A Trial of Levodopa in Angelman Syndrome

Tracking Information
First Submitted Date ICMJE	January 20, 2011
First Posted Date ICMJE	January 24, 2011
Results First Submitted Date	August 6, 2016
Results First Posted Date	January 13, 2017
Last Update Posted Date	January 9, 2018
Study Start Date ICMJE	January 2011
Actual Primary Completion Date	July 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: November 16, 2016)	Bayley Cognitive Age Equivalent at 1 Year [ Time Frame: 12 months ]
Original Primary Outcome Measures ICMJE; (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.
Change History	Complete list of historical versions of study NCT01281475 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: November 16, 2016)	Presence of Tremors [ Time Frame: 1 year ]
Original Secondary Outcome Measures ICMJE; (submitted: January 21, 2011)	EEG [ Time Frame: 12 months, 24 months ]; Changes in electroencephalogram (EEG) scores at 12 months and 24 months.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Trial of Levodopa in Angelman Syndrome
Official Title ICMJE	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 ICMJE	Interventional
Study Phase	Phase 2; Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Angelman Syndrome
Intervention ICMJE	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
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: November 16, 2016)	67
Original Estimated Enrollment ICMJE; (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 ICMJE	Inclusion Criteria: Age between 4 years and 12 years (i.e., before the 13th birthday); 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; Not on LD, CD, or any dopamine agonists in the 2 weeks prior to participation Exclusion Criteria: Co-morbid disorders that may be associated with developmental or cognitive delays; Poorly controlled seizures - An average of more than 2 clinical seizures per month in the 12 months prior to enrollment.; 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; Presence of cardiovascular disease or instability, respiratory disease, liver disease, peptic ulcer disease, renal impairment, or hematological disorders; Pregnancy
Sex/Gender	Sexes Eligible for Study: All
Ages	4 Years to 12 Years (Child)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01281475
Other Study ID Numbers ICMJE	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 ICMJE	Wen-Hann Tan
Collaborators ICMJE	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 ICMJE	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	December 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP