A Trial of Levodopa in Angelman Syndrome

A Phase 2 Randomized Placebo-Controlled Trial of Levodopa in Angelman Syndrome

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

Study Overview

• Status: Completed
• Conditions: Angelman Syndrome
• Intervention / Treatment: Drug: Levodopa; Drug: Placebo Oral Capsule

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 Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 12 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Bayley Cognitive Age Equivalent at 1 Year	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Presence of Tremors	1 year

Collaborators and Investigators

• Sponsor: Wen-Hann Tan
• Collaborators: Baylor College of Medicine; University of California, San Francisco; Vanderbilt University Medical Center; Children's Hospital Medical Center, Cincinnati; Rady Children's Hospital, San Diego; Greenwood Genetic Center; Angelman Syndrome Foundation, Inc.
• Investigators: Principal Investigator: Lynne M. Bird, MD, Rady Children's Hospital, San Diego; 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

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): July 1, 2015
• Study Completion (ACTUAL): July 1, 2015

Study Registration Dates

• First Submitted: January 20, 2011
• First Submitted That Met QC Criteria: January 21, 2011
• First Posted (ESTIMATE): January 24, 2011

Study Record Updates

• Last Update Posted (ACTUAL): July 15, 2020
• Last Update Submitted That Met QC Criteria: July 4, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Angelman syndrome; Levodopa; Carbidopa; L-dopa
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Angelman Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Levodopa
• Other Study ID Numbers: 09-12-0610; 3523 (OTHER_GRANT: OOPD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED