GM1 Gangliosidoses, GM2 Gangliosidoses, Tay-Sachs Disease, Sandhoff Disease
Conditions
Keywords
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
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.
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).
Interventions
DRUGmiglustat
The Syner-G therapy regimen includes treating with orally-administered miglustat for the duration of the 60-month study.
OTHERKetogenic 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.
Sponsors
Rare Diseases Clinical Research Network
National Center for Advancing Translational Sciences (NCATS)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Lysosomal Disease Network
University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 204 Months
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 13 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Syner-G Therapy Regimen |
|---|---|
| Age, Categorical <=18 years | 16 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 16 |
| other Total, other adverse events | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
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.
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
Population: No participants completed the trial. Outcome measure data was not collected due to small sample size.
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.
Time frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment
Population: No participants completed the trial. Outcome measure data was not collected due to small sample size.