Trial Outcomes & Findings for Maintenance of Efficacy of Extended-Release Guanfacine HCl in Children and Adolescents With Attention-deficit/Hyperactivity Disorder (ADHD) (NCT NCT01081145)

Results Overview

Treatment failure was defined as \>= 50% increase (worsening) in ADHD-RS-IV total score and a \>= 2 point increase (worsening) in CGI-S score compared with the respective scores at the Double-blind Randomized-withdrawal Baseline Visit at 2 consecutive Double-blind Randomized-withdrawal Phase visits. Subjects meeting these criteria were regarded as treatment failures regardless of whether or not they were withdrawn. All subjects who discontinued the study for any reason were regarded as treatment failures for the primary analysis.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

528 participants

Primary outcome timeframe

26 weeks

Results posted on

2021-06-14

Participant Flow

Participant milestones

Participant milestones
Measure	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight	Placebo Administered as a once-daily oral dose
Open-Label Phase STARTED	528	0
Open-Label Phase COMPLETED	316	0
Open-Label Phase NOT COMPLETED	212	0
Double-Blind Randomized-Withdrawal Phase STARTED	157	159
Double-Blind Randomized-Withdrawal Phase COMPLETED	76	53
Double-Blind Randomized-Withdrawal Phase NOT COMPLETED	81	106

Reasons for withdrawal

Reasons for withdrawal
Measure	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight	Placebo Administered as a once-daily oral dose
Open-Label Phase Lack of Efficacy	56	0
Open-Label Phase Response criteria not met	46	0
Open-Label Phase Adverse Event	42	0
Open-Label Phase Withdrawal by Subject	41	0
Open-Label Phase Other	12	0
Open-Label Phase Lost to Follow-up	11	0
Open-Label Phase Protocol Violation	4	0
Double-Blind Randomized-Withdrawal Phase Adverse Event	3	2
Double-Blind Randomized-Withdrawal Phase Protocol Violation	1	0
Double-Blind Randomized-Withdrawal Phase Withdrawal by Subject	10	8
Double-Blind Randomized-Withdrawal Phase Lost to Follow-up	3	2
Double-Blind Randomized-Withdrawal Phase Lack of Efficacy	13	20
Double-Blind Randomized-Withdrawal Phase Treatment failure criteria met	47	71
Double-Blind Randomized-Withdrawal Phase Other	4	3

Baseline Characteristics

Maintenance of Efficacy of Extended-Release Guanfacine HCl in Children and Adolescents With Attention-deficit/Hyperactivity Disorder (ADHD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Guanfacine Hydrochloride n=526 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Age, Continuous	10.7 Years STANDARD_DEVIATION 2.7 • n=5 Participants
Age, Customized 6-12 years	391 Participants n=5 Participants
Age, Customized 13-17 years	135 Participants n=5 Participants
Sex: Female, Male Female	130 Participants n=5 Participants
Sex: Female, Male Male	396 Participants n=5 Participants
Region of Enrollment BELGIUM	19 Participants n=5 Participants
Region of Enrollment CANADA	30 Participants n=5 Participants
Region of Enrollment FRANCE	14 Participants n=5 Participants
Region of Enrollment GERMANY	27 Participants n=5 Participants
Region of Enrollment ITALY	31 Participants n=5 Participants
Region of Enrollment NETHERLANDS	29 Participants n=5 Participants
Region of Enrollment SPAIN	68 Participants n=5 Participants
Region of Enrollment SWEDEN	5 Participants n=5 Participants
Region of Enrollment UNITED KINGDOM	25 Participants n=5 Participants
Region of Enrollment UNITED STATES	278 Participants n=5 Participants

PRIMARY outcome

Timeframe: 26 weeks

Population: Randomized Full Analysis Set (FAS) defined as all subjects who were randomized and took at least 1 dose of investigational product during the Double-blind Randomized-withdrawal Phase. Subjects from Site 801 were excluded from the Randomized FAS.

Treatment failure was defined as \>= 50% increase (worsening) in ADHD-RS-IV total score and a \>= 2 point increase (worsening) in CGI-S score compared with the respective scores at the Double-blind Randomized-withdrawal Baseline Visit at 2 consecutive Double-blind Randomized-withdrawal Phase visits. Subjects meeting these criteria were regarded as treatment failures regardless of whether or not they were withdrawn. All subjects who discontinued the study for any reason were regarded as treatment failures for the primary analysis.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride n=150 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Percentage of Participants With Treatment Failures During the Double-Blind Randomized-Withdrawal Phase	64.9 percentage of treatment failures Interval 57.3 to 72.5	49.3 percentage of treatment failures Interval 41.3 to 57.3

SECONDARY outcome

Timeframe: 26 weeks

Population: Randomized FAS

Treatment failure was defined as \>= 50% increase (worsening) in ADHD-RS-IV total score and a \>= 2 point increase (worsening) in CGI-S score compared with the respective scores at the Double-blind Randomized-withdrawal Baseline Visit at 2 consecutive Double-blind Randomized-withdrawal Phase visits. Subjects meeting these criteria were regarded as treatment failures regardless of whether or not they were withdrawn. All subjects who discontinued the study for any reason were regarded as treatment failures for the primary analysis.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride n=150 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Time to Treatment Failure During the Double-Blind Randomized-Withdrawal Phase	56.0 Days Interval 44.0 to 97.0	218.0 Days Interval 118.0 to There were not enough treatment failure events by study completion to calculate an upper CI.

