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

Tracking Information

• First Submitted Date: January 20, 2011
• First Posted Date: January 24, 2011
• Results First Submitted Date: August 6, 2016
• Results First Posted Date: January 13, 2017
• Last Update Posted Date: July 15, 2020
• Study Start Date: January 2011
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 16, 2016): Bayley Cognitive Age Equivalent at 1 Year [ Time Frame: 12 months ]

Original Primary Outcome Measures (submitted: January 21, 2011)

• Developmental Outcome Measures [ Time Frame: 12 months ]
  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 ]
  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.

• Current Secondary Outcome Measures (submitted: November 16, 2016): Presence of Tremors [ Time Frame: 1 year ]

Original Secondary Outcome Measures (submitted: January 21, 2011)

EEG [ Time Frame: 12 months, 24 months ]

Changes in electroencephalogram (EEG) scores at 12 months and 24 months.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Trial of Levodopa in Angelman Syndrome
• Official Title: A Phase 2 Randomized Placebo-Controlled Trial of Levodopa in Angelman Syndrome

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

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
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Angelman Syndrome

Intervention

• 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
• Drug: Placebo Oral Capsule
  The placebo contains excipients similar to those in the active drug, but it does not contain levodopa or carbidopa.

Study Arms

• 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.
  Intervention: Drug: Levodopa
• 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.
  Intervention: Drug: Placebo Oral Capsule

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 16, 2016): 67
• Original Estimated Enrollment (submitted: January 21, 2011): 100
• Actual Study Completion Date: July 2015
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 12 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01281475
• Other Study ID Numbers: 09-12-0610; 3523 ( Other Grant/Funding Number: OOPD )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Wen-Hann Tan, Boston Children's Hospital
• Study 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.

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

• PRS Account: Boston Children's Hospital
• Verification Date: July 2020