Effect of Guanfacine Extended-Release on Attention Deficit Hyperactivity Disorder (ADHD)-Associated Insomnia

• Sponsor: Children's Specialized Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01156051
• Collaborator: Shire (Industry)
• Enrollment: 29
• Locations: 2
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 14.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Attention-Deficit/Hyperactivity Disorder; Attention Deficit Disorder; Insomnia; Sleep Disorders	Drug: Guanfacine extended-release tablets; Drug: Placebo comparator	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Guanfacine Extended-Release on Attention Deficit Hyperactivity Disorder (ADHD)-Associated Insomnia
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Guanfacine Extended-Release Tablets Guanfacine Extended-Release Tablets 1mg, 2mg, 3mg, and 4mg	Drug: Guanfacine 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; Other Names: Intuniv (TM), guanfacine HCl, SPD503
Placebo Comparator: Placebo comparator Placebo control	Drug: Placebo comparator; Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg, 2mg, 3mg, 4mg, but without the active ingredient (guanfacine).; Other Names: "sugar pill"

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Specialized Hospital	Hamilton	New Jersey	United States	08619
2	Children's Specialized Hospital	Toms River	New Jersey	United States	08755

Sponsors and Collaborators

• Children's Specialized Hospital
• Shire

Investigators

• Principal Investigator: Thomas A Rugino, MD, Children's Specialized Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thomas Rugino, Principal Investigator, Children's Specialized Hospital
• ClinicalTrials.gov Identifier: NCT01156051
• Other Study ID Numbers: CSHTR-TR-0901; NCT01153178
• First Posted: Jul 2, 2010
• Last Update Posted: Aug 11, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Thomas Rugino, Principal Investigator, Children's Specialized Hospital: ADHD; ADD; sleep disturbance
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Hyperkinesis; Sleep Wake Disorders; Disease; Attention Deficit Disorder with Hyperactivity; Guanfacine

Study Results

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 Detail	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).

Arm/Group Title	Treatment Group	Control
Arm/Group Description	Children who received (double blinded, randomized) guanfacine extended release tablets in a flexible dosing protocol, with doses ranging from 1mg to 4mg administered once daily in the morning.	Children who received a matching placebo tablet administered once daily in the morning in a flexible dosing protocol, with tablets identical to guanfacine extended release from 1mg to 4mg.
Period Title: Overall Study
STARTED	12	17
COMPLETED	11	16
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Guanfacine Extended-Release Tablets	Placebo Comparator	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	11	16	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.1 (1.8)	8.8 (1.9)	8.9 (1.9)
Sex: Female, Male (Count of Participants)
Female	2 18.2%	8 50%	10 37%
Male	9 81.8%	8 50%	17 63%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 12.5%	2 7.4%
Not Hispanic or Latino	11 100%	14 87.5%	25 92.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	10 90.9%	12 75%	22 81.5%
African-American	1 9.1%	4 25%	5 18.5%
Region of Enrollment (participants) [Number]
United States	11 100%	16 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Change in Polysomnographic Total Sleep Time (TST)
Description	Change in objective measures of sleep, using polysomnography
Time Frame	Baseline to last observation carried forward (after at least one week of dose stability)

Outcome Measure Data

Analysis Population Description

29 children were enrolled, one (treatment) was lost to follow up an one (placebo) was discontinued due to noncompliance with protocol.

Arm/Group Title	Guanfacine Extended-Release Tablets	Placebo Comparator
Arm/Group Description	Guanfacine Extended-Release Tablets 1mg, 2mg, 3mg, and 4mg Guanfacine 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	Placebo control Placebo comparator: Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg, 2mg, 3mg, 4mg, but without the active ingredient (guanfacine).
Measure Participants	11	16
Mean (Standard Deviation) [minutes]	-57.32 (89.17)	31.32 (59.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Guanfacine Extended-Release Tablets, Placebo Comparator
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change in Baseline to Treatment ADHD-Rating Scale IV Total Score
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Guanfacine Extended-Release Tablets	Placebo Comparator
Arm/Group Description	Guanfacine Extended-Release Tablets 1mg, 2mg, 3mg, and 4mg Guanfacine 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	Placebo control Placebo comparator: Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg, 2mg, 3mg, 4mg, but without the active ingredient (guanfacine).
Measure Participants	11	16
Mean (Standard Deviation) [units on a scale]	-18.27 (11.31)	-1.69 (9.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Guanfacine Extended-Release Tablets, Placebo Comparator
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Change in Baseline to Treatment Latency to Persistent Sleep (LPS)
Description	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)

Outcome Measure Data

Analysis Population Description

29 children were enrolled; two were disqualified: one (treatment) was lost to follow-up,and one (placebo) was noncompliant with the protocol.