SECONDARY outcome

Timeframe: Baseline and week 26

Population: Randomized FAS

The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride n=150 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Change From Double-Blind Randomized-Withdrawal Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - Last Observation Carried Forward (LOCF)	15.89 units on a scale Standard Error 1.225	9.64 units on a scale Standard Error 1.21

SECONDARY outcome

Timeframe: 26 weeks

Population: Randomized FAS

CGI-S assesses the severity of the subject's condition on a 7-point scale: 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the most extremely ill)

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride n=150 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on Clinical Global Impression-Severity of Illness (CGI-S) Scale During the Double-Blind Randomized-Withdrawal Phase - LOCF	32.5 percentage of subjects	50.0 percentage of subjects

SECONDARY outcome

Timeframe: Baseline and week 26

Population: Randomized FAS

The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride n=150 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Change From Double-Blind Randomized-Withdrawal Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - LOCF	0.23 units on a scale Standard Error 0.036	0.16 units on a scale Standard Error 0.035

SECONDARY outcome

Timeframe: 26 weeks

Population: Randomized FAS

HUI is used to describe health status and to obtain utility scores by collecting data using one or more questionnaires in formats selected to match the specific study design criteria. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status.

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride n=138 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Health Utilities Index-2/3 (HUI 2/3) Scores During the Double-Blind Randomized-Withdrawal Phase - LOCF	0.899 units on a scale Standard Deviation 0.1272	0.900 units on a scale Standard Deviation 0.1229

SECONDARY outcome

Timeframe: 26 weeks

Population: Randomized Safety Population defined as all subjects who were randomized and who took at least 1 dose of investigational product during the Double-blind Randomized-withdrawal Phase.

C-SSRS is a semi-structured interview that captures the occurence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The assessment is done by the nature of the responses, not by a numbered scale.

Outcome measures

Outcome measures
Measure	Placebo n=158 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride n=157 Participants Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Columbia-Suicide Severity Rating Scale During Double-Blind Randomized-Withdrawal Phase Suicidal ideation	2 participants	2 participants
Columbia-Suicide Severity Rating Scale During Double-Blind Randomized-Withdrawal Phase Suicidal behavior	0 participants	0 participants

SECONDARY outcome

Timeframe: Baseline and 13 weeks

Population: Open-label Full Analysis Set (FAS) defined as all subjects who took at least 1 dose of any investigational product during the study. The Subjects from Site 801 were excluded from the Open-label FAS.

The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.

Outcome measures

Outcome measures
Measure	Placebo n=497 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Change From Open-Label Baseline in ADHD-RS-IV Total Score at Week 13 of the Open-Label Phase - LOCF	-25.2 units on a scale Standard Deviation 11.97	—

SECONDARY outcome

Timeframe: 13 weeks

Population: Open-label FAS

Response is defined as a percentage decrease (improvement) from Baseline in the ADHD-RS-IV total score of \>=30% and a CGI-S score of 1 or 2.

Outcome measures

Outcome measures
Measure	Placebo n=497 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Percentage of Responders in the Open-Label Phase - LOCF	68.6 percentage of participants	—

SECONDARY outcome

Timeframe: 13 weeks

Population: Open-label FAS

Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.

Outcome measures

Outcome measures
Measure	Placebo n=497 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores During Open-Label Phase - LOCF	76.1 percentage of participants	—

SECONDARY outcome

Timeframe: 13 weeks

Population: Open-label FAS

CGI-S assesses the severity of the subject's condition on a 7-point scale: 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the most extremely ill)

Outcome measures

Outcome measures
Measure	Placebo n=503 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on CGI-S Scale During the Open-Label Phase - LOCF	68.9 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and week 13

Population: Open-label FAS

The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

Outcome measures

Outcome measures
Measure	Placebo n=405 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Change From Open-Label Baseline in WFIRS-P Global Score at Week 13 of the Open-Label Phase - LOCF	-0.35 units on a scale Standard Deviation 0.414	—

SECONDARY outcome

Timeframe: 13 weeks

Population: Open-label FAS

HUI is used to describe health status and to obtain utility scores by collecting data using one or more questionnaires in formats selected to match the specific study design criteria. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status.

Outcome measures

Outcome measures
Measure	Placebo n=417 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
HUI 2/3 Scores During the Open-Label Phase - LOCF	0.892 units on a scale Standard Deviation 0.1230	—

SECONDARY outcome

Timeframe: 13 weeks

Population: Open-label Safety Population defined as all subjects who took at least 1 dose of any investigational product during the study.

C-SSRS is a semi-structured interview that captures the occurence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The assessment is done by the nature of the responses, not by a numbered scale.

