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Although stimulant medication is a well-established treatment for ADHD, it is often necessary for doctors to increase the dose over time to maintain the benefits of the medication. While medication can be very effective for improving symptoms of ADHD during the first year of use, it has not been found to significantly improve the long term course of children with ADHD. For example, in large research studies, groups of children who take medication for ten years do not have consistently better academic grades than groups of children who never used medication (individual results will vary from child to child).
In order to help children with ADHD achieve the best possible outcomes, it is important for doctors to study why this happens. One possible reason is development of tolerance to the medication. Tolerance means that a drug's effects decrease when it is taken consistently over time, so that an increased dose is needed to continue showing effects. Some doctors believe that children who take stimulant medication for ADHD develop tolerance to it which would explain why benefits may not persist over time, but no research studies have been done to measure whether this occurs. This study aims to see if children show a tolerance effect to stimulant medication and whether that tolerance can be prevented by taking short breaks from the medication called medication holidays.
This is an innovative evaluation of tolerance using an objective measure in an analog classroom. Each subject will complete the a 10-minute math test twice a day for three weeks on optimal dose or placebo, and then be crossed over to the other condition. Within-subject drug/placebo differences will be compared over the three weeks of exposure to assess tolerance in the analog setting.
When school commences, 50% of the sample will be randomized to 7-day-a-week (continuous) dosing and 50% to 5-day-a- week (weekend holidays) dosing to examine the efficacy of prescribed weekend drug holidays for combatting need for dose escalations (tolerance) during the school year.
Participants will be assessed monthly to detect deteriorating functioning. Using a standardized protocol, study physicians will increase dose for subjects in either arm who meet defined impairment thresholds. The difference between the two dosing conditions will inform regarding how best to deal with tolerance in clinical application.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methylphenidate 7-day dosing | Active Comparator | During the school year, children in this arm will receive 7-day dosing of medication. |
|
| Methylphenidate 5-day dosing | Active Comparator | During the school year phase, these children will receive 5-day dosing with weekend holidays. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methylphenidate | Drug | Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Dose Changes Required Per Protocol | Monthly evaluations of medication efficacy will be used to determine whether dose adjustments are needed due to anticipated tolerance effects. | 10 months |
| Measure | Description | Time Frame |
|---|---|---|
| Time to First Dose Increase | The amount of time elapsed before a child requires a dose increase during the school year will be measured in months. | 10 months |
| Endpoint Medication Dose | Dose of medication reported in mg/kg/day |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| William E Pelham, Ph.D. | Florida International University | Principal Investigator |
| James M Swanson, Ph.D. | Florida International University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Florida International University Center for Children and Families | Miami | Florida | 33199 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35604744 | Derived | Pelham WE, Altszuler AR, Merrill BM, Raiker JS, Macphee FL, Ramos M, Gnagy EM, Greiner AR, Coles EK, Connor CM, Lonigan CJ, Burger L, Morrow AS, Zhao X, Swanson JM, Waxmonsky JG, Pelham WE. The effect of stimulant medication on the learning of academic curricula in children with ADHD: A randomized crossover study. J Consult Clin Psychol. 2022 May;90(5):367-380. doi: 10.1037/ccp0000725. |
| Label | URL |
|---|---|
| Center for Children and Families General Information | View source |
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Because all participants were required to be enrolled in a Summer Treatment Program, some participants withdrew after consenting because they were unable to make the time commitment to the 8-week summer program.
Participants were recruited in 4 annual cohorts from 2013-2016. Participants could be referred by schools, physicians, or community advertisement; interested parents completed phone screens and a clinic intake to assess inclusionary and exclusionary criteria.
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| ID | Title | Description |
|---|---|---|
| FG000 | Phase 1-Summer; Medication First, Then Placebo | In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Medication First group received their optimal dose of methylphenidate for 13 days, a 2-day medication/placebo probe, a 2-day washout, then placebo for 13 days and a 2-day medication/placebo probe. |
| FG001 | Phase 1-Summer; Placebo First, Then Medication | In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Placebo First group received placebo for 13 days, a 2-day medication/placebo probe, a 2-day washout, then optimal-dose medication for 13 days and a 2-day medication/placebo probe. |
| FG002 | Phase 2 School Year - 7-Day Dosing | During the school year, all participants took their optimal dose determined in Phase 1 of the study for the entire school year. These partcipants received medication 7-days a week for the entire year. |
| FG003 | Phase 2 School Year; 5-Day Dosing | During the school year, all participants took their optimal dose determined during Phase 1 for the entire school year. These participants received medication on school-days only with drug holidays over weekends. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1-Summer |
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| ||||||||||||||||||
| Phase 2-School Year |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Phase 1-Summer | In the first phase of the study, all children participate in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. |
| 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 | Number of Dose Changes Required Per Protocol | Monthly evaluations of medication efficacy will be used to determine whether dose adjustments are needed due to anticipated tolerance effects. | All participants who began Phase 2 were included in analysis | Posted | Mean | Standard Deviation | Number of Increases | 10 months |
|
During Phase 1, side effects ratings were collected from parents daily for the first 2 weeks of the summer and weekly for the final 6 weeks of the summer. During Phase 2, side-effects ratings were completed by parents monthly at medication dispensing visits.
