Trial of Dextromethorphan in Rett Syndrome

Study Overview
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Brief Summary
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Increased brain glutamate and its N-methyl-D-aspartate (NMDA) receptors found in the brain of younger Rett syndrome (RTT) patients cause toxic damage to neurons (the brain's nerve cells), and contributing to EEG spikes. Dextromethorphan (DM) acts by blocking NMDA/glutamate receptors. This study is being done to determine if DM will prevent the harmful over-stimulation of the neurons thereby reducing EEG spike activity. Treatment with DM consists of one of 3 different doses (0.25 mg/kg per day; or 2.5 mg/kg/day; or 5mg/kg/day), and aims to find out which dose if any will help improve EEG abnormalities, behavior, cognition, and reduce seizures, as well as improve breathing abnormalities, motor capabilities, bone density, and GI dysfunction. The study will include 90 females and males with RTT, 2 years-14.99 years of age, with a mutation in the methyl CpG binding protein 2 (MECP2) gene, and spikes on EEG, with or without clinical seizures.

Detailed Description
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Patients meeting eligibility criteria(mutation +ve and having EEG spikes), will be admitted to the Pediatric Clinical Research Unit at Johns Hopkins Hospital and will have pharmacokinetics of DM determined to establish that they are rapid metabolizers of the drug. The baseline studies on initial admission include neurological, neuropsychology,EEG, gastroenterology, Occupational and Physical therapy evaluations. If the subject is a rapid metabolizer they will be randomized to one of the three drug doses. They are contacted by telephone, weekly in the first month, and monthly thereafter. They will be examined by a neurologist at 2 weeks,1 month, and 3 months during the drug trial. At each of these visits they will also be monitored for changes in complete blood count (CBC), electrolytes, and EKG. At the end of the 6 month drug trial the patients will be readmitted to Johns Hopkins Hospital when all baseline studies are repeated. Cost of travel, hospitalization and interim tests are free to participants.

Official Title
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Trial of Dextromethorphan in Rett Syndrome

Conditions
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Rett Syndrome

Intervention / Treatment
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* Drug: Dextromethorphan
* Drug: Dextromethorphan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: those who have classic or atypical RTT with a proven mutation in the MeCP2 gene; those with documented EEG evidence of spike activity who may or may not have clinical seizures; subjects must be between 2years -14.99 years of age. Exclusion Criteria: those without an established mutation in the MeCP2 gene; those who do not have EEG evidence of spike activity; those with mutations in the MeCP2 gene but who have had brain resection or surgical intervention; for example, tumor, hydrocephalus, severe head trauma; or, an associated severe medical illnesses such as vasculopathies, malignancies, diabetes, thyroid dysfunction, etc; those on medications that could interact with DM, e.g. monoamine oxidase (MAO) inhibitors, selective serotonin reuptake inhibitor (SSRI), sibutramine etc. to avoid a serotonin syndrome; quinidine and drugs metabolized by the Cytochrome P450 (CYP450) isoform cytochrome P450 2D6 (CYP2D6) (e.g. amiodarone, haloperidol, propafenone, thioridazine); those proven to be intermediate or slow metabolizers of DM; those with reported adverse reactions to DM; those whose pregnancy test is positive; and, those showing poor compliance with any aspect of the study; foster children

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DM1( 0.25 mg/kg /day)<br>Dextromethorphan 0.25 mg/kg per day | Drug: Dextromethorphan<br>* Subjects will be randomized to receive one of three dosage groups either 0.25 mg/kg per day; or 2.5 mg/kg/day; or 5mg/kg/day of Dextromethorphan Polistirex (Delsym)oral syrup, which will be given exactly 12 hours apart in two divided doses during the 6 month trial.<br>* Other names: Delsym;Drug: Dextromethorphan<br>* Dextromethorphan polistirex. Doses are 0.25 mg/kg/day, 2.5mg/kg/day, and 5 mg/kg/day. The drug is given in two divided doses 12 hours apart for 6 months.<br>* Other names: Delsym;|
| Experimental: DM2 (2.5 mg/kg/day)<br>Dextromethorphan 2.5 mg/kg/day | Drug: Dextromethorphan<br>* Subjects will be randomized to receive one of three dosage groups either 0.25 mg/kg per day; or 2.5 mg/kg/day; or 5mg/kg/day of Dextromethorphan Polistirex (Delsym)oral syrup, which will be given exactly 12 hours apart in two divided doses during the 6 month trial.<br>* Other names: Delsym;Drug: Dextromethorphan<br>* Dextromethorphan polistirex. Doses are 0.25 mg/kg/day, 2.5mg/kg/day, and 5 mg/kg/day. The drug is given in two divided doses 12 hours apart for 6 months.<br>* Other names: Delsym;|
| Experimental: DM3 (5mg/kg/day)<br>Dextromethorphan 5mg/kg/day | Drug: Dextromethorphan<br>* Subjects will be randomized to receive one of three dosage groups either 0.25 mg/kg per day; or 2.5 mg/kg/day; or 5mg/kg/day of Dextromethorphan Polistirex (Delsym)oral syrup, which will be given exactly 12 hours apart in two divided doses during the 6 month trial.<br>* Other names: Delsym;Drug: Dextromethorphan<br>* Dextromethorphan polistirex. Doses are 0.25 mg/kg/day, 2.5mg/kg/day, and 5 mg/kg/day. The drug is given in two divided doses 12 hours apart for 6 months.<br>* Other names: Delsym;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | Difference in EEG spike count means pre and 6 months post-treatment in each of three treatment groups. | Initial and 6-month post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in Receptive Language as Measured by the Mullen Scale. | The Mullen Receptive language scale pre and 6 months post DM, measured as a change in the mean score of language, by age in months. | Change in mean between Initial and 6-month follow-up | 
| Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | The Screen for Social Interaction (SSI) is a 54-item parent/caregiver-report screening instrument that emphasizes reciprocal social interaction including joint attention skills. The items are positive (prosocial) and are scored on a four-point frequency scale (child displays the behavior almost never = 0 to almost all the time = 3). Thus lower scores reflect a slower or delayed development, and higher scores reflect more normative development. SSI total scores range from 0-162. There are no subscales. Difference in Screen for Social Interaction (SSI) mean scores between baseline and 6 months post-treatment for each treatment arm are reported. | Initial and 6 month followup | 
| Mean SSI Score for Total Subjects at Baseline and 6 Months | Analysis of Difference in Mean Screen for Social Interaction (SSI) Score between 0-6 months for total sample (n=19). | 0-6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rett Syndrome, Dextromethorphan