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Traumatic Brain Injury (TBI) - methylphenidate treatment
The objectives of the study are to (1) determine the efficacy and dose-response of methylphenidate treatment of attention problems after pediatric traumatic brain injury (TBI) and (2) provide a better understanding of the relationship of a prior history of attention deficit hyperactivity disorder (ADHD), ADHD subtypes after TBI, executive function, and attentional control to treatment efficacy. The proposed clinical trial will enroll 50 children, age 6-17 years, with attention problems >6 months after moderate to severe TBI into a randomized, double-blind, placebo-controlled, cross-over design trial with 3 dose conditions (low, medium, and high).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methylphenidate | Experimental | The study medication will consist of identical capsules filled Concerta® over-encapsulated to preserve double-blinding. The weekly dosages will be low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration trial. Weekly ratings monitoring behavioral and side effect symptoms score and the Pittsburgh Side Effects Rating Scale. |
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| Placebo | Placebo Comparator | The study medication will consist of identical capsules filled with an inert white power (placebo). Weekly ratings monitoring behavioral and side effect symptoms score and the Pittsburgh Side Effects Rating Scale. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methylphenidate | Drug |
|
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Parent Outcome-Vanderbilt ADHD Parent Rating Scales (VADPRS) | Changes in symptom ratings were assessed on the Vanderbilt ADHD parent rating scales (VADPRS). A measure of ADHD symptom severity (Total Symptom Score [TSS]) is computed by totaling the scores from items 1-18 (Inattentive +Hyperactive-impulse domains), with a rating of none=0, occasionally=1, often=2, very often=3, provided. Scores for inattentive and hyperactive-impulsive domains were generated by totaling the 9 symptoms in these domains, and a TSS was computed by totaling items across domains. | Reported at End of Methylphenidate Arm (Week 4 or 8) |
| Parent Outcome-Behavior Rating Inventory of Executive Functioning (BRIEF) | The Behavior Rating Inventory of Executive Functioning (BRIEF)-Parent was used to assess executive functioning behaviors. The global executive composite (GEC), behavior regulatory index (BRI), and metacognitive index (MI) T-scores were used, with higher scores reflecting poorer executive functioning. T-scores were normalized to 50 with a standard deviation of 10. | Reported at End of Methylphenidate Arm (Week 4 or 8) |
| Measure | Description | Time Frame |
|---|---|---|
| Neuropsychological Outcome- Wechsler Intelligence Scale for Children, 4th Edition Processing Speed Index (WISC-IV-PSI) | The Wechsler Intelligence Scale for Children, 4th Edition Processing Speed Index (WISC-IV-PSI) has been designed for children 6-16:11 years of age and provides a measure of processing speed. For this index scale, the average score is 100 with a standard deviation of 15. Higher scores reflect better processing speed. One participant was administered the Wechsler Adult Intelligence Scale 4th Edition Processing Speed Index (WAIS-IV-PSI). All scores were included in the combined WISC/WAIS processing speed variable since both measures yield highly correlated standard scores. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Brad Kurowski, MS, MD | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30169436 | Derived | Kurowski BG, Epstein JN, Pruitt DW, Horn PS, Altaye M, Wade SL. Benefits of Methylphenidate for Long-Term Attention Problems After Traumatic Brain Injury in Childhood: A Randomized, Double-Masked, Placebo-Controlled, Dose-Titration, Crossover Trial. J Head Trauma Rehabil. 2019 Mar/Apr;34(2):E1-E12. doi: 10.1097/HTR.0000000000000432. |
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Of the 321 assessed for eligibility, 40 participants scheduled a baseline assessment. 163 did not meet inclusion criteria and 118 declined to participate. 26 of the 40 participants were enrolled and randomized. Of those not randomized, 5 dropped before baseline visit and 9 did not show for scheduled baseline visit.
Recruitment period for the study was January 2014 through July 2017. Participants were recruited from a tertiary pediatric hospital in the Midwestern United States with a Level 1 trauma designation. 321 participants were screened for eligibility.
