Angelman Syndrome
Conditions
Keywords
Angelman syndrome, Levodopa, Carbidopa, L-dopa
Brief summary
This study is designed to determine the highest dose of levodopa/carbidopa that can be tolerated without any serious side effects by children with Angelman syndrome. It has been hypothesized that levodopa may lead to an improvement in the neurodevelopment and abnormal movements (e.g. tremors) in children with Angelman syndrome. Data from this study will be used to design a phase II trial to determine the efficacy of levodopa in treating children with Angelman syndrome.
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, so we do not know what dose of levodopa is most appropriate for children with Angelman syndrome. Therefore, the purpose of this study is to find out the highest dose of levodopa that children with Angelman syndrome can tolerate without any serious side effects. Once we know the dose of levodopa that can be tolerated by children with Angelman syndrome, we will conduct a larger follow-up study to find out whether levodopa will lead to an improvement in their development and tremor.
Interventions
DRUGLevodopa/Carbidopa (4:1)
Dosages are based on levodopa. Each cohort of 3 subjects will be placed on an increasing dose of levodopa (2, 5, 10, and 15 mg/kg/day) for 1 week, provided subjects in the preceding cohort tolerated the lower dose. Levodopa/Carbidopa is a combined formulation that will be dispensed as capsules. It should be taken 3 times a day.
Sponsors
Boston Children's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Angelman syndrome, confirmed by molecular testing * Must be willing to come for research visit on 2 days, exactly 1 week apart
Exclusion criteria
* On levodopa, carbidopa, or any dopamine agonists in the 2 weeks prior to participation * Other medical conditions that may be associated with developmental or cognitive delays * More than 2 clinical seizures per month * Used monoamine oxidase (MAO) inhibitors within the last 2 weeks * Used phenytoin within the last 2 weeks * Used phenothiazines, butyrophenones, and thioxanthenes within last 2 weeks * Hypersensitive to levodopa or carbidopa * Cardiovascular disease or instability * Respiratory diseases, including asthma, emphysema, chronic cough, and shortness of breath * Liver disease * Stomach or intestinal ulcers * Kidney disease * Hematological problems, including anemia, leucopenia, and thrombocytopenia * Used investigational drugs/interventions within the past three months
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Dose of Levodopa/Carbidopa That Can be Tolerated (Without Any Dose Limiting Toxicity) by at Least 3 Subjects. | 1 week |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levodopa/Carbidopa Other Names:
Sinemet L-dopa
Dosages are based on levodopa.
Each cohort of 3 subjects will be placed on an increasing dose of levodopa (2, 5, 10, and 15 mg/kg/day) for 1 week, provided subjects in the preceding cohort tolerated the lower dose.
Levodopa/Carbidopa is a combined formulation that will be dispensed as capsules. It should be taken 3 times a day.
Levodopa/Carbidopa (4:1): Dosages are based on levodopa.
Each cohort of 3 subjects will be placed on an increasing dose of levodopa (2, 5, 10, and 15 mg/kg/day) for 1 week, provided subjects in the preceding cohort tolerated the lower dose.
Levodopa/Carbidopa is a combined formulation that will be dispensed as capsules. It should be taken 3 times a day. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Levodopa/Carbidopa |
|---|---|
| Age, Categorical <=18 years | 16 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
Maximum Dose of Levodopa/Carbidopa That Can be Tolerated (Without Any Dose Limiting Toxicity) by at Least 3 Subjects.
Time frame: 1 week
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levodopa/Carbidopa | Maximum Dose of Levodopa/Carbidopa That Can be Tolerated (Without Any Dose Limiting Toxicity) by at Least 3 Subjects. | 15 mg/kg/day |