Outcome measures

Outcome measures
Measure	Placebo n=526 Participants Administered as a once-daily oral dose	Guanfacine Hydrochloride Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Columbia-Suicide Severity Rating Scale During Open-Label Phase Suicidal ideation	1 participants	—
Columbia-Suicide Severity Rating Scale During Open-Label Phase Suicidal behavior	2 participants	—

Adverse Events

Guanfacine Hydrochloride (Open-Label Phase)

Serious events: 5 serious events

Other events: 423 other events

Deaths: 0 deaths

Placebo (Randomized-Withdrawal Phase)

Serious events: 4 serious events

Other events: 51 other events

Deaths: 0 deaths

Guanfacine Hydrochloride (Randomized-Withdrawal Phase)

Serious events: 2 serious events

Other events: 65 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Guanfacine Hydrochloride (Open-Label Phase) n=526 participants at risk Administered as a once-daily oral dose between 1-7mg/day depending on age and weight	Placebo (Randomized-Withdrawal Phase) n=158 participants at risk Administered as a once-daily oral dose	Guanfacine Hydrochloride (Randomized-Withdrawal Phase) n=157 participants at risk Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Cardiac disorders Sinus bradycardia	0.19% 1/526 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Nervous system disorders Somnolence	0.19% 1/526 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Nervous system disorders Syncope	0.38% 2/526 • Number of events 2 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.63% 1/158 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Psychiatric disorders Aggression	0.19% 1/526 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.63% 1/158 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/526 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.63% 1/158 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Nervous system disorders Grand mal convulsion	0.00% 0/526 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.64% 1/157 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Psychiatric disorders Conduct disorder	0.00% 0/526 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.64% 1/157 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Renal and urinary disorders Nephrolithiasis	0.00% 0/526 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.63% 1/158 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Social circumstances Family stress	0.00% 0/526 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.63% 1/158 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.

Other adverse events

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Publication restrictions are in place

Restriction type: OTHER

Measure	Guanfacine Hydrochloride (Open-Label Phase) n=526 participants at risk Administered as a once-daily oral dose between 1-7mg/day depending on age and weight	Placebo (Randomized-Withdrawal Phase) n=158 participants at risk Administered as a once-daily oral dose	Guanfacine Hydrochloride (Randomized-Withdrawal Phase) n=157 participants at risk Administered as a once-daily oral dose between 1-7mg/day depending on age and weight
Gastrointestinal disorders Abdominal pain upper	11.4% 60/526 • Number of events 70 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	5.1% 8/158 • Number of events 10 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.9% 3/157 • Number of events 4 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Gastrointestinal disorders Constipation	5.9% 31/526 • Number of events 38 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.9% 3/158 • Number of events 3 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	3.2% 5/157 • Number of events 5 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Gastrointestinal disorders Diarrhoea	7.0% 37/526 • Number of events 46 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.9% 3/158 • Number of events 4 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	2.5% 4/157 • Number of events 5 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Gastrointestinal disorders Nausea	6.3% 33/526 • Number of events 42 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	2.5% 4/158 • Number of events 4 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	3.2% 5/157 • Number of events 5 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
General disorders Fatigue	24.7% 130/526 • Number of events 186 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.3% 2/158 • Number of events 2 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	5.1% 8/157 • Number of events 11 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
General disorders Irritability	7.0% 37/526 • Number of events 41 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.9% 3/158 • Number of events 3 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.3% 2/157 • Number of events 2 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Infections and infestations Nasopharyngitis	6.8% 36/526 • Number of events 39 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	8.2% 13/158 • Number of events 14 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	7.0% 11/157 • Number of events 14 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Infections and infestations Upper respiratory tract infection	5.9% 31/526 • Number of events 33 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	6.3% 10/158 • Number of events 10 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	5.1% 8/157 • Number of events 8 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Metabolism and nutrition disorders Decreased appetite	5.7% 30/526 • Number of events 32 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/157 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Nervous system disorders Dizziness	9.5% 50/526 • Number of events 62 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.3% 2/158 • Number of events 2 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.9% 3/157 • Number of events 3 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Nervous system disorders Headache	27.4% 144/526 • Number of events 242 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	11.4% 18/158 • Number of events 24 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	15.9% 25/157 • Number of events 34 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Nervous system disorders Sedation	8.9% 47/526 • Number of events 61 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	1.3% 2/157 • Number of events 2 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Nervous system disorders Somnolence	48.3% 254/526 • Number of events 386 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	12.1% 19/157 • Number of events 27 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Vascular disorders Hypotension	5.5% 29/526 • Number of events 32 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.00% 0/158 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	0.64% 1/157 • Number of events 1 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
Respiratory, thoracic and mediastinal disorders Cough	2.7% 14/526 • Number of events 14 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	5.7% 9/158 • Number of events 11 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	3.2% 5/157 • Number of events 6 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.
General disorders Pyrexia	4.2% 22/526 • Number of events 28 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	3.2% 5/158 • Number of events 5 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.	6.4% 10/157 • Number of events 10 Open-label and Randomized Safety Populations consist of all subjects who took at least 1 dose of investigational product during their specific Phase. Two subjects in the Open-label Phase (n=526) and one subject in the Randomized-withdrawal Phase (n=315) did not receive investigational product and were excluded from their respective populations.