Trial of Dextromethorphan in Rett Syndrome

This study has been terminated.
(Study changed to a placebo controlled trial of dextromethorphan)
Sponsor:
Information provided by (Responsible Party):
SakkuBai Naidu, M.D., Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ClinicalTrials.gov Identifier:
NCT00593957
First received: January 4, 2008
Last updated: March 26, 2014
Last verified: July 2013
  Purpose

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 Intervention Phase
Rett Syndrome
Drug: Dextromethorphan
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Trial of Dextromethorphan in Rett Syndrome

Resource links provided by NLM:


Further study details as provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:

Primary Outcome Measures:
  • Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. [ Time Frame: Initial and 6-month post-treatment ] [ Designated as safety issue: No ]
    Difference in EEG spike count means pre and 6 months post-treatment in each of three treatment groups.


Secondary Outcome Measures:
  • Improvement in Receptive Language as Measured by the Mullen Scale. [ Time Frame: Change in mean between Initial and 6-month follow-up ] [ Designated as safety issue: No ]
    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.

  • Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. [ Time Frame: Initial and 6 month followup ] [ Designated as safety issue: No ]
    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.

  • Mean SSI Score for Total Subjects at Baseline and 6 Months [ Time Frame: 0-6 months ] [ Designated as safety issue: No ]
    Analysis of Difference in Mean Screen for Social Interaction (SSI) Score between 0-6 months for total sample (n=19).


Enrollment: 38
Study Start Date: August 2004
Study Completion Date: June 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   2 Years to 15 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00593957

Locations
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
Principal Investigator: SakkuBai Naidu, MD Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
  More Information

No publications provided

Responsible Party: SakkuBai Naidu, M.D., Professor of Neurology and Pediatrics, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ClinicalTrials.gov Identifier: NCT00593957     History of Changes
Other Study ID Numbers: FD2408
Study First Received: January 4, 2008
Results First Received: March 8, 2013
Last Updated: March 26, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:
Rett Syndrome
Dextromethorphan

Additional relevant MeSH terms:
Rett Syndrome
Syndrome
Disease
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System
Intellectual Disability
Mental Retardation, X-Linked
Nervous System Diseases
Neurobehavioral Manifestations
Neurodegenerative Diseases
Neurologic Manifestations
Pathologic Processes
Dextromethorphan
Antitussive Agents
Central Nervous System Agents
Excitatory Amino Acid Agents
Excitatory Amino Acid Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014