Project1: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder

• Sponsor: University of California, Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT00429273
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 212
• Location: 1
• Arms: 3
• Duration (Months): 53.9
• Patients Per Site Per Month: 3.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Attention Deficit Disorder With Hyperactivity	Drug: Guanfacine; Drug: Methylphenidate (MPH)	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 212 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Eight-Week, Randomized, Double-Blind Comparison of Guanfacine, Focalin XR, and the Combination, With a Twelve Month Open-Label Extension for the Treatment of ADHD in Pediatric Subjects Aged 7 to 14 Years
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group 1: Guan-Guan+Placebo weeks 1-4: Guanfacine weeks 5-8: Guanfacine + Placebo	Drug: Guanfacine; 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; Other Names: Tenex
Active Comparator: Group 2: Placebo-Placebo+DMPH weeks 1-4: Placebo weeks 5-8: Placebo+DMPH	Drug: Methylphenidate (MPH); 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.; Other Names: Focalin XR
Experimental: Group 3: Guan-Guan+DMPH (Comb) weeks 1-4: Guanfacine weeks 5-8: Guanfacine+DMPH	Drug: Guanfacine; 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; Other Names: Tenex ; Drug: Methylphenidate (MPH); 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.; Other Names: Focalin XR

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 14 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles	Los Angeles	California	United States	90095

Sponsors and Collaborators

• University of California, Los Angeles
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: James T. McCracken, MD, University of California, Los Angeles
• Study Director: James J. McGough, MD, University of California, Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: James McCracken, Chair, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT00429273
• Other Study ID Numbers: P50MH077248-01; P50MH077248-01; 10-000453
• First Posted: Jan 31, 2007
• Last Update Posted: Jul 30, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by James McCracken, Chair, University of California, Los Angeles: ADHD; Guanfacine; Methylphenidate; Focalin XR; Pediatric; Cognitive function; Combination therapy
• Additional relevant MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity; Guanfacine; Methylphenidate; Dexmethylphenidate Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Group 1: Guan-Guan+Placebo	Group 2: Placebo-Placebo+DMPH	Group 3: Guan-Guan+DMPH
Arm/Group Description	weeks 1-4: Guanfacine weeks 5-8: Guanfacine+Placebo	weeks 1-4: Placebo weeks 5-8: Placebo+DMPH	weeks 1-4: Guanfacine weeks 5-8: Guanfacine+DMPH (comb)
Period Title: Overall Study
STARTED	68	69	70
COMPLETED	60	61	61
NOT COMPLETED	8	8	9

Baseline Characteristics

Arm/Group Title	Group 1: Guan-Guan+Placebo	Group 2: Placebo-Placebo+DMPH	Group 3: Guan-Guan+DMPH (Comb)	Total
Arm/Group Description	weeks 1-4: Guanfacine weeks 5-8: Guanfacine +Placebo	weeks 1-4: Placebo weeks 5-8: Placebo+DMPH	weeks 1-4: Guanfacine weeks 5-8: Guanfacine+DMPH (comb)	Total of all reporting groups
Overall Participants	68	69	70	207
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.1 (2.1)	10.1 (2.0)	9.9 (2.2)	10.0 (2.1)
Sex: Female, Male (Count of Participants)
Female	23 33.8%	23 33.3%	19 27.1%	65 31.4%
Male	45 66.2%	46 66.7%	51 72.9%	142 68.6%
Race/Ethnicity, Customized (Count of Participants)
White	51 75%	51 73.9%	41 58.6%	143 69.1%
African American	7 10.3%	10 14.5%	19 27.1%	36 17.4%
Asian, Pacific Islander	7 10.3%	4 5.8%	5 7.1%	16 7.7%
Other	3 4.4%	4 5.8%	5 7.1%	12 5.8%
Hispanic	16 23.5%	10 14.5%	18 25.7%	44 21.3%

