Attention Deficit Disorder With Hyperactivity
Conditions
Keywords
ADHD, Guanfacine, Methylphenidate, Focalin XR, Pediatric, Cognitive function, Combination therapy
Brief summary
This study will evaluate the effectiveness of a single drug versus a combination of drugs in treating attention deficit hyperactivity disorder in children.
Detailed description
Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood mental disorders. Children with ADHD have impaired functioning in multiple settings, including home and school. They also have difficulty relating with peers. If left untreated, the disorder may cause adverse effects that can last into adolescence and adulthood. Stimulant medications, such as methylphenidate, are effective in reducing ADHD symptoms on a short-term basis. However, few long-term benefits in academic or general functioning from current ADHD therapies have been demonstrated. Focalin XR is a stimulant medication that is FDA-approved for treating ADHD. Guanfacine is another medication that is currently approved for the treatment of hypertension, but has long been used for treating ADHD. This study will determine the effectiveness of a combination of Focalin XR and guanfacine in enhancing cognitive functioning and improving the long-term benefit of ADHD treatment. Participants in this study will be randomly assigned to one of three treatment regimens: Methylphenidate (Focalin XR) and placebo; guanfacine and placebo; or Focalin XR and guanfacine. The study will be conducted in two phases: an 8-week double-blind treatment phase and a 12-month open-label treatment phase. In Phase I, one third of participants will receive placebo for the initial 4 weeks, followed by Focalin XR alone for the remaining 4 weeks. All other participants will receive their assigned medications for the full 8 weeks. All participants will attend two study visits prior to beginning treatment and one study visit per week throughout Phase I. At the end of Phase I, treatment assignments will be unblinded. Participants who experienced adequate improvement with their assigned treatment will then continue in Phase II on the same medication(s) for an additional 12 months. Participants will attend study visits once per month until the end of the study. Study visits will include self-report measures, clinical assessments, and cognitive testing. Participants will also undergo four electroencephalography (EEG) tests and two fMRI scans over the course of the study. All Phase II participants will receive a follow-up telephone call 1 month after the final study visit.
Interventions
DRUGGuanfacine
Week 1: 0.5 mg twice daily; Week 2: 1 mg twice daily; Week 3: 1.5 mg twice daily; Weeks 4 through 8: best dose as determined by efficacy measures
Participants less than 25 kg will receive 10 mg once daily for Week 5, 20 mg once daily for Week 6, and 30 mg once daily for Week 7. Subjects greater than 25 kg will receive 20 mg once daily for Week 5, 30 mg once daily for Week 6, 40 mg once daily for Week 7, and best doses as determined by efficacy measures for Week 8.
Sponsors
National Institute of Mental Health (NIMH)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to 14 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of DSM-IV ADHD by K-SADS-PL and confirmed by clinical interview * Clinical Global Impression-Severity score of at least 4 for ADHD * Resided with primary caretaker for at least 6 months prior to study entry
Exclusion criteria
* History of autism, pervasive developmental disorder, chronic tic disorder, psychosis, or bipolar disorder * Current major depression or panic disorder * Systolic or diastolic blood pressure at screening greater than the 95th percentile or less than the 5th percentile for age and body mass index (BMI) * Any medical condition that might make stimulant or alpha agonist therapy medically inadvisable * Need for chronic use of other medications with central nervous system effects * Pregnant, breastfeeding, or beyond menarche and has a positive urine pregnancy test * History of structural heart defects, syncope, or fainting while exercising * Clinically significant cardiac abnormality as determined by echocardiogram (ECG) at study entry * Mental retardation as determined by clinical functional assessment and an IQ estimate of less than 70 based on Wechsler Adult Intelligence Scale (WAIS) subtests
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Measured at baseline Week 4 and Week 8 | The primary clinical efficacy variable for treatment was the ADHD-RS-IV (Attention-Deficit/Hyperactivity Disorder Rating Scale) Total Score and two sub-scales (Inattentive and Hyperactive-Impulsive ). The rating scale has 18 questions with answer options: None (0), Mild (1), Moderate (2) and Severe (3). Min 0; max 3. Scores are obtained by summing each item; The higher the score, the worse the outcome. Total score range: 0-54 Total Inattentive score range: 0-27 Total Hyperactive/Impulsive score range: 0-27 |