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| ID | Title | Description |
|---|---|---|
| FG000 | Methylphenidate, Then Placebo | For the first week, participants received the low-dose Methylphenidate condition (Concerta® over-encapsulated). Over the subsequent 3 weeks, the dose was titrated based on medication response and side effects to determine the optimal dose used for week 4. At the end of week 4, participants crossed-over and repeated the same procedures for the placebo condition. No wash-out period was used. The weekly dosages were low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration trial. |
| FG001 | Placebo, Then Methlyphenidate | For the first week, participants received the low-dose Placebo condition (white powder pills). Over the subsequent 3 weeks, the dose was titrated based on medication response and side effects to determine the optimal dose used for week 4. At the end of week 4, participants crossed-over and repeated the same procedures for the Methlyphenidate condition. No wash-out period was used. The weekly dosages were low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration trial. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomization (4 Weeks) |
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| |||||||||||||||||||||
| Crossover (4 Weeks) |
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| ID | Title | Description |
|---|---|---|
| BG000 | Methylphenidate, Then Placebo | For the first week, participants received the low-dose Methylphenidate condition (Concerta® over-encapsulated). Over the subsequent 3 weeks, the dose was titrated based on medication response and side effects to determine the optimal dose used for week 4. At the end of week 4, participants crossed-over and repeated the same procedures for the placebo condition. No wash-out period was used. The weekly dosages were low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration 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 | Parent Outcome-Vanderbilt ADHD Parent Rating Scales (VADPRS) | Changes in symptom ratings were assessed on the Vanderbilt ADHD parent rating scales (VADPRS). A measure of ADHD symptom severity (Total Symptom Score [TSS]) is computed by totaling the scores from items 1-18 (Inattentive +Hyperactive-impulse domains), with a rating of none=0, occasionally=1, often=2, very often=3, provided. Scores for inattentive and hyperactive-impulsive domains were generated by totaling the 9 symptoms in these domains, and a TSS was computed by totaling items across domains. | All participants who completed outcome data and full cross-over intervention | Posted | Mean | Standard Error | units on a scale | Reported at End of Methylphenidate Arm (Week 4 or 8) |
|
Weeks 1-8
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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 | Methylphenidate | For the first week, participants received the low-dose Methylphenidate condition (Concerta® over-encapsulated). Over the subsequent 3 weeks, the dose was titrated based on medication response and side effects to determine the optimal dose used for week 4. The weekly dosages were low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration trial. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Suicidal Ideation | Psychiatric disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Brad Kurowski, MD, MS | Children's Hospital Medical Center, Cincinnati | 513-803-3655 | brad.kurowski@cchmc.org |
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| ID | Term |
|---|---|
| D000070642 | Brain Injuries, Traumatic |
| D001289 | Attention Deficit Disorder with Hyperactivity |
| ID | Term |
|---|---|
| D001930 | Brain Injuries |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D008774 | Methylphenidate |
| ID | Term |
|---|---|
| D010648 | Phenylacetates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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| Drug |
|
| Reported at End of Methylphenidate Arm (Week 4 or 8) |
| Teacher Outcome Measure | Used to assess child behavior. | January 1, 2014 - July 20, 2017 |
| NOT COMPLETED |
|
| BG001 | Placebo, Then Methylphenidate | For the first week, participants received the low-dose Placebo condition (white powder pills). Over the subsequent 3 weeks, the dose was titrated based on medication response and side effects to determine the optimal dose used for week 4. At the end of week 4, participants crossed-over and repeated the same procedures for the Methlyphenidate condition. No wash-out period was used. The weekly dosages were low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration trial. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | For the first week, participants received the low-dose Placebo condition (white powder pills). Over the subsequent 3 weeks, the dose was titrated based on medication response and side effects to determine the optimal dose used for week 4. The weekly dosages were low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration trial. |
|
|
| Primary | Parent Outcome-Behavior Rating Inventory of Executive Functioning (BRIEF) | The Behavior Rating Inventory of Executive Functioning (BRIEF)-Parent was used to assess executive functioning behaviors. The global executive composite (GEC), behavior regulatory index (BRI), and metacognitive index (MI) T-scores were used, with higher scores reflecting poorer executive functioning. T-scores were normalized to 50 with a standard deviation of 10. | All participants who completed outcome data and full cross-over intervention | Posted | Mean | Standard Error | score on a scale | Reported at End of Methylphenidate Arm (Week 4 or 8) |
|
|
|
| Secondary | Neuropsychological Outcome- Wechsler Intelligence Scale for Children, 4th Edition Processing Speed Index (WISC-IV-PSI) | The Wechsler Intelligence Scale for Children, 4th Edition Processing Speed Index (WISC-IV-PSI) has been designed for children 6-16:11 years of age and provides a measure of processing speed. For this index scale, the average score is 100 with a standard deviation of 15. Higher scores reflect better processing speed. One participant was administered the Wechsler Adult Intelligence Scale 4th Edition Processing Speed Index (WAIS-IV-PSI). All scores were included in the combined WISC/WAIS processing speed variable since both measures yield highly correlated standard scores. | All participants who completed outcome data and full cross-over intervention | Posted | Mean | Standard Error | score on a scale | Reported at End of Methylphenidate Arm (Week 4 or 8) |
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|
|
| Secondary | Teacher Outcome Measure | Used to assess child behavior. | Challenges with engaging teachers made it difficult to collect teacher outcome measures. | Posted | January 1, 2014 - July 20, 2017 |
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 0 |
| 20 |
| EG001 | Placebo | For the first week, participants received the low-dose Placebo condition (white powder pills). Over the subsequent 3 weeks, the dose was titrated based on medication response and side effects to determine the optimal dose used for week 4. The weekly dosages were low, medium, and high based on weight cut-offs. Participants weighing less than 25kg will receive 18mg (low), 27mg (medium), and 36mg (high) dosages and participants weighing above 25kg will receive 18mg (low), 36mg (medium), and 54mg (high) dosages during the 3-week upward titration trial. | 0 | 20 | 1 | 20 | 0 | 20 |
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| D006259 |
| Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
| D010880 |
| Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| BRIEF MI-Overall |
|