Outcome Measures

1. Primary Outcome

Title	ADHD IV Rating Scale (Attention Deficit Hyperactivity Disorder Rating Scale)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Estimated Difference Between Guan and Placebo	Estimated Difference Between DMPH and Placebo	Estimated Difference Between Placebo and Combo
Arm/Group Description	Contrasts based on all observations of patients treated with guam and all patients on placebo controlling for time effects. For placebo this included patients in the guan-guan arm at baseline, the guan-combo arm at baseline, and the placebo-DMPH arm at baseline and 4 weeks, while the estimates for guan are based on the guan-guan arm both at 4 weeks and 8 weeks, and the guan-combo arm at 4 weeks only. Participant specific effects and time effects are controlled for based on estimates from all participants and all time points.	Contrasts based on all observations of patients treated with dmph and all patients on placebo controlling for time effects. For placebo this included patients in the guan-guan arm at baseline, the guan-combo arm at baseline, and the placebo-DMPH arm at baseline and 4 weeks, while the estimates for DMPH are based on the placebo-guan arm at 8 weeks. Participant specific effects and time effects are controlled for based on estimates from all participants and all time points.	Contrasts based on all observations of patients treated with combo and all patients on placebo controlling for time effects. For placebo this included patients in the guan-guan arm at baseline, the guan-combo arm at baseline, and the placebo-DMPH arm at baseline and 4 weeks, while the estimates for DMPH are based on the guan-combo arm at 8 weeks. Participant specific effects and time effects are controlled for based on estimates from all participants and all time points.
Measure Participants	207	207	207
Total ADHD-RS Score	-7.77 (1.70)	-7.99 (1.22)	-10.66 (1.99)
Inattentive Subscale	-4.14 (0.99)	-4.10 (0.71)	-5.89 (1.15)
Hyperactive Impulsive Subscale	-3.73 (0.92)	-4.0 (0.69)	-5.10 (1.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Estimated Difference Between Guan and Placebo, Estimated Difference Between DMPH and Placebo, Estimated Difference Between Placebo and Combo
	Comments	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.
	Type of Statistical Test	Other
	Comments	Test for differences in treatment outcomes between three different tx
Statistical Test of Hypothesis	p-Value	<.01
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	F-Value for variance component
	Estimated Value	18.90
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Group 1: Guan-Guan+Placebo		Group 2: Placebo-Placebo+DMPH		Group 3: Guan-Guan+DMPH
Arm/Group Description	week 1-4: Guanfacine weeks 5-8: Guanfacine+Placebo		week 1-4: Placebo week 5-8: Placebo+DMPH		week 1-4: Guanfacine week 5-8: Guanfacine+DMPH (comb)
All Cause Mortality
	Group 1: Guan-Guan+Placebo		Group 2: Placebo-Placebo+DMPH		Group 3: Guan-Guan+DMPH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/68 (0%)		0/69 (0%)		0/70 (0%)
Serious Adverse Events
	Group 1: Guan-Guan+Placebo		Group 2: Placebo-Placebo+DMPH		Group 3: Guan-Guan+DMPH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/68 (0%)		0/69 (0%)		0/70 (0%)
Other (Not Including Serious) Adverse Events
	Group 1: Guan-Guan+Placebo		Group 2: Placebo-Placebo+DMPH		Group 3: Guan-Guan+DMPH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/68 (97.1%)		66/69 (95.7%)		69/70 (98.6%)
Gastrointestinal disorders
Abdominal Pain Upper	11/68 (16.2%)	11	10/69 (14.5%)	10	10/70 (14.3%)	10
Abdominal Pain	19/68 (27.9%)	19	18/69 (26.1%)	18	16/70 (22.9%)	16
General disorders
Insomnia	18/68 (26.5%)	18	20/69 (29%)	20	24/70 (34.3%)	24
Lethargy	23/68 (33.8%)	23	9/69 (13%)	9	16/70 (22.9%)	16
Fatigue	22/68 (32.4%)	22	5/69 (7.2%)	5	12/70 (17.1%)	12
Metabolism and nutrition disorders
Decreased Appetite	15/68 (22.1%)	15	31/69 (44.9%)	31	25/70 (35.7%)	25
Psychiatric disorders
Headache	34/68 (50%)	34	23/69 (33.3%)	23	23/70 (32.9%)	23
Irritability	15/68 (22.1%)	15	12/69 (17.4%)	12	18/70 (25.7%)	18
Sedation	12/68 (17.6%)	12	4/69 (5.8%)	4	16/70 (22.9%)	16
Somnolence	16/68 (23.5%)	16	3/69 (4.3%)	3	15/70 (21.4%)	15
Affect Lability	7/68 (10.3%)	7	14/69 (20.3%)	14	8/70 (11.4%)	8
Vascular disorders
Dizziness	8/68 (11.8%)	8	6/69 (8.7%)	6	7/70 (10%)	7

Limitations/Caveats

Larger group sizes would enable more conclusive tests of treatment differences; Study design began with guanfacine first and addition of a stimulant second, making difficult to compare to those study designs adding guanfacine to ongoing stimulants.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.