Rett Syndrome
Conditions
Keywords
Rett Syndrome, Dextromethorphan
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.
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.
Interventions
DRUGDextromethorphan
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.
Sponsors
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 15 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | 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
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Receptive Language as Measured by the Mullen Scale. | 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. |
| Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | 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. |
| Mean SSI Score for Total Subjects at Baseline and 6 Months | 0-6 months | Analysis of Difference in Mean Screen for Social Interaction (SSI) Score between 0-6 months for total sample (n=19). |
Countries
United States
Participant flow
Recruitment details
Recruitment was from 2004 to 2010. Study initiation was delayed due to the closure of Johns Hopkins Medicine Institutional Review Board(JHMIRB). Patients were recruited from our Kennedy Krieger Institute (KKI)medical clinics, physician referrals,and parent organizations. Parents were sent letters of invitation.
Pre-assignment details
Pharmacokinetics in enrolled subjects required her to be a fast metabolizer of Dextromethorphan (DM).
Participants by arm
| Arm | Count |
|---|---|
| DM1( 0.25 mg/kg /Day) Dextromethorphan 0.25 mg/kg per day
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.
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. | 13 |
| DM2 (2.5 mg/kg/Day) Dextromethorphan 2.5 mg/kg/day
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.
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. | 13 |
| DM3 (5mg/kg/Day) Dextromethorphan 5mg/kg/day
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.
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. | 12 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | DM2 (2.5 mg/kg/Day) | DM3 (5mg/kg/Day) | DM1( 0.25 mg/kg /Day) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 13 Participants | 12 Participants | 13 Participants | 38 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 6.31 years STANDARD_DEVIATION 3.5 | 6.08 years STANDARD_DEVIATION 3.06 | 6.54 years STANDARD_DEVIATION 2.7 | 6.32 years STANDARD_DEVIATION 3.02 |
| Region of Enrollment United States | 13 participants | 12 participants | 13 participants | 38 participants |
| Sex: Female, Male Female | 13 Participants | 12 Participants | 13 Participants | 38 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 0 / 12 | 0 / 10 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Initial and 6-month post-treatment
Population: 33/35 participants who completed the protocol with two epochs of 5 mins of non-Rapid eye movement (REM)sleep during which spikes could be counted pre and post DM intake.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dextromethorphan (DM)1 EEG Spike Counts at Baseline | Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | 44.22 EEG spike counts per minute | Standard Deviation 23.77 |
| DM2 EEG Spike Counts at Baseline | Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | 25.44 EEG spike counts per minute | Standard Deviation 18.6 |
| DM3 EEG Spike Counts at Baseline | Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | 40.67 EEG spike counts per minute | Standard Deviation 27.83 |
| DM1 EEG Spike Count at 6 Months | Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | 38.29 EEG spike counts per minute | Standard Deviation 30.24 |
| DM2 EEG Spike Counts at 6 Months | Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | 27.58 EEG spike counts per minute | Standard Deviation 19.52 |
| DM3 EEG Spike Counts at 6 Months | Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm. | 36.01 EEG spike counts per minute | Standard Deviation 23.29 |
p-value: <0.4t-test, 2 sided
p-value: <0.62t-test, 2 sided
p-value: <0.38t-test, 2 sided
Secondary
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.
Time frame: Initial and 6 month followup
Population: Those who provided complete information only were included. Others did not provide adequate or complete information for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dextromethorphan (DM)1 EEG Spike Counts at Baseline | Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | 40.25 scores on a scale | Standard Deviation 18.59 |
| DM2 EEG Spike Counts at Baseline | Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | 70.00 scores on a scale | Standard Deviation 19.1 |
| DM3 EEG Spike Counts at Baseline | Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | 84.29 scores on a scale | Standard Deviation 17.51 |
| DM1 EEG Spike Count at 6 Months | Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | 48.63 scores on a scale | Standard Deviation 18.58 |
| DM2 EEG Spike Counts at 6 Months | Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | 74.50 scores on a scale | Standard Deviation 22.78 |
| DM3 EEG Spike Counts at 6 Months | Difference in SSI Mean Score at Six Months Compared to Baseline for Each Treatment Arm. | 88.29 scores on a scale | Standard Deviation 18.88 |
Comparison: Null hypothesis is that there would be no significant difference in social abilities as measured by the SSI score in this treatment group baseline to 6 months post-treatment.p-value: <0.1ANOVA
p-value: <0.5ANOVA
p-value: <0.48ANOVA
Secondary
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.
Time frame: Change in mean between Initial and 6-month follow-up
Population: 25/35 enrolled participants completed the receptive language scale of the Mullen and underwent the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dextromethorphan (DM)1 EEG Spike Counts at Baseline | Improvement in Receptive Language as Measured by the Mullen Scale. | 0 age in months | Standard Deviation 2.94 |
| DM2 EEG Spike Counts at Baseline | Improvement in Receptive Language as Measured by the Mullen Scale. | -0.44 age in months | Standard Deviation 2.96 |
| DM3 EEG Spike Counts at Baseline | Improvement in Receptive Language as Measured by the Mullen Scale. | 03 age in months | Standard Deviation 2.45 |
Secondary
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).
Time frame: 0-6 months
Population: 19 subjects (total sample) for whom complete data was available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dextromethorphan (DM)1 EEG Spike Counts at Baseline | Mean SSI Score for Total Subjects at Baseline and 6 Months | 62.737 scores on a scale | Standard Deviation 26.729 |
| DM2 EEG Spike Counts at Baseline | Mean SSI Score for Total Subjects at Baseline and 6 Months | 68.684 scores on a scale | Standard Deviation 25.987 |
p-value: <0.05ANOVA