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| ID | Type | Description | Link |
|---|---|---|---|
| U54NS065768 | U.S. NIH Grant/Contract | View source | |
| 1311M46101 | Other Identifier | Univ. of Minnesota IRB Identifier Number |
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Efficacy
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| Name | Class |
|---|---|
| Rare Diseases Clinical Research Network | NETWORK |
| National Center for Advancing Translational Sciences (NCATS) | NIH |
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Syner-G Therapy Regimen | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| miglustat | Drug | The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study. |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Duration of Survival of Each Research Subject, Measured in Months and Years | 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. | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Change in Neurocognitive Functioning | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeanine R. Jarnes, PharmD | University of Minnesota Fairview Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Minnesota | Minneapolis | Minnesota | 55455 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22025593 | Background | 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. | |
| 15446395 | Background | Nalini A, Christopher R. Cerebral glycolipidoses: clinical characteristics of 41 pediatric patients. J Child Neurol. 2004 Jun;19(6):447-52. doi: 10.1177/088307380401900610. |
| Label | URL |
|---|---|
| Orphanet links to detailed information about the gangliosidoses | View source |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Duration of Survival of Each Research Subject, Measured in Months and Years | 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. | No participants completed the trial. Outcome measure data was not collected due to small sample size. | Posted | 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 |
|
Participants were followed for the length of study participation; up to 60 months or 5 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeanine Jarnes, PharmD | University of Minnesota | 612-626-5131 | utzx0002@umn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 6, 2017 | Feb 19, 2021 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Nov 13, 2017 | Feb 19, 2021 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D020143 | Gangliosidoses, GM2 |
| D013661 | Tay-Sachs Disease |
| D012497 | Sandhoff Disease |
| C564782 | Tay-Sachs Disease, Juvenile |
| D016537 | Gangliosidosis, GM1 |
| D005733 | Gangliosidoses |
| ID | Term |
|---|---|
| D013106 | Sphingolipidoses |
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
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| ID | Term |
|---|---|
| C059896 | miglustat |
| D055423 | Diet, Ketogenic |
| ID | Term |
|---|---|
| D050528 | Diet, Carbohydrate-Restricted |
| D004035 | Diet Therapy |
| D044623 | Nutrition Therapy |
| D013812 | Therapeutics |
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| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
| Lysosomal Disease Network | OTHER |
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| Ketogenic Diet | Other | The Syner-G therapy regimen includes switching the research subject to a full-time ketogenic diet for the 60-month duration of this study. |
|
| Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment |
| 17015493 | Background | 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. doi: 10.1542/peds.2006-0588. Epub 2006 Oct 2. |
| 19447653 | Background | 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. |
| 19346952 | Background | 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. |
| 21779792 | Background | 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. |
| 18823325 | Background | 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. |
| 15210895 | Background | 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. doi: 10.1212/01.wnl.0000130498.19019.02. |
| 16434676 | Background | 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. doi: 10.1212/01.wnl.0000194225.78917.de. |
| 19033218 | Background | 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. |
| 20374428 | Background | 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. |
| 25557439 | Background | 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. |
| 28716012 | Background | 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. |
| 28577204 | Background | 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 Oct;32(5):1529-1536. doi: 10.1007/s11011-017-0044-y. Epub 2017 Jun 3. |
| 28192816 | Background | Brackmann F, Kehrer C, Kustermann W, Bohringer J, Krageloh-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. |
| 27491214 | Background | 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(Suppl 1):663-73. |
| 29352662 | Background | Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR. Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. Mol Genet Metab. 2018 Feb;123(2):97-104. doi: 10.1016/j.ymgme.2017.12.432. Epub 2017 Dec 20. |
| 28476546 | Result | 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. |
| Educational information for the layperson about Tay-Sachs disease from the National Organization for Rare Disorders (NORD) | View source |
| Educational information for the layperson about Tay-Sachs disease from the National Human Genome Research Institute at the NIH | View source |
| Talking Glossary of Genetic Terms from the National Human Genome Research Institute at the NIH. (Uses Adobe Flash plugin.) This Talking Glossary is also available as an app for mobile devices, from a link on this page. | View source |
| Rare Diseases Clinical Research Network, an NIH-funded research network | View source |
| The Lysosomal Disease Network's page on the Rare Diseases Clinical Research Network's web site | View source |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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. |
|
| Secondary | Rate of Change in Neurocognitive Functioning | 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. | No participants completed the trial. Outcome measure data was not collected due to small sample size. | Posted | Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment |
|
|
| 13 |
| 16 |
| 0 |
| 16 |
| 0 |
| 16 |
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| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008064 | Lipidoses |
| D008052 | Lipid Metabolism, Inborn Errors |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D052439 | Lipid Metabolism Disorders |
| D004032 |
| Diet |
| D009747 | Nutritional Physiological Phenomena |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |