Synergistic Enteral Regimen for Treatment of the Gangliosidoses (Syner-G)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2016 by University of Minnesota - Clinical and Translational Science Institute
Sponsor:
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT02030015
First received: December 17, 2013
Last updated: February 9, 2016
Last verified: February 2016
  Purpose
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. The ketogenic diet has been used for seizure management for more than 100 years. In this study, the ketogenic diet will be used to minimize or prevent gastrointestinal side-effects of miglustat, and to improve central nervous system response to miglustat therapy. Patients with infantile and juvenile gangliosidoses do commonly suffer from seizure disorders, and use of the ketogenic diet in these patients may therefore also improve seizure management.

Condition Intervention Phase
GM1 Gangliosidoses
GM2 Gangliosidoses
Tay-Sachs Disease
Sandhoff Disease
Drug: miglustat
Behavioral: Ketogenic Diet
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Synergistic Enteral Regimen for Treatment of the Gangliosidoses (Syner-G)

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • The duration of survival of each research subject, measured in months and years [ 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 ] [ Designated as safety issue: No ]
    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 and the investigators' extensive clinical experience, in order to arrive at an expert assessment of the impact of the Syner-G therapy upon patient longevity.


Secondary Outcome Measures:
  • Rate of Change in Adaptive Behavior [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
    The Vineland Adaptive Behavior Scales will be administered upon enrollment and annually thereafter for five years. The assessed functional domain is the research subject's adaptive behavior. The rate of change in the resulting adaptive behavior data (i.e. slope) will be calculated over the duration of follow-up, and will be compared to available natural history data. This measurement and analysis will be performed separately for each of the two gangliosidoses sub-types: infantile-onset and juvenile-onset.

  • Assessment of Changes in Research Subjects' Seizure Frequency and Severity [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
    Changes in research subjects' seizure frequency and severity will be assessed by a qualified neurologist, using interviews of the research subjects' caregivers. This assessment will be performed upon enrollment and annually for five years.

  • Assessment of Changes in Research Subjects' Movement Disorders [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
    Changes in research subjects' movement disorders, if any movement disorders are present, will be assessed by a qualified neurologist, using interviews of the research subjects' caregivers. This assessment will be performed upon enrollment and annually for five years.

  • Rate of Change in Neurocognitive Functioning [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
    The Bayley Scales of Infant and Toddler Development will be administered upon enrollment and annually thereafter for five years. The rate of change in the resulting neurocognitive functional domains data (i.e. slope) will be calculated over the duration of follow-up, and will be compared to available natural history data. This measurement and analysis will be performed separately for each of the two gangliosidoses sub-types: infantile-onset and juvenile-onset.


Estimated Enrollment: 30
Study Start Date: March 2014
Estimated Study Completion Date: March 2019
Estimated Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

The miglustat oral dose will be gradually titrated over approximately 8 weeks to a goal-dose of 100 mg 3 times daily in the pediatric patients in this study. The specific details of the 8-week dose-titration schedule greatly exceed the maximum number of characters permitted in this field. Please contact the investigators for these specific details.

Drug: miglustat

The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study.

The miglustat dose will be gradually titrated over approximately 8 weeks to a goal-dose of 100 mg 3 times daily in the pediatric patients in this study. The specific details of the 8-week dose-titration schedule greatly exceed the maximum number of characters permitted in this field. Please contact the investigators for these specific details.

Other Name: Zavesca®
Behavioral: 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.

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 significant increase 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 the miglustat be more effective in the central nervous system, and to reduce food-miglustat interactions. It may also help in management of seizures. (The ketogenic diet has been used as an anti-seizure treatment in a variety of medical conditions for many decades.) The goal is to have 4 parts of fat for every 1 part of protein/carbohydrate. Each research subject's caregiver(s) will work with ketogenic diet teams that will include a ketogenic dietitian, a neurologist trained in the ketogenic diet, and a pharmacist, to help their child to achieve this diet goal. Caregiver(s) will be working with a ketogenic diet team at the University of Minnesota, and also with their local ketogenic diet team. There will be close and frequent ongoing communication between the two ketogenic diet teams, and with the research subject's caregiver(s).

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. The dose of miglustat will increase every 2 weeks until the child reaches a goal dose of 300 mg per day. It will take approximately 8 weeks to reach the full dose of miglustat. This dose titration process may take longer if the child needs more time to adjust to each dose level.

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

  Eligibility

Ages Eligible for Study:   up to 204 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 work closely with their University of Minnesota ketogenic diet team, and with their local ketogenic diet team, which must include a ketogenic dietician and a neurologist trained in the 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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02030015

Contacts
Contact: Jeanine R. Utz, PharmD 612-626-5131 utzx0002@umn.edu
Contact: Evelyn S. Redtree, M.S. 612-625-0974 eredtree@umn.edu

Locations
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Jeanine R. Utz, PharmD    612-626-5131    utzx0002@umn.edu   
Contact: Evelyn S. Redtree, M.S.    612-625-0974    eredtree@umn.edu   
Principal Investigator: Jeanine R. Utz, PharmD         
Sub-Investigator: Chester B. Whitley, MD, PhD         
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Investigators
Principal Investigator: Jeanine R. Utz, PharmD University of Minnesota Fairview Hospital
  More Information

Additional Information:
Publications:

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT02030015     History of Changes
Other Study ID Numbers: Syner_G_Regimen 
Study First Received: December 17, 2013
Last Updated: February 9, 2016
Health Authority: United States: Data and Safety Monitoring Board
United States: Food and Drug Administration

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
infantile Tay-Sachs disease
juvenile Tay-Sachs disease
Sandhoff disease
Tay-Sachs disease
Tay Sachs disease
infantile GM1 gangliosidosis
juvenile GM1 gangliosidosis
infantile GM2 gangliosidosis
juvenile GM2 gangliosidosis
gangliosidoses
miglustat
ketogenic diet
SYNER-G regimen
Syner-G
Zavesca

Additional relevant MeSH terms:
Sandhoff Disease
Tay-Sachs Disease
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Lipid Metabolism Disorders
Lysosomal Storage Diseases
Lysosomal Storage Diseases, Nervous System
Metabolic Diseases
Nervous System Diseases
Gangliosidoses
Gangliosidoses, GM2
Gangliosidosis, GM1
Lipid Metabolism, Inborn Errors
Lipidoses
Metabolism, Inborn Errors
Sphingolipidoses
Miglustat
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on February 11, 2016