Attention Deficit Disorder, Attention-Deficit/Hyperactivity Disorder, Insomnia, Sleep Disorders
Conditions
Keywords
ADHD, ADD, sleep disturbance
Brief summary
This study seeks to determine, using special sleep tests (polysomnography and actigraphy) if guanfacine extended release is able to improve nighttime sleep in children with ADHD - associated insomnia while improving daytime ADHD symptoms. Male and female children with diagnosed or suspected ADHD with sleep problems (difficulty falling asleep, difficulty staying asleep, or less than expected hours of sleep) will be recruited. After obtaining informed consent and assent (when appropriate) and after discontinuation of excluded medications, children will have evaluations of his or her sleep and evaluations confirming the ADHD diagnosis. Children who successfully pass screening will be enrolled into the double-blind, placebo-controlled, randomized investigation with 50% of participants receiving guanfacine extended release and 50% of participants receiving matching placebo. Using a flexible-dose optimization design based on ADHD symptom improvement and medication tolerability, the dose will be adjusted between 1 to 4 mg over the course of four weeks. At the end of medication adjustment (week 4 or 5), ADHD questionnaires, sleep questionnaires, and sleep tests will be repeated and analyzed. The medication will be weaned over the course of the following 3-10 days.
Interventions
DRUGGuanfacine extended-release tablets
Guanfacine extended-release tablets will be started at 1mg and then increased at weekly intervals to 2mg, 3mg, or 4mg as needed and as tolerated
DRUGPlacebo comparator
Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg, 2mg, 3mg, 4mg, but without the active ingredient (guanfacine).
Sponsors
Shire
Children's Specialized Hospital
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
1. Subject must be male or female, aged 6 - 12 years with ADHD. 2. Subject must (a) be taking methylphenidate, amphetamine, or atomoxetine for treatment of ADHD with parent or subject concerns of inadequate efficacy or intolerable side effects, or (b) free of any other medication used to treat ADHD for at least 30 days at the time of the initial sleep study. 3. Subject must have repeated difficulty with sleep initiation or persistence despite attempts at adequate sleep hygiene. 4. Subject must be able to swallow tablets.
Exclusion criteria
1. Subject or parent/LAR is unable or unwilling to discontinue present medications used to treat ADHD. 2. Subject has a body mass index \< 5th percentile for age, using the Centers for Disease Control standards reported in 2000. 3. Subject has a body weight \> 176 pounds. 4. Subject has a diagnosis of Autism or Autism Spectrum Disorder. 5. Subject has other serious psychiatric diagnoses. 6. Subject has a medical condition that may require treatment with an unapproved medication, that may cause a safety concern, or that may confound outcome results 7. Subject has an excessive caffeine intake (greater than 2.5 mg/kg/d). 8. Subject has a prior problem with clonidine or guanfacine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Polysomnographic Total Sleep Time (TST) | Baseline to last observation carried forward (after at least one week of dose stability) | Change in objective measures of sleep, using polysomnography |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Baseline to Treatment ADHD-Rating Scale IV Total Score | Baseline to last observation carried forward (after at least one week of dose stability) | Change in baseline to treatment ADHD-Rating Scale IV (Investigator-interview ) total. This scale quantitates ADHD symptoms based on DSM-IV criteria with a minimum score of 0 and a maximum score of 54 (higher scores suggesting more ADHD symptoms). The total score is a sum of the 9 items on the ADHD Rating Scale IV inattention score and the 9 items on the ADHD Rating Scale IV hyperactivity-impulsivity score (scores for each 0-27). |
| Change in Baseline to Treatment Latency to Persistent Sleep (LPS) | Baseline to last observation carried forward (after at least one week of dose stability) | Change in an objective measure of sleep onset, using polysomnography. |
| Change in Baseline to Treatment Minutes of Wake Time After Sleep Onset (WASO) | Baseline to last observation carried forward (after at least one week of dose stability) | Polysomnographic parameter of sleep assessing how many minutes of wakefulness occurred after sleep onset and before full morning awakening. |
Countries
United States
Participant flow
Recruitment details
From 2010 to 2012, children were referred primarily from the outpatient practice affiliated with a community based hospital dedicated to the evaluation and management of children with special needs. Four patients were referred from community pediatricians who commonly refer to the practice.
Pre-assignment details
Medications for ADHD, that would affect sleep/alertness, or that had psychoactive properties were discontinued prior to polysomnography. Of the 35 who entered screening, 29 were enrolled. Children were disquialified for not meeting diagnostic criteria or for having disqualifying conditions (e.g., depression, heart pathology).
