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

This study is ongoing, but not recruiting participants.
ClinicalTrials.gov Identifier:
First Posted: January 8, 2014
Last Update Posted: August 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
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 Intervention Phase
GM1 Gangliosidoses GM2 Gangliosidoses Tay-Sachs Disease Sandhoff Disease Drug: miglustat Other: Ketogenic Diet Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (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 ]
    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:
  • Rate of Change in Neurocognitive Functioning [ Time Frame: 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.

Enrollment: 6
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.
Drug: miglustat
The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study.
Other Name: 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.

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).


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.

Ages Eligible for Study:   up to 204 Months   (Child)
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
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): NCT02030015

United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
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
Principal Investigator: Jeanine R. Jarnes, PharmD University of Minnesota Fairview Hospital
  More Information

Additional Information:
Jarnes Utz JR, Kim S, King K, Ziegler R, Schema L, Redtree ES, Whitley CB. Infantile gangliosidoses: Mapping a timeline of clinical changes. Mol Genet Metab. 2017 Jun;121(2):170-179. doi: 10.1016/j.ymgme.2017.04.011. Epub 2017 Apr 29.
Bley AE, Giannikopoulos OA, Hayden D, Kubilus K, Tifft CJ, Eichler FS. Natural history of infantile G(M2) gangliosidosis. Pediatrics. 2011 Nov;128(5):e1233-41. doi: 10.1542/peds.2011-0078. Epub 2011 Oct 24.
Nalini A, Christopher R. Cerebral glycolipidoses: clinical characteristics of 41 pediatric patients. J Child Neurol. 2004 Jun;19(6):447-52.
Maegawa GH, Stockley T, Tropak M, Banwell B, Blaser S, Kok F, Giugliani R, Mahuran D, Clarke JT. The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics. 2006 Nov;118(5):e1550-62. Epub 2006 Oct 2. Review. Erratum in: Pediatrics. 2007 Oct;120(4):936.
Maegawa GH, van Giersbergen PL, Yang S, Banwell B, Morgan CP, Dingemanse J, Tifft CJ, Clarke JT. Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis. Mol Genet Metab. 2009 Aug;97(4):284-91. doi: 10.1016/j.ymgme.2009.04.013. Epub 2009 May 3.
Shapiro BE, Pastores GM, Gianutsos J, Luzy C, Kolodny EH. Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genet Med. 2009 Jun;11(6):425-33. doi: 10.1097/GIM.0b013e3181a1b5c5.
Belmatoug N, Burlina A, Giraldo P, Hendriksz CJ, Kuter DJ, Mengel E, Pastores GM. Gastrointestinal disturbances and their management in miglustat-treated patients. J Inherit Metab Dis. 2011 Oct;34(5):991-1001. doi: 10.1007/s10545-011-9368-7. Epub 2011 Jul 21. Review.
Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Helen Cross J, Dahlin MG, Donner EJ, Klepper J, Jehle RS, Kim HD, Christiana Liu YM, Nation J, Nordli DR Jr, Pfeifer HH, Rho JM, Stafstrom CE, Thiele EA, Turner Z, Wirrell EC, Wheless JW, Veggiotti P, Vining EP; Charlie Foundation, Practice Committee of the Child Neurology Society; Practice Committee of the Child Neurology Society; International Ketogenic Diet Study Group. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 2009 Feb;50(2):304-17. doi: 10.1111/j.1528-1167.2008.01765.x. Epub 2008 Sep 23.
Zaroff CM, Neudorfer O, Morrison C, Pastores GM, Rubin H, Kolodny EH. Neuropsychological assessment of patients with late onset GM2 gangliosidosis. Neurology. 2004 Jun 22;62(12):2283-6.
Bembi B, Marchetti F, Guerci VI, Ciana G, Addobbati R, Grasso D, Barone R, Cariati R, Fernandez-Guillen L, Butters T, Pittis MG. Substrate reduction therapy in the infantile form of Tay-Sachs disease. Neurology. 2006 Jan 24;66(2):278-80.
Zupec-Kania BA, Spellman E. An overview of the ketogenic diet for pediatric epilepsy. Nutr Clin Pract. 2008 Dec-2009 Jan;23(6):589-96. doi: 10.1177/0884533608326138. Review.
Denny CA, Heinecke KA, Kim YP, Baek RC, Loh KS, Butters TD, Bronson RT, Platt FM, Seyfried TN. Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. J Neurochem. 2010 Jun;113(6):1525-35. doi: 10.1111/j.1471-4159.2010.06733.x. Epub 2010 Apr 3.
Utz JR, Crutcher T, Schneider J, Sorgen P, Whitley CB. Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses. Mol Genet Metab. 2015 Feb;114(2):274-80. doi: 10.1016/j.ymgme.2014.11.015. Epub 2014 Dec 6.
Karimzadeh P, Naderi S, Modarresi F, Dastsooz H, Nemati H, Farokhashtiani T, Shamsian BS, Inaloo S, Faghihi MA. Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene. BMC Med Genet. 2017 Jul 17;18(1):73. doi: 10.1186/s12881-017-0417-4.
Deodato F, Procopio E, Rampazzo A, Taurisano R, Donati MA, Dionisi-Vici C, Caciotti A, Morrone A, Scarpa M. The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression. Metab Brain Dis. 2017 Jun 3. doi: 10.1007/s11011-017-0044-y. [Epub ahead of print]
Brackmann F, Kehrer C, Kustermann W, Böhringer J, Krägeloh-Mann I, Trollmann R. Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency. Neuropediatrics. 2017 Apr;48(2):127-130. doi: 10.1055/s-0037-1598646. Epub 2017 Feb 13.
Regier DS, Proia RL, D'Azzo A, Tifft CJ. The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy. Pediatr Endocrinol Rev. 2016 Jun;13 Suppl 1:663-73. Review.

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT02030015     History of Changes
Other Study ID Numbers: Syner_G_Regimen
U54NS065768 ( U.S. NIH Grant/Contract )
1311M46101 ( Other Identifier: Univ. of Minnesota IRB Identifier Number )
First Submitted: December 17, 2013
First Posted: January 8, 2014
Last Update Posted: August 21, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual data is input to the NIH-funded Rare Diseases Clinical Research Network's Data Management & Coordinating Center ("DMCC"). Eventually this data will become part of the database of Genotypes and Phenotypes ("dbGaP"), which is part of the National Center for Biotechnology Information, U.S. National Library of Medicine.

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

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
ketogenic diet
SYNER-G regimen

Additional relevant MeSH terms:
Tay-Sachs Disease
Sandhoff Disease
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Gangliosidoses, GM2
Gangliosidosis, GM1
Metabolism, Inborn Errors
Lipid Metabolism, Inborn Errors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Glycoside Hydrolase Inhibitors
Hypoglycemic Agents
Physiological Effects of Drugs

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