Angelman Syndrome
Conditions
Keywords
Angelman syndrome, Levodopa, Carbidopa, L-dopa
Brief summary
This study is designed to determine whether levodopa will lead to an improvement in the development and tremor in children with Angelman syndrome (AS). It has been suggested that levodopa, a medication that is usually used to treat Parkinson disease in adults, may help children with AS in their overall development and reduce the tremor that some of them have. If levodopa is found to be beneficial for children with AS, this could lead to a new treatment for AS. Funding Source - FDA-OOPD
Detailed description
Levodopa is a prodrug that delivers dopamine to the brain. It is usually given with carbidopa, a peripheral decarboxylase inhibitor, to increase the bioavailability of levodopa. Animal studies have suggested that levodopa can reverse the excess phosphorylation of some enzymes involved in synaptic and neuronal function, including calcium/calmodulin-dependent kinase type 2 (CaMKII). Recently, it was shown that excess phosphorylation of CaMKII may be responsible for some of the neurological deficits seen in Angelman syndrome. Therefore, it is hypothesized that levodopa may lead to an improvement in the neurodevelopment and abnormal movements (e.g. tremors) in children with Angelman syndrome. Although many children have used levodopa for a variety of medical conditions over the last 30 years, it has not been approved by the Food and Drug Administration (FDA) for use in children, and it has not been formally studied in children with Angelman syndrome. Therefore, the purpose of this study is to find out whether levodopa will lead to an improvement in the development and in the tremor in children with AS.
Interventions
DRUGLevodopa
Levodopa/Carbidopa (4:1) Dosages are based on levodopa. Subjects randomized to the levodopa arm will receive a levodopa dose of 5 mg/kg/day in the first 2 weeks of the study, a levodopa dose of 10 mg/kg/day in the second 2 weeks of the study, and a levodopa dose of 15 mg/kg/day (up to a maximum of 800 mg per day) for the remaining duration of the study. Levodopa/Carbidopa is a combined formulation that will be dispensed as capsules. It should be taken 3 times a day.
DRUGPlacebo Oral Capsule
The placebo contains excipients similar to those in the active drug, but it does not contain levodopa or carbidopa.
Sponsors
Rady Children's Hospital, San Diego
University of California, San Francisco
Baylor College of Medicine
Vanderbilt University Medical Center
Greenwood Genetic Center
Children's Hospital Medical Center, Cincinnati
Angelman Syndrome Foundation, Inc.
Wen-Hann Tan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 4 years and 12 years (i.e., before the 13th birthday) 2. Molecular confirmation of the diagnosis of AS, which may include abnormal methylation studies or UBE3A mutation analyses - only subjects with a molecular diagnosis will be allowed to enroll 3. Not on LD, CD, or any dopamine agonists in the 2 weeks prior to participation
Exclusion criteria
1. Co-morbid disorders that may be associated with developmental or cognitive delays 2. Poorly controlled seizures - An average of more than 2 clinical seizures per month in the 12 months prior to enrollment. 3. Use of medications that may interact with LD/CD including atypical antipsychotics (aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, risperidone, ziprasidone), monoamine oxidase inhibitors (isocarboxazid, phenelzine, selegiline, tranylcypromine), or phenytoin within the last 14 days, or other investigational interventions within the past 3 months 4. Presence of cardiovascular disease or instability, respiratory disease, liver disease, peptic ulcer disease, renal impairment, or hematological disorders 5. Pregnancy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Bayley Cognitive Age Equivalent at 1 Year | 12 months |
Secondary
| Measure | Time frame |
|---|---|
| Presence of Tremors | 1 year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levodopa Levodopa is a prodrug that delivers dopamine to the brain. It is usually given with carbidopa, a peripheral decarboxylase inhibitor, to increase the bioavailability of levodopa.
Levodopa/carbidopa: Levodopa/Carbidopa (4:1)
Dosages are based on levodopa.
Subjects randomized to the levodopa arm will receive a levodopa dose of 5 mg/kg/day in the first 2 weeks of the study, a levodopa dose of 10 mg/kg/day in the second 2 weeks of the study, and a levodopa dose of 15 mg/kg/day (up to a maximum of 800 mg per day) for the remaining duration of the study.
Levodopa/Carbidopa is a combined formulation that will be dispensed as capsules. It should be taken 3 times a day. | 29 |
| Placebo The placebo (in this study, microcellulose) is not expected to have any effect.
It is also taken 3 times a day, just like Levodopa. | 26 |
| Total | 55 |
Baseline characteristics
| Characteristic | Placebo | Total | Levodopa |
|---|---|---|---|
| Age, Categorical <=18 years | 26 Participants | 55 Participants | 29 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Developmental age - Bayley Cognitive | 18 months STANDARD_DEVIATION 6 | 19 months STANDARD_DEVIATION 7 | 19 months STANDARD_DEVIATION 8 |
| Sex/Gender, Customized Female | 12 participants | 25 participants | 13 participants |
| Sex/Gender, Customized Male | 14 participants | 30 participants | 16 participants |
| Tremors | 15 Participants | 31 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 33 | 9 / 34 |
| serious Total, serious adverse events | 3 / 33 | 1 / 34 |
Outcome results
Primary
Bayley Cognitive Age Equivalent at 1 Year
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levodopa | Bayley Cognitive Age Equivalent at 1 Year | 19 months | Standard Deviation 7 |
| Placebo | Bayley Cognitive Age Equivalent at 1 Year | 19 months | Standard Deviation 8 |
Comparison: We performed generalized estimating equations with an unstructured covariance matrix to account for inter-correlations within measurements on the same participant over time.p-value: 0.75Generalized estimating equations
Secondary
Presence of Tremors
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levodopa | Presence of Tremors | 14 Participants |
| Placebo | Presence of Tremors | 12 Participants |