A Trial of Levodopa in Angelman Syndrome

• ClinicalTrials.gov Identifier: NCT01281475
• Recruitment Status: Completed
• First Posted: January 24, 2011
• Results First Posted: January 13, 2017
• Last Update Posted: July 15, 2020
• Sponsor: Wen-Hann Tan
• Collaborators: 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.
• Information provided by (Responsible Party): Wen-Hann Tan, Boston Children's Hospital

Study Description

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

• 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

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

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

• 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

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

• Responsible Party: Wen-Hann Tan, Attending Physician in Genetics, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT01281475
• 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: July 15, 2020
• Last Verified: July 2020

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; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs