A Trial of Levodopa in Angelman Syndrome

NCT ID: NCT01281475

Last Updated: 2020-07-15

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

67 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-01-31

Study Completion Date

2015-07-31

Brief Summary

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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

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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.

Conditions

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Angelman Syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Levodopa

Levodopa is prescribed as a combination of levodopa/carbidopa (4:1) to reduce the peripheral side effects. The dosage used was 15 mg/kg/day in 3 divided doses.

Group Type EXPERIMENTAL

Levodopa

Intervention Type DRUG

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.

Placebo

The placebo contains excipients similar to those in the active drug, but it does not contain levodopa or carbidopa, so it is not expected to have any effect.

Group Type PLACEBO_COMPARATOR

Placebo Oral Capsule

Intervention Type DRUG

The placebo contains excipients similar to those in the active drug, but it does not contain levodopa or carbidopa.

Interventions

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Levodopa

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.

Intervention Type DRUG

Placebo Oral Capsule

The placebo contains excipients similar to those in the active drug, but it does not contain levodopa or carbidopa.

Intervention Type DRUG

Other Intervention Names

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Sinemet L-dopa

Eligibility Criteria

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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
Minimum Eligible Age

4 Years

Maximum Eligible Age

12 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Rady Children's Hospital, San Diego

OTHER

Sponsor Role collaborator

University of California, San Francisco

OTHER

Sponsor Role collaborator

Baylor College of Medicine

OTHER

Sponsor Role collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role collaborator

Greenwood Genetic Center

OTHER

Sponsor Role collaborator

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role collaborator

Angelman Syndrome Foundation, Inc.

OTHER

Sponsor Role collaborator

Wen-Hann Tan

OTHER

Sponsor Role lead

Responsible Party

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Wen-Hann Tan

Attending Physician in Genetics

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Wen-Hann Tan, BMBS

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Lynne M. Bird, MD

Role: PRINCIPAL_INVESTIGATOR

Rady Children's Hospital, San Diego

Steven A. Skinner, MD

Role: PRINCIPAL_INVESTIGATOR

Greenwood Genetic Center

Carlos A. Bacino, MD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Anne Slavotinek, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Cary Fu, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Logan Wink, M.D

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Locations

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Rady Children's Hospital, San Diego

San Diego, California, United States

Site Status

University of California, San Francisco

San Francisco, California, United States

Site Status

Children's Hospital Boston

Boston, Massachusetts, United States

Site Status

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

Site Status

Greenwood Genetic Center

Greenwood, South Carolina, United States

Site Status

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status

Baylor College of Medicine

Houston, Texas, United States

Site Status

Countries

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United States

Other Identifiers

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3523

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

09-12-0610

Identifier Type: -

Identifier Source: org_study_id

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