A Trial of Levodopa in Angelman Syndrome

Study Description

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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

Condition or disease	Intervention/treatment	Phase
Angelman Syndrome	Drug: Levodopa; Drug: Placebo Oral Capsule	Phase 2; Phase 3

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.

Study Design

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	67 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Phase 2 Randomized Placebo-Controlled Trial of Levodopa in Angelman Syndrome
Study Start Date :	January 2011
Actual Primary Completion Date :	July 2015
Actual Study Completion Date :	July 2015

Arms and Interventions

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: 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.	Drug: 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.; Other Names: Sinemet; L-dopa
Placebo Comparator: 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.	Drug: Placebo Oral Capsule; The placebo contains excipients similar to those in the active drug, but it does not contain levodopa or carbidopa.

Outcome Measures

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Bayley Cognitive Age Equivalent at 1 Year [ Time Frame: 12 months ]

Secondary Outcome Measures :

1. Presence of Tremors [ Time Frame: 1 year ]

Eligibility Criteria

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	4 Years to 12 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, California
Rady Children's Hospital, San Diego
San Diego, California, United States, 92123
University of California, San Francisco
San Francisco, California, United States, 94121
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Ohio
Cincinnati Children's Hospital
Cincinnati, Ohio, United States, 45229
United States, South Carolina
Greenwood Genetic Center
Greenwood, South Carolina, United States, 29646
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37212
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030

Sponsors and Collaborators

Wen-Hann Tan

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.

Investigators

Principal Investigator:	Wen-Hann Tan, BMBS	Boston Children’s Hospital
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:	Cary Fu, MD	Vanderbilt University Medical Center
Principal Investigator:	Logan Wink, M.D	Children's Hospital Medical Center, Cincinnati

More Information

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Wen-Hann Tan, Attending Physician in Genetics, Boston Children’s Hospital
ClinicalTrials.gov Identifier:	NCT01281475 History of Changes
Other Study ID Numbers:	09-12-0610; 3523 ( Other Grant/Funding Number: OOPD )
First Posted:	January 24, 2011
Results First Posted:	January 13, 2017
Last Update Posted:	January 9, 2018
Last Verified:	December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Keywords provided by Wen-Hann Tan, Boston Children’s Hospital:

Angelman syndrome; Levodopa; Carbidopa; L-dopa

Additional relevant MeSH terms:

Angelman Syndrome; Syndrome; Disease; Pathologic Processes; Movement Disorders; Central Nervous System Diseases; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn	Levodopa; Carbidopa; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Aromatic Amino Acid Decarboxylase Inhibitors; Enzyme Inhibitors