Arm/Group Title	Guanfacine Extended-Release Tablets	Placebo Comparator
Arm/Group Description	Guanfacine Extended-Release Tablets 1mg, 2mg, 3mg, and 4mg Guanfacine 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	Placebo control Placebo comparator: Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg, 2mg, 3mg, 4mg, but without the active ingredient (guanfacine).
Measure Participants	11	16
Mean (Standard Deviation) [minutes]	10.54 (88.44)	-19.94 (54.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Guanfacine Extended-Release Tablets, Placebo Comparator
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.392
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Change in Baseline to Treatment Minutes of Wake Time After Sleep Onset (WASO)
Description	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)

Outcome Measure Data

Analysis Population Description

29 children were enrolled; two were disqualified: one (treatment) was lost to follow-up,and one (placebo) was noncompliant with the protocol.

Arm/Group Title	Guanfacine Extended-Release Tablets	Placebo Comparator
Arm/Group Description	Guanfacine Extended-Release Tablets 1mg, 2mg, 3mg, and 4mg Guanfacine 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	Placebo control Placebo comparator: Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg, 2mg, 3mg, 4mg, but without the active ingredient (guanfacine).
Measure Participants	11	16
Mean (Standard Deviation) [minutes]	21.80 (18.51)	-3.90 (17.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Guanfacine Extended-Release Tablets, Placebo Comparator
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	ANOVA
	Comments

Adverse Events

Arm/Group Title	Guanfacine Extended-Release Tablets		Placebo Comparator
Arm/Group Description	Guanfacine Extended-Release Tablets 1mg, 2mg, 3mg, and 4mg Guanfacine 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		Placebo control Placebo comparator: Placebo tablets identical to the experimental arm guanfacine extended-release tablets 1mg, 2mg, 3mg, 4mg, but without the active ingredient (guanfacine).
All Cause Mortality
	Guanfacine Extended-Release Tablets		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Guanfacine Extended-Release Tablets		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Guanfacine Extended-Release Tablets		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/12 (75%)		11/17 (64.7%)
Gastrointestinal disorders
stomachache / abdominal pain	1/12 (8.3%)	1	2/17 (11.8%)	2
acute gastroenteritis	1/12 (8.3%)	1	2/17 (11.8%)	2
inguinal hernia	0/12 (0%)	0	1/17 (5.9%)	1
General disorders
oral pain due to loose teeth	1/12 (8.3%)	1	0/17 (0%)	0
Infections and infestations
febrile illness	1/12 (8.3%)	1	0/17 (0%)	0
upper respiratory infection	3/12 (25%)	3	3/17 (17.6%)	3
Metabolism and nutrition disorders
decreased appetite	0/12 (0%)	0	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
musculoskeletal chest pain	1/12 (8.3%)	1	0/17 (0%)	0
Nervous system disorders
somnolence / sedation	8/12 (66.7%)	8	1/17 (5.9%)	1
headache	4/12 (33.3%)	4	2/17 (11.8%)	2
dizziness	1/12 (8.3%)	1	0/17 (0%)	0
Psychiatric disorders
stuttering	0/12 (0%)	0	1/17 (5.9%)	1
Renal and urinary disorders
enuresis	1/12 (8.3%)	1	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders
exacerbation of allergic rhinitis	1/12 (8.3%)	1	5/17 (29.4%)	5
exacerbation of asthma	0/12 (0%)	0	1/17 (5.9%)	1
cough	1/12 (8.3%)	1	0/17 (0%)	0
Skin and subcutaneous tissue disorders
dermatitis	1/12 (8.3%)	1	2/17 (11.8%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.