A Trial of Levodopa in Angelman Syndrome

• Sponsor: Wen-Hann Tan (Other)
• Overall Status: Completed
• CT.gov ID: NCT01281475
• Collaborator: Rady Children's Hospital, San Diego (Other), University of California, San Francisco (Other), Baylor College of Medicine (Other), Vanderbilt University Medical Center (Other), Greenwood Genetic Center (Other), Children's Hospital Medical Center, Cincinnati (Other), Angelman Syndrome Foundation, Inc. (Other)
• Enrollment: 67
• Locations: 7
• Arms: 2
• Duration (Months): 53.9
• Patients Per Site: 9.6
• Patients Per Site Per Month: 0.2

Study Details

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
• 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: Jan 1, 2011
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 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 [12 months]

Secondary Outcome Measures

1. Presence of Tremors [1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Rady Children's Hospital, San Diego	San Diego	California	United States	92123
2	University of California, San Francisco	San Francisco	California	United States	94121
3	Children's Hospital Boston	Boston	Massachusetts	United States	02115
4	Cincinnati Children's Hospital	Cincinnati	Ohio	United States	45229
5	Greenwood Genetic Center	Greenwood	South Carolina	United States	29646
6	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212
7	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• 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
• First Posted: Jan 24, 2011
• Last Update Posted: Jul 15, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Wen-Hann Tan, Attending Physician in Genetics, Boston Children's Hospital: Angelman syndrome; Levodopa; Carbidopa; L-dopa
• Additional relevant MeSH terms: Angelman Syndrome; Syndrome; Levodopa

Study Results

Participant Flow

Arm/Group Title	Levodopa	Placebo
Arm/Group 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. Levodopa/carbidopa: 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.	The placebo (in this study, microcellulose) is not expected to have any effect.
Period Title: Overall Study
STARTED	33	34
COMPLETED	29	26
NOT COMPLETED	4	8

Baseline Characteristics

Arm/Group Title	Levodopa	Placebo	Total
Arm/Group 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. Levodopa/carbidopa: 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.	The placebo (in this study, microcellulose) is not expected to have any effect. It is also taken 3 times a day, just like Levodopa.	Total of all reporting groups
Overall Participants	29	26	55
Age (Count of Participants)
<=18 years	29 100%	26 100%	55 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex/Gender, Customized (participants) [Number]
Female	13 44.8%	12 46.2%	25 45.5%
Male	16 55.2%	14 53.8%	30 54.5%
Developmental age - Bayley Cognitive (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	19 (8)	18 (6)	19 (7)
Tremors (Count of Participants)
Count of Participants [Participants]	16 55.2%	15 57.7%	31 56.4%

Outcome Measures

1. Primary Outcome

Title	Bayley Cognitive Age Equivalent at 1 Year
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Levodopa	Placebo
Arm/Group 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. Levodopa/carbidopa: 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.	The placebo (in this study, microcellulose) is not expected to have any effect. The placebo capsules are taken 3 times a day, just like the levodopa / carbidopa capsules
Measure Participants	29	26
Mean (Standard Deviation) [months]	19 (7)	19 (8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Levodopa, Placebo
	Comments	We performed generalized estimating equations with an unstructured covariance matrix to account for inter-correlations within measurements on the same participant over time.
	Type of Statistical Test	Superiority
	Comments	We modeled each outcome variable as a function of treatment (ie, levodopa versus placebo), visit (ie, baseline vs. 12-month follow-up) and the treatment-by-visit interaction; the interaction term tests whether the effect of levodopa treatment over time is significantly greater than that of the placebo group.
Statistical Test of Hypothesis	p-Value	0.75
	Comments	This was the calculated p value without correction for multiple comparisons
	Method	Generalized estimating equations
	Comments

2. Secondary Outcome

Title	Presence of Tremors
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Levodopa	Placebo
Arm/Group Description	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. 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.	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. Placebo Oral Capsule: The placebo contains excipients similar to those in the active drug, but it does not contain levodopa or carbidopa.
Measure Participants	29	26
Count of Participants [Participants]	14 48.3%	12 46.2%

Adverse Events

Arm/Group Title	Levodopa		Placebo
Arm/Group 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. Levodopa/carbidopa: 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.		The placebo (in this study, microcellulose) is not expected to have any effect.
All Cause Mortality
	Levodopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Levodopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/33 (9.1%)		1/34 (2.9%)
Gastrointestinal disorders
Vomiting	1/33 (3%)	1	0/34 (0%)	0
General disorders
Fever	0/33 (0%)	0	1/34 (2.9%)	1
Nervous system disorders
Seizure	2/33 (6.1%)	2	0/34 (0%)	0
Other (Not Including Serious) Adverse Events
	Levodopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/33 (33.3%)		9/34 (26.5%)
Nervous system disorders
Seizures	11/33 (33.3%)		9/34 (26.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.