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Trial of Dextromethorphan in Rett Syndrome

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ClinicalTrials.gov Identifier: NCT00593957
Recruitment Status : Terminated (Study changed to a placebo controlled trial of dextromethorphan)
First Posted : January 15, 2008
Results First Posted : April 23, 2014
Last Update Posted : April 23, 2014
Sponsor:
Information provided by (Responsible Party):
SakkuBai Naidu, M.D., Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Rett Syndrome Drug: Dextromethorphan Phase 2

Detailed Description:
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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Trial of Dextromethorphan in Rett Syndrome
Study Start Date : August 2004
Actual Primary Completion Date : April 2010
Actual Study Completion Date : June 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Rett Syndrome

Arms and Interventions
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Arm Intervention/treatment
Experimental: DM1( 0.25 mg/kg /day)
Dextromethorphan 0.25 mg/kg per day
 Drug: Dextromethorphan
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.
Other Name: Delsym

Drug: Dextromethorphan
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.
Other Name: Delsym
Experimental: DM2 (2.5 mg/kg/day)
Dextromethorphan 2.5 mg/kg/day
 Drug: Dextromethorphan
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.
Other Name: Delsym

Drug: Dextromethorphan
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.
Other Name: Delsym
Experimental: DM3 (5mg/kg/day)
Dextromethorphan 5mg/kg/day
 Drug: Dextromethorphan
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.
Other Name: Delsym

Drug: Dextromethorphan
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.
Other Name: Delsym


Outcome Measures
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Primary Outcome Measures :
  1. Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. [ Time Frame: Initial and 6-month post-treatment ]
    Difference in EEG spike count means pre and 6 months post-treatment in each of three treatment groups.


Secondary Outcome Measures :
  1. Improvement in Receptive Language as Measured by the Mullen Scale. [ Time Frame: Change in mean between Initial and 6-month follow-up ]
    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.

  2. Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. [ Time Frame: Initial and 6 month followup ]
    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.

  3. Mean SSI Score for Total Subjects at Baseline and 6 Months [ Time Frame: 0-6 months ]
    Analysis of Difference in Mean Screen for Social Interaction (SSI) Score between 0-6 months for total sample (n=19).


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. those who have classic or atypical RTT with a proven mutation in the MeCP2 gene;
  2. those with documented EEG evidence of spike activity who may or may not have clinical seizures;
  3. subjects must be between 2years -14.99 years of age.

Exclusion Criteria:

  1. those without an established mutation in the MeCP2 gene;
  2. those who do not have EEG evidence of spike activity;
  3. 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;
  4. 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);
  5. those proven to be intermediate or slow metabolizers of DM;
  6. those with reported adverse reactions to DM;
  7. those whose pregnancy test is positive; and,
  8. those showing poor compliance with any aspect of the study;
  9. foster children
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00593957


Locations
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United States, Maryland
Kennedy Krieger Institute/Johns Hopkins Medical Institutions
Baltimore, Maryland, United States, 21205
Sponsors and Collaborators
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
Investigators
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Principal Investigator: SakkuBai Naidu, MD Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
More Information
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Responsible Party: SakkuBai Naidu, M.D., Professor of Neurology and Pediatrics, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ClinicalTrials.gov Identifier: NCT00593957    
Other Study ID Numbers: FD2408
First Posted: January 15, 2008    Key Record Dates
Results First Posted: April 23, 2014
Last Update Posted: April 23, 2014
Last Verified: July 2013
Keywords provided by SakkuBai Naidu, M.D., Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:
Rett Syndrome
Dextromethorphan
Additional relevant MeSH terms:
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Rett Syndrome
Syndrome
Disease
Pathologic Processes
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Levomethorphan
Dextromethorphan
 Antitussive Agents
Respiratory System Agents
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Analgesics
Sensory System Agents
Peripheral Nervous System Agents