Participants by arm
| Arm | Count |
|---|---|
| Guanfacine Extended-Release Tablets Guanfacine Extended-Release Tablets 1mg, 2mg, 3mg, and 4mg
Guanfacine extended-release tablets: Guanfacine extended-release tablets were started at 1mg and then increased at weekly intervals to 2mg, 3mg, or 4mg as needed and as tolerated | 11 |
| Placebo Comparator Placebo control
Placebo comparator: Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg were started and then increased at weekly intervals to 2mg, 3mg, or 4mg as needed and as tolerated | 16 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | patient not compliant with protocol | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Comparator | Total | Guanfacine Extended-Release Tablets |
|---|---|---|---|
| Age, Continuous | 8.8 years STANDARD_DEVIATION 1.9 | 8.9 years STANDARD_DEVIATION 1.9 | 9.1 years STANDARD_DEVIATION 1.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 25 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized African-American | 4 participants | 5 participants | 1 participants |
| Race/Ethnicity, Customized White | 12 participants | 22 participants | 10 participants |
| Region of Enrollment United States | 16 participants | 27 participants | 11 participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 2 Participants |
| Sex: Female, Male Male | 8 Participants | 17 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 12 | 11 / 17 |
| serious Total, serious adverse events | 0 / 12 | 0 / 17 |
Outcome results
Primary
Change in Polysomnographic Total Sleep Time (TST)
Change in objective measures of sleep, using polysomnography
Time frame: Baseline to last observation carried forward (after at least one week of dose stability)
Population: 29 children were enrolled, one (treatment) was lost to follow up an one (placebo) was discontinued due to noncompliance with protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine Extended-Release Tablets | Change in Polysomnographic Total Sleep Time (TST) | -57.32 minutes | Standard Deviation 89.17 |
| Placebo Comparator | Change in Polysomnographic Total Sleep Time (TST) | 31.32 minutes | Standard Deviation 59.54 |
Comparison: Null hypothesis: no difference in total sleep time (TST) from baseline to termination. ANOVA single measure, two-tailed, Type II analysis was completed using SPSS.p-value: 0.005ANOVA
Secondary
Change in Baseline to Treatment ADHD-Rating Scale IV Total Score
Change in baseline to treatment ADHD-Rating Scale IV (Investigator-interview ) total. This scale quantitates ADHD symptoms based on DSM-IV criteria with a minimum score of 0 and a maximum score of 54 (higher scores suggesting more ADHD symptoms). The total score is a sum of the 9 items on the ADHD Rating Scale IV inattention score and the 9 items on the ADHD Rating Scale IV hyperactivity-impulsivity score (scores for each 0-27).
Time frame: Baseline to last observation carried forward (after at least one week of dose stability)
Population: 29 children enrolled, but two were discontinued before termination data was available: one (treatment) was lost to follow up and one (placebo) was noncompliant with the protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine Extended-Release Tablets | Change in Baseline to Treatment ADHD-Rating Scale IV Total Score | -18.27 units on a scale | Standard Deviation 11.31 |
| Placebo Comparator | Change in Baseline to Treatment ADHD-Rating Scale IV Total Score | -1.69 units on a scale | Standard Deviation 9.16 |
Comparison: Null hypothesis: no difference in ADHD Rating Scales - IV total scores from baseline to termination. ANOVA single measure, two-tailed, Type II analysis was completed using SPSS.p-value: <0.001ANOVA
Secondary
Change in Baseline to Treatment Latency to Persistent Sleep (LPS)
Change in an objective measure of sleep onset, using polysomnography.
Time frame: Baseline to last observation carried forward (after at least one week of dose stability)
Population: 29 children were enrolled; two were disqualified: one (treatment) was lost to follow-up,and one (placebo) was noncompliant with the protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine Extended-Release Tablets | Change in Baseline to Treatment Latency to Persistent Sleep (LPS) | 10.54 minutes | Standard Deviation 88.44 |
| Placebo Comparator | Change in Baseline to Treatment Latency to Persistent Sleep (LPS) | -19.94 minutes | Standard Deviation 54.12 |
Comparison: Null hypothesis: no difference in latency to persistent sleep (LPS) from baseline to termination. ANOVA single measure, two-tailed, Type II analysis was completed using SPSS.p-value: 0.392ANOVA
Secondary
Change in Baseline to Treatment Minutes of Wake Time After Sleep Onset (WASO)
Polysomnographic parameter of sleep assessing how many minutes of wakefulness occurred after sleep onset and before full morning awakening.
Time frame: Baseline to last observation carried forward (after at least one week of dose stability)
Population: 29 children were enrolled; two were disqualified: one (treatment) was lost to follow-up,and one (placebo) was noncompliant with the protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine Extended-Release Tablets | Change in Baseline to Treatment Minutes of Wake Time After Sleep Onset (WASO) | 21.80 minutes | Standard Deviation 18.51 |
| Placebo Comparator | Change in Baseline to Treatment Minutes of Wake Time After Sleep Onset (WASO) | -3.90 minutes | Standard Deviation 17.2 |
Comparison: Null hypothesis: no difference in total sleep time (TST) from baseline to termination. ANOVA single measure, two-tailed, Type II analysis was completed using SPSS.p-value: 0.059ANOVA