Countries
United States
Participant flow
Pre-assignment details
212 randomized (deemed eligible and enrolled). 71 randomized to Group 1: 3 dropped prior to receiving drug; thus 68 started drug. 70 randomized to Group 2: 1 dropped before receiving drug; thus 69 started drug. 71 randomized to Group 3:1 dropped before receiving drug; thus 70 started drug.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Guan-Guan+Placebo weeks 1-4: Guanfacine weeks 5-8: Guanfacine +Placebo | 68 |
| Group 2: Placebo-Placebo+DMPH weeks 1-4: Placebo weeks 5-8: Placebo+DMPH | 69 |
| Group 3: Guan-Guan+DMPH (Comb) weeks 1-4: Guanfacine weeks 5-8: Guanfacine+DMPH (comb) | 70 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 | 2 |
| Overall Study | Physician Decision | 6 | 5 | 5 |
Baseline characteristics
| Characteristic | Group 1: Guan-Guan+Placebo | Group 2: Placebo-Placebo+DMPH | Group 3: Guan-Guan+DMPH (Comb) | Total |
|---|---|---|---|---|
| Age, Continuous | 10.1 years STANDARD_DEVIATION 2.1 | 10.1 years STANDARD_DEVIATION 2 | 9.9 years STANDARD_DEVIATION 2.2 | 10.0 years STANDARD_DEVIATION 2.1 |
| Race/Ethnicity, Customized African American | 7 Participants | 10 Participants | 19 Participants | 36 Participants |
| Race/Ethnicity, Customized Asian, Pacific Islander | 7 Participants | 4 Participants | 5 Participants | 16 Participants |
| Race/Ethnicity, Customized Hispanic | 16 Participants | 10 Participants | 18 Participants | 44 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 4 Participants | 5 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 51 Participants | 51 Participants | 41 Participants | 143 Participants |
| Sex: Female, Male Female | 23 Participants | 23 Participants | 19 Participants | 65 Participants |
| Sex: Female, Male Male | 45 Participants | 46 Participants | 51 Participants | 142 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 69 | 0 / 70 |
| other Total, other adverse events | 66 / 68 | 66 / 69 | 69 / 70 |
| serious Total, serious adverse events | 0 / 68 | 0 / 69 | 0 / 70 |
Outcome results
Primary
ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale)
The primary clinical efficacy variable for treatment was the ADHD-RS-IV (Attention-Deficit/Hyperactivity Disorder Rating Scale) Total Score and two sub-scales (Inattentive and Hyperactive-Impulsive ). The rating scale has 18 questions with answer options: None (0), Mild (1), Moderate (2) and Severe (3). Min 0; max 3. Scores are obtained by summing each item; The higher the score, the worse the outcome. Total score range: 0-54 Total Inattentive score range: 0-27 Total Hyperactive/Impulsive score range: 0-27
Time frame: Measured at baseline Week 4 and Week 8
Population: Every contrast includes estimates of maturation/time trend and the within subject covariance structure based on all participants using full information maximum likelihood estimation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Estimated Difference Between Guan and Placebo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Total ADHD-RS Score | -7.77 units on a scale | Standard Error 1.7 |
| Estimated Difference Between Guan and Placebo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Hyperactive Impulsive Subscale | -3.73 units on a scale | Standard Error 0.92 |
| Estimated Difference Between Guan and Placebo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Inattentive Subscale | -4.14 units on a scale | Standard Error 0.99 |
| Estimated Difference Between DMPH and Placebo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Inattentive Subscale | -4.10 units on a scale | Standard Error 0.71 |
| Estimated Difference Between DMPH and Placebo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Hyperactive Impulsive Subscale | -4.0 units on a scale | Standard Error 0.69 |
| Estimated Difference Between DMPH and Placebo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Total ADHD-RS Score | -7.99 units on a scale | Standard Error 1.22 |
| Estimated Difference Between Placebo and Combo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Total ADHD-RS Score | -10.66 units on a scale | Standard Error 1.99 |
| Estimated Difference Between Placebo and Combo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Hyperactive Impulsive Subscale | -5.10 units on a scale | Standard Error 1.12 |
| Estimated Difference Between Placebo and Combo | ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale) | Inattentive Subscale | -5.89 units on a scale | Standard Error 1.15 |
Comparison: Analyses are based on a generalized linear mixed model (GLMM) modelling the effects of the medication when calibrated to optimal dosage and controlling for time effects and within-subject effects. The design is a combined within-between subject design, where each participant is exposed to, and provides information about multiple tx modalities.p-value: <0.01Mixed Models Analysis