Attention-deficit/Hyperactivity Disorder
Conditions
Keywords
Tolerance to stimulant medication
Brief summary
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.
Detailed description
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.
Interventions
DRUGMethylphenidate
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.
Sponsors
Florida International University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of attention-deficit/hyperactivity disorder * Full Scale IQ above 80
Exclusion criteria
* Psychotropic medications for conditions other than ADHD * Active medical or psychiatric conditions that could be worsened by stimulants * Diagnosis of Autism or Asperger's Disorder * Documented intolerance fo methylphenidate or failed trial of OROS MPH
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Changes Required Per Protocol | 10 months | Monthly evaluations of medication efficacy will be used to determine whether dose adjustments are needed due to anticipated tolerance effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Dose Increase | 10 months | The amount of time elapsed before a child requires a dose increase during the school year will be measured in months. |
| Endpoint Medication Dose | End of Phase 2 School Year | Dose of medication reported in mg/kg/day |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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 by arm
| Arm | Count |
|---|---|
| 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. | 267 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1-Summer | Protocol Violation | 6 | 0 | 0 | 0 |
| Phase 1-Summer | Withdrawal by Subject | 7 | 6 | 0 | 0 |
| Phase 2-School Year | Lost to Follow-up | 0 | 0 | 1 | 3 |
| Phase 2-School Year | Protocol Violation | 0 | 0 | 3 | 0 |
| Phase 2-School Year | Withdrawal by Subject | 0 | 0 | 8 | 5 |
Baseline characteristics
| Characteristic | Phase 1-Summer |
|---|---|
| Age, Categorical <=18 years | 267 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 224 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants |
| Race (NIH/OMB) More than one race | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 237 Participants |
| Region of Enrollment United States | 267 participants |
| Sex: Female, Male Female | 54 Participants |
| Sex: Female, Male Male | 213 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 129 | 0 / 138 | 0 / 121 | 0 / 124 |
| other Total, other adverse events | 72 / 129 | 78 / 138 | 91 / 121 | 85 / 124 |
| serious Total, serious adverse events | 1 / 129 | 0 / 138 | 1 / 121 | 1 / 124 |
Outcome results
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.
Time frame: 10 months
Population: All participants who began Phase 2 were included in analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate 7-day Dosing | Number of Dose Changes Required Per Protocol | 1.79 Number of Increases | Standard Deviation 1.16 |
| Methylphenidate 5-day Dosing | Number of Dose Changes Required Per Protocol | 1.61 Number of Increases | Standard Deviation 1.08 |
Secondary
Endpoint Medication Dose
Dose of medication reported in mg/kg/day
Time frame: End of Phase 2 School Year
Population: Only participants who completed the entire school year are used in endpoint medication dosing calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate 7-day Dosing | Endpoint Medication Dose | 1.30 Mg/kg/day | Standard Deviation 0.43 |
| Methylphenidate 5-day Dosing | Endpoint Medication Dose | 1.24 Mg/kg/day | Standard Deviation 0.41 |
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.
Time frame: 10 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate 7-day Dosing | Time to First Dose Increase | 3.8 Months | Standard Deviation 3.4 |
| Methylphenidate 5-day Dosing | Time to First Dose Increase | 4.1 Months | Standard Deviation 3.5 |