A Trial of Levodopa in Angelman Syndrome
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Angelman Syndrome |
Drug: Levodopa/carbidopa |
Phase 2 Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | A Phase 2 Randomized Placebo-Controlled Trial of Levodopa in Angelman Syndrome |
- Developmental Outcome Measures [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Changes in raw or standard scores between baseline and after 12 months of treatment with either placebo or LD/CD of:
I. Bayley Scales of Infant and Toddler Development, 3rd edition (or the Mullen Scales of Early Learning in the more developmentally advanced subjects) II. Vineland Adaptive Behavior Scales, 2nd edition (standard scores only) III. Preschool Language Scale, 4th edition IV. Aberrant Behavior Checklist - Community version
- Tremor and Movement Disorder [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]Changes in raw score of a modified Unified Parkinson's Disease Rating Scale (mUPDRS), a measure of tremor and movement disorder, from baseline after 12 months in the placebo or the LD/CD group.
- EEG [ Time Frame: 12 months, 24 months ] [ Designated as safety issue: No ]Changes in electroencephalogram (EEG) scores at 12 months and 24 months.
| Estimated Enrollment: | 100 |
| Study Start Date: | January 2011 |
| Estimated Study Completion Date: | June 2014 |
| Estimated Primary Completion Date: | June 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 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.
|
Drug: 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. Other Names:
|
|
Placebo Comparator: Placebo
The placebo (in this study, microcellulose) is not expected to have any effect.
|
Drug: 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. Other Names:
|
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.
Eligibility| Ages Eligible for Study: | 4 Years to 12 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age between 4 years and 12 years (i.e., before the 13th birthday)
- 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
- Not on LD, CD, or any dopamine agonists in the 2 weeks prior to participation
Exclusion Criteria:
- Co-morbid disorders that may be associated with developmental or cognitive delays
- Poorly controlled seizures - An average of more than 2 clinical seizures per month in the 12 months prior to enrollment.
- 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
- Presence of cardiovascular disease or instability, respiratory disease, liver disease, peptic ulcer disease, renal impairment, or hematological disorders
- Pregnancy
Contacts and Locations| Contact: Wen-Hann Tan, BMBS | 617-355-4697 | wen-hann.tan@childrens.harvard.edu |
| United States, California | |
| Rady Children's Hospital, San Diego | Recruiting |
| San Diego, California, United States, 92123 | |
| Contact: Rachel Bollenbecker, BSN 858-966-8453 rbollenbecker@rchsd.org | |
| Principal Investigator: Lynne M. Bird, MD | |
| University of California, San Francisco | Recruiting |
| San Francisco, California, United States, 94121 | |
| Contact: Anne Slavotinek, MD 415-514-1783 slavotia@peds.ucsf.edu | |
| Principal Investigator: Anne Slavotinek, MD | |
| United States, Massachusetts | |
| Children's Hospital Boston | Recruiting |
| Boston, Massachusetts, United States, 02115 | |
| Contact: Jennifer Willen, MA 617-355-4241 jennifer.willen@childrens.harvard.edu | |
| Principal Investigator: Wen-Hann Tan, BMBS | |
| United States, South Carolina | |
| Greenwood Genetic Center | Recruiting |
| Greenwood, South Carolina, United States, 29646 | |
| Contact: Fran Annese, MSW 864-941-8100 fran@ggc.org | |
| Principal Investigator: Steven A. Skinner, MD | |
| United States, Tennessee | |
| Vanderbilt University Medical Center | Recruiting |
| Nashville, Tennessee, United States, 37212 | |
| Contact: Selena Carpenter, MEd 615-875-4897 selena.m.carpenter@Vanderbilt.Edu | |
| Principal Investigator: Gregory Barnes, MD, PhD | |
| United States, Texas | |
| Baylor College of Medicine | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Beverly Feldman, MSN 832-822-4301 bfeldman@bcm.edu | |
| Principal Investigator: Carlos Bacino, MD | |
| Principal Investigator: | Wen-Hann Tan, BMBS | Children's Hospital Boston |
| Principal Investigator: | Lynne M. Bird, MD | Rady Children's Hospital, San Diego |
| Principal Investigator: | Steven A. Skinner, MD | Greenwood Genetic Center |
| Principal Investigator: | Carlos A. Bacino, MD | Baylor College of Medicine |
| Principal Investigator: | Anne Slavotinek, MD | University of California, San Francisco |
| Principal Investigator: | Gregory Barnes, MD | Vanderbilt University |
More Information
No publications provided
| Responsible Party: | Wen-Hann Tan, Attending Physician in Genetics, Children's Hospital, Boston |
| ClinicalTrials.gov Identifier: | NCT01281475 History of Changes |
| Other Study ID Numbers: | 09-12-0610 |
| Study First Received: | January 20, 2011 |
| Last Updated: | October 3, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Children's Hospital Boston:
|
Angelman syndrome Levodopa Carbidopa L-dopa |
Additional relevant MeSH terms:
|
Angelman Syndrome Movement Disorders Central Nervous System Diseases Nervous System Diseases Abnormalities, Multiple Congenital Abnormalities Chromosome Disorders Genetic Diseases, Inborn Carbidopa Levodopa |
Antiparkinson Agents Anti-Dyskinesia Agents Central Nervous System Agents Therapeutic Uses Pharmacologic Actions Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Dopamine Agents Neurotransmitter Agents Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on May 16, 2013