Parents completed the Pittsburgh Side Effects Rating Scale, rating each of the most common side effects of stimulant medication on a scale of None, Mild, Moderate, or Severe. Adverse events were counted if parents rated the side effect at the Moderate or Severe level on at least one occasion,
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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 | Phase 1-Medication First | In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Medication First group received methylphenidate for 13 days, a 2-day medication/placebo probe, a 2-day washout, then placebo for 13 days and a 2-day medication/placebo probe. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalized | Psychiatric disorders | Non-systematic Assessment | Referred by parent for inpatient psychiatric treatment due to comorbid mental health issues. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Appetite Loss | Gastrointestinal disorders | Systematic Assessment | Moderate or Severe Appetite Loss |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| William E. Pelham, Jr., Ph.D. | Florida International University | 305-348-0477 | wpelham@fiu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 22, 2013 | Aug 27, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001289 | Attention Deficit Disorder with Hyperactivity |
| ID | Term |
|---|---|
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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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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|
| End of Phase 2 School Year |
| Protocol Violation |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
During the school year phase, these children will receive 5-day dosing with weekend holidays. Methylphenidate: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected. |
|
|
| Secondary | Time to First Dose Increase | The amount of time elapsed before a child requires a dose increase during the school year will be measured in months. | Posted | Mean | Standard Deviation | Months | 10 months |
|
|
|
| Secondary | Endpoint Medication Dose | Dose of medication reported in mg/kg/day | Only participants who completed the entire school year are used in endpoint medication dosing calculations. | Posted | Mean | Standard Deviation | Mg/kg/day | End of Phase 2 School Year |
|
|
|
| 0 |
| 129 |
| 1 |
| 129 |
| 72 |
| 129 |
| EG001 | Phase 1 - Placebo First | In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Placebo First group received placebo for 13 days, a 2-day medication/placebo probe, a 2-day washout, then optimal-dose medication for 13 days and a 2-day medication/placebo probe. | 0 | 138 | 0 | 138 | 78 | 138 |
| EG002 | Phase 2 - 7-Day Dosing | During the school year, all participants took their optimal dose determined in Phase 1 of the study for the entire school year. These participants received medication 7-days a week for the entire year | 0 | 121 | 1 | 121 | 91 | 121 |
| EG003 | Phase 2 - 5-Day Dosing | During the school year, all participants took their optimal dose determined during Phase 1 for the entire school year. These participants received medication on school-days only with drug holidays over weekends. | 0 | 124 | 1 | 124 | 85 | 124 |
|
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| Insomnia | General disorders | Systematic Assessment |
|
| Motor Tics | General disorders | Systematic Assessment | Rating of moderate or severe motor tics |
|
| Buccal-lingual movements | General disorders | Systematic Assessment | Parent rating of moderate or severe buccal-lingual movements |
|
| Picking at skin, nailbiting | General disorders | Systematic Assessment | Parent rating of moderate or severe picking, nail-biting, etc. |
|
| Worried/Anxious | General disorders | Systematic Assessment | Parent rating of moderate or severe worry/anxiety |
|
| Dull, tired, listless | General disorders | Systematic Assessment | Parent rating of moderate or severe dullness/tiredness/listlessness |
|
| Headache | General disorders | Systematic Assessment | Parent rating of moderate or severe headache |
|
| Stomachache | Gastrointestinal disorders | Systematic Assessment | Parent rating of moderate or severe stomach ache |
|
| Irritability | General disorders | Systematic Assessment | Parent rating of moderate or severe irritability |
|
| Tearful, depressed | General disorders | Systematic Assessment | Parent rating of moderate or severe tearfulness or sadness |
|
| Social Withdrawal | General disorders | Systematic Assessment | Parent rating of moderate or severe social withdrawal |
|
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| D010880 |
| Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |