Placebo Controlled Trial of Dextromethorphan in Rett Syndrome

Study Overview
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Brief Summary
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Dr. Sakkubai Naidu, Principal Investigator, is initiating a double blinded placebo controlled clinical drug trial using dextromethorphan (DM) in Rett Syndrome (RTT), at the Pediatric Clinical Research Unit (PCRU) of the Johns Hopkins Hospital/Kennedy Krieger Institute. Funding source , FDA-00PD It has been shown that receptors for a certain brain chemical called glutamate, in particular the NMDA type, are increased in the brain of young RTT patients (<10 years of age). This chemical and its receptors, when in excess, cause harmful over-stimulation of nerve cells in the brain, contributing in part to the seizures, behavioral problems, and learning disabilities in RTT. The investigators propose to initiate a specific treatment using DM to counter/block the effects of this brain chemical and its excessive receptors to improve the ill effects of increased glutamate/NMDA receptors, because of DM's identified ability to block NMDA receptors. DM is available for human consumption. Infants and children with respiratory infections and cough, as well as non-ketotic hyperglycinemia, are treated with DM, which has been well tolerated.

Detailed Description
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The study will last for 3 months and will be limited to MECP2 mutation-positive children, one year - 9.99 years of age. This clinical trial, which is a placebo-controlled study, will randomize patients to the drug or placebo to determine the benefits of DM vs placebo on cognition, behavior, or seizures if present. Your child will stay twice in the Pediatric Clinical Research Unit (PCRU) at Johns Hopkins ICTR, for 3 days during each admission. The first hospital stay will be for 3 days, before she starts the DM or placebo. The follow-up 3-day hospital stay will be 3 months after she starts taking DM or placebo. There will also be two interim follow up evaluations at 2 weeks and 1 month after she starts taking the DM or placebo consisting of a neurological evaluation, EKG, and blood work, which can take place at your local doctor's office or at Johns Hopkins, and will be paid for by this study. Our research nurse or research associate will contact you at least weekly during the first month, and at least monthly thereafter until the end of the 3-month study.

Official Title
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Placebo Controlled Trial of Dextromethorphan in Rett Syndrome

Conditions
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Rett Syndrome

Intervention / Treatment
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* Drug: dextromethorphan
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: males and females who have classic or atypical RTT with a proven mutation in the MECP2 gene; subjects must be between one year - 10 years of age. Exclusion Criteria: those without an established mutation in the MECP2 gene; 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. MAO inhibitors, SSRI, sibutramine etc. to avoid a serotonin syndrome; quinidine and drugs metabolized by the CYP450 isoform 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; those showing poor compliance with any aspect of the study; foster children.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 10 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study drug-dextromethorphan (DM)<br>MECP2 mutation positive subjects randomized to receive DM | Drug: dextromethorphan<br>* The DM group will take 5mg/kg/day orally in 2 divided doses 12 hours apart for the 3 month period of the study. The pharmacists will dispense the DM to the study participants.<br>* Other names: Delsym;|
| Placebo Comparator: Placebo group<br>MECP2 positive subjects randomized to the placebo compound | Drug: placebo<br>* The placebo will be dispensed to equal the volume of DM of 5mg/kg/day. It is taken orally in 2 divided doses 12 hours apart during the study period of 3 months. The Research pharmacist will dispense the placebo to the participants.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mullen; Visual Reception Sub-scale Scores, Pre- and Post-Intervention | The Mullen Scales of Early Learning (MULLEN) Visual reception subscale raw scores range from Minimum=0 to Maximum=50. A higher score is a better outcome. Age equivalents from 1 month to 70 months can be computed for each subscale separately. | Initial evaluation and at the end of the 3 month trial | 
| Change in Mullen; Fine Motor Sub-scale Scores, Pre- and Post-Intervention | The Mullen Scales of Early Learning (MULLEN) Fine motor scale raw scores range from Minimum=0 to Maximum=49. A higher score is a better outcome. Age equivalents from 1 month to 70 months can be computed for each subscale separately. | Baseline and 3 months | 
| Change in Mullen; Receptive Language Subscale Scores, Pre- and Post-Intervention | The Mullen Scales of Early Learning (MULLEN) Receptive Language scale raw scores range from Minimum=0 to Maximum=50. A higher score is a better outcome. Age equivalents from 1 month to 70 months can be computed for each subscale separately. | Baseline and 3 months | 
| Change in Mullen, Expressive Language Sub-scale Scores, Pre- and Post-Intervention | The Mullen Scales of Early Learning (MULLEN) Expressive Language scale raw scores range from Minimum=0 to Maximum=50. A higher score is a better outcome. Age equivalents from 1 month to 70 months can be computed for each subscale separately. | Baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in VABS: Motor Skills Domain Scores, Pre- and Post-Intervention | Vineland Adaptive Behavior Scales-II (VABS): Motor Skills Domain Scores individual items are scored on a Likert scale from 2=Usually, 1=Sometimes or Partially, 0= Seldom or Never. Motor Skills Domain raw scores range from: Minimum=0 to Maximum=100. A higher score is a better outcome. | Baseline evaluation and at the end of the 3 month study | 
| Change in VABS:Daily Living Skills Domain Scores, Pre- and Post-Intervention | Vineland Adaptive Behavior Scales-II (VABS): Daily Living Skills Domain individual items are scored on a Likert scale from 2=Usually, 1=Sometimes or Partially, 0= Seldom or Never. The Daily Living Skills Domain measures personal behavior as well as domestic and community interaction skills. Daily Living Skills Domain raw scores range from Minimum=0 to Maximum=218. | Baseline and at the end of the 3 month trial | 
| Change in VABS: Socialization Domain Scores, Pre- and Post-Intervention | Vineland Adaptive Behavior Scales-II (VABS): Socialization Domain. Critical behaviors are scored on a Likert scale from 2=Usually, 1=Sometimes or Partially, 0= Seldom or Never. Socialization Domain raw scores range from: Minimum=0 to Maximum=152. A higher score is a better outcome. | Baseline and at the end of the 3 month trial | 
| Change in VABS:Communication Domain Scores, Pre- and Post-Intervention | Vineland Adaptive Behavior Scales (VABS)-II Communication Domain Scores. The Communication Domain evaluates the receptive, expressive, and written communication skills of the child. Critical behaviors in each Subdomain item are rated as 2=Usually, 1=Sometimes or Partially, 0= Seldom or Never. Communication Domain raw scores range from: Minimum=0 to Maximum=198. A higher score is a better outcome. | Baseline and at the end of the 3 month trial | 
| Change in Ghuman-Folstein Screen for Social Interaction (SSI) Score, Pre- and Post-Intervention. | The Ghuman-Folstein Screen for Social Interaction (SSI) assesses the change in behavior and temperament dysregulation as a total score. The score ranges from 0-162, with 0 being most Impaired /has the strongest autism features and 162 having no impairment/no autism features. | Initial evaluation and at the end of the 3 month study. The test lasts 45 minutes | 
| Change in Rett Syndrome Behavior Questionnaire Score, Pre- and Post-Intervention | The Rett Syndrome Behavior Questionnaire (RSBQ) total score was assessed. The total score ranges from 0 to 90, with 0 exhibiting no Rett syndrome related symptoms and 90 showing the greatest amount of symptoms (worse outcome). | Initial evaluation and at the end of the 3 month study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RTT, Rett syndrome, MECP2, dextromethorphan, DM