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Study changed to a placebo controlled trial of dextromethorphan
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| DM1( 0.25 mg/kg /day) | Experimental | Dextromethorphan 0.25 mg/kg per day |
|
| DM2 (2.5 mg/kg/day) | Experimental | Dextromethorphan 2.5 mg/kg/day |
|
| DM3 (5mg/kg/day) | Experimental | Dextromethorphan 5mg/kg/day |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dextromethorphan | Drug | 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. |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| SakkuBai Naidu, MD | Hugo W. Moser Research Institute at Kennedy Krieger, Inc. | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kennedy Krieger Institute/Johns Hopkins Medical Institutions | Baltimore | Maryland | 21205 | United States |
Pharmacokinetics in enrolled subjects required her to be a fast metabolizer of Dextromethorphan (DM).
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Standard Deviation | EEG spike counts per minute | Initial and 6-month post-treatment |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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The trial was terminated due to the FDA requiring a placebo controlled trial instead of the ongoing open label trial. As recruitment was delayed,the total number of participants was also less than anticipated.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Sakkubai Naidu Professor of Neurology and Pediatrics | Kennedy Krieger Institute | 443-923-2778 | naidu@kennedykrieger.org |
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| ID | Term |
|---|---|
| D015518 | Rett Syndrome |
| ID | Term |
|---|---|
| D038901 | X-Linked Intellectual Disability |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
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| ID | Term |
|---|---|
| D003915 | Dextromethorphan |
| ID | Term |
|---|---|
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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|
|
| Dextromethorphan | Drug | 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. |
|
|
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 |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
DM2 group participants received Dextromethorphan 2.5 mg/kg/day. The drug is given in two divided doses 12 hours apart for 6 months. DM2 EEG spike counts at baseline. |
| OG002 | DM3 EEG Spike Counts at Baseline | DM3 group received Dextromethorphan 5mg/kg/day. The drug is given in two divided doses 12 hours apart for 6 months. EEG spike counts at baseline. |
| OG003 | DM1 EEG Spike Count at 6 Months | DM1 group received Dextromethorphan 0.25 mg/kg per day. The drug is given in two divided doses 12 hours apart for 6 months. EEG spike count for DM1 group measured at 6 months. |
| OG004 | DM2 EEG Spike Counts at 6 Months | DM2 group participants received Dextromethorphan 2.5 mg/kg/day. The drug is given in two divided doses 12 hours apart for 6 months. DM2 EEG spike counts at 6 months. |
| OG005 | DM3 EEG Spike Counts at 6 Months | DM3 group received Dextromethorphan 5mg/kg/day. The drug is given in two divided doses 12 hours apart for 6 months. EEG spike counts at 6 months. |
|
|
|
| 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. | 25/35 enrolled participants completed the receptive language scale of the Mullen and underwent the analysis. | Posted | Mean | Standard Deviation | age in months | Change in mean between Initial and 6-month follow-up |
|
|
|
| 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. | Those who provided complete information only were included. Others did not provide adequate or complete information for analysis. | Posted | Mean | Standard Deviation | scores on a scale | Initial and 6 month followup |
|
|
|
|
| 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). | 19 subjects (total sample) for whom complete data was available | Posted | Mean | Standard Deviation | scores on a scale | 0-6 months |
|
|
|
|
| 0 |
| 13 |
| 0 |
| 13 |
| EG001 | 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. | 0 | 12 | 0 | 12 |
| EG002 | 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. | 0 | 10 | 0 | 10 |
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| D009422 | Nervous System Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D006572 |
| Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| <0.50 |
| Mean Difference (Final Values) |
| 4.5 |
| No |
| Superiority or Other |
| ANOVA | <0.48 | Mean Difference (Final Values) | 4.0 | No | Superiority or Other |