall Participants 16
    Age (Count of Participants)
    <=18 years
    16
    100%
    Between 18 and 65 years
    0
    0%
    >=65 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    6
    37.5%
    Male
    10
    62.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    6.3%
    Asian
    3
    18.8%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    2
    12.5%
    White
    8
    50%
    More than one race
    2
    12.5%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    16
    100%

    Outcome Measures

    1. Primary Outcome
    Title The Duration of Survival of Each Research Subject, Measured in Months and Years
    Description The survival duration of patients with infantile and juvenile forms of gangliosidoses will be assessed, in order to judge the clinical impact of the Syner-G therapy regimen. This will be accomplished by recording the subject's age on the date of enrollment in this study, and the subject's age at the conclusion of this study, or on the date of their death, whichever comes first. The duration of each subject's survival, expressed in months and years, will be compared to available natural history data in order to arrive at an expert assessment of the impact of the Syner-G therapy upon patient longevity.
    Time Frame From date of enrollment until 60 months thereafter, or the date of subject's death from any cause, whichever comes first, assessed up to 60 months

    Outcome Measure Data

    Analysis Population Description
    No participants completed the trial. Outcome measure data was not collected due to small sample size.
    Arm/Group Title Syner-G Therapy Regimen
    Arm/Group Description The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet, and daily treatment with orally-administered miglustat, for the duration of the 60-month study. miglustat: The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study. Ketogenic Diet: The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet for the 60-month duration of this study.
    Measure Participants 0
    2. Secondary Outcome
    Title Rate of Change in Neurocognitive Functioning
    Description The Bayley Scales of Infant and Toddler Development and the Vineland Adaptive Behavior Scales will be administered upon enrollment and annually thereafter for five years. Changes in these neurodevelopmental assessments will be evaluated over the duration of follow-up. Ability of the child to have these assessments yearly may be subject to patient's insurance coverage for such assessments.
    Time Frame Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment

    Outcome Measure Data

    Analysis Population Description
    No participants completed the trial. Outcome measure data was not collected due to small sample size.
    Arm/Group Title Syner-G Therapy Regimen
    Arm/Group Description The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet, and daily treatment with orally-administered miglustat, for the duration of the 60-month study. miglustat: The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study. Ketogenic Diet: The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet for the 60-month duration of this study.
    Measure Participants 0

    Adverse Events

    Time Frame Participants were followed for the length of study participation; up to 60 months or 5 years
    Adverse Event Reporting Description
    Arm/Group Title Syner-G Therapy Regimen
    Arm/Group Description The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet, and daily treatment with orally-administered miglustat, for the duration of the 60-month study. miglustat: The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study. Ketogenic Diet: The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet for the 60-month duration of this study.
    All Cause Mortality
    Syner-G Therapy Regimen
    Affected / at Risk (%) # Events
    Total 13/16 (81.3%)
    Serious Adverse Events
    Syner-G Therapy Regimen
    Affected / at Risk (%) # Events
    Total 0/16 (0%)
    Other (Not Including Serious) Adverse Events
    Syner-G Therapy Regimen
    Affected / at Risk (%) # Events
    Total 0/16 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Jeanine Jarnes, PharmD
    Organization University of Minnesota
    Phone 612-626-5131
    Email utzx0002@umn.edu
    Responsible Party:
    University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT02030015
    Other Study ID Numbers:
    • Syner_G_Regimen
    • U54NS065768
    • 1311M46101
    First Posted:
    Jan 8, 2014
    Last Update Posted:
    Apr 14, 2021
    Last Verified:
    Mar 1, 2021