Safety and Tolerability Study of SHP465 in Children Aged 4 to 12 Years Diagnosed With Attention-deficit/Hyperactivity Disorder (ADHD)

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the long-term safety and tolerability of SHP465 at 6.25 milligram (mg) in children aged 4 to 12 years diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD).

Official Title
-----------------
A Phase 3, Open-label, Multicenter, 12-Month Safety and Tolerability Study of SHP465 in Children Aged 4 to 12 Years Diagnosed With Attention-deficit/Hyperactivity Disorder

Conditions
-----------------
Attention Deficit Hyperactivity Disorder (ADHD)

Intervention / Treatment
-----------------
* Drug: SHP465


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant is male or female aged 4-12 years inclusive at the time of consent. Participant's parent or legally authorized representative (LAR) must provide signature of informed consent, and there must be documentation of assent (as applicable) by the participant. Participant must meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD (any subtype). Participant who is a female and of child-bearing potential must not be pregnant and agree to comply with any applicable contraceptive requirements.. Participant has an ADHD-RS-5 Child, Home Version Total Score of greater than or equal to (>=) 28 and Clinical Global Impression - Severity of Illness (CGI-S) score >=4 at baseline (Visit 2). Participant is currently not on ADHD therapy, or is not completely satisfied with their current ADHD therapy. Exclusion Criteria: Participant is required or anticipated to take medications that have central nervous system effects or affect performance. Stable use of bronchodilator inhalers is not exclusionary. Participant has a concurrent chronic or acute illness, disability, or other condition that might confound the results of safety assessments conducted in the study or that might increase risk to the participant. - Participant has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product. Participant has failed to fully respond, based on investigator judgment, to an adequate course of amphetamine therapy. Participant has a known family history of sudden cardiac death or ventricular arrhythmia. Participant has a blood pressure measurement >=95th percentile for age, sex, and height at screening (Visit 1) and/or baseline (Visit 2). Participant has a height less than or equal to (<=) 5th percentile for age and sex at screening (Visit 1) or baseline (Visit 2). Participant has a weight <=5th percentile for age and sex at screening (Visit 1) or baseline (Visit 2). Participant has a known history of symptomatic cardiovascular disease, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac conditions placing them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Participant has a history of seizures (other than infantile febrile seizures). Participant is taking any medication that is excluded per the protocol. Participant had any clinically significant ECG or clinical laboratory abnormalities at the screening (Visit 1) or baseline visit (Visit 2). Participant has current abnormal thyroid function, defined as abnormal thyroid-stimulating hormone and thyroxine at the screening or baseline visit. Treatment with a stable dose of thyroid medication for at least 3 months is permitted. Participant is currently considered a suicide risk in the opinion of the investigator, has previously made a suicide attempt, or has a prior history of or currently demonstrating suicidal ideation.

Ages Eligible for Study
-----------------
Minimum Age: 4 Years
Maximum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHP465<br>Group A participants who have been rolled-over from antecedent SHP465 studies and Group B participants who will be newly enrolled into the study will receive SHP465 capsule 6.25 mg orally once daily for 360 days. | Drug: SHP465<br>* SHP465 capsule will be administered in a dose of 6.25 mg orally once daily for 360 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of investigational product. | From start of study drug administration up to follow-up (approximately up to 367 days) | 
| Change From Baseline in Pulse Rate at Final On-Treatment Assessment (FoTA) | Change from baseline in pulse rate at FoTA was reported. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study. | Baseline, FoTA (up to 330 days) | 
| Change From Baseline in Blood Pressure at Final On-Treatment Assessment (FoTA) | Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at FoTA was reported. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study. | Baseline, FoTA (up to 330 days) | 
| Change From Baseline in Height at Final On-Treatment Assessment (FoTA) | Height was measured in centimeters (cm) without shoes and with light clothing using a stadiometer. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study. | Baseline, FoTA (up to 330 days) | 
| Change From Baseline in Weight at Final On-Treatment Assessment (FoTA) | Weight was measured in kilograms (kg) without shoes and with light clothing using a calibrated scale. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study. | Baseline, FoTA (up to 330 days) | 
| Change From Baseline in Hematology Parameters at Early Termination/Day 360 | Change from baseline in hematology parameter basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils band form, segmented neutrophils, neutrophils/total cells and platelets were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Leukocytes at Early Termination/Day 360 | Change from baseline in hematology leukocytes parameter: basophils, eosinophils, lymphocytes, monocytes and neutrophil were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Erythrocytes at Early Termination/Day 360 | Change from baseline in hematology parameter erythrocytes were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin Concentration at Early Termination/Day 360 | Change from baseline in hematology parameter erythrocytes mean corpuscular hemoglobin concentration were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin at Early Termination/Day 360 | Change from baseline in hematology parameter erythrocytes mean corpuscular hemoglobin were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Hematocrit at Early Termination/Day 360 | Change from baseline in hematology parameter hematocrit were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Hemoglobin at Early Termination/Day 360 | Change from baseline in hematology parameter hemoglobin were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Hematology Parameters (Erythrocytes Mean Corpuscular Volume and Mean Platelet Volume) at Early Termination/ Day 360 | Change from baseline in hematology parameter erythrocytes mean corpuscular volume and mean platelet volume were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Chemistry Parameters at Early Termination/Day 360 | Change from baseline in chemistry parameter alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma glutamyl transferase, and lactate dehydrogenase were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Chemistry Parameters (Albumin and Protein) at Early Termination/Day 360 | Change from baseline in chemistry parameters albumin and protein were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 | Change from baseline in chemistry parameters blood urea nitrogen, cholesterol, glucose, phosphate, potassium, sodium and urate were studies. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Chemistry Parameters (Bilirubin and Creatinine) at Early Termination/Day 360 | Change from baseline in chemistry parameters bilirubin and creatinine were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Thyrotropin at Early Termination/ Day 360 | Change from baseline in thyrotropin were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Thyroxine,Free at Early Termination/Day 360 | Change from baseline in thyroxine,free were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Urinalysis (Specific Gravity) at Early Termination/Day 360 | Change from baseline in urine specific gravity were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Urobilinogen at Early Termination/Day 360 | Change from baseline in urobilinogen were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early termination/Day 360 | 
| Change From Baseline in Urine Potential of Hydrogen (pH) at Early Termination/Day 360 | Change from baseline in urine pH were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | Baseline, Early Termination/Day 360 | 
| Change From Baseline in Heart Rate at Final On-Treatment Assessment (FoTA) | Heart rate was measured by Electrocardiogram (ECG). ECG was performed using the central ECG provider's equipment and was send to the central ECG provider electronically. Change from baseline in heart rate at FoTA were reported. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the average of all valid ECG measurements as the last assessment obtained before the first dose of investigational product. | Baseline, FoTA (up to 330 days) | 
| Change From Baseline in Electrocardiogram Parameters at Final On-Treatment Assessment (FoTA) | ECG was performed using the central ECG provider's equipment and was sent to the central ECG provider electronically to measure PR, RR, QRS , QT, QTcB and QTcF intervals. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date).Group A baseline was the baseline of the antecedent studies. Group B baseline was the average of all valid ECG measurements as the last assessment obtained before the first dose of investigational product. | Baseline, FoTA (up to 330 days) | 
| Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) | PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last week. The assessment was done by the nature of the responses, not by a numbered scale. Participants analyzed for number of times woke up per night category were only the participants who responded as yes for the woke up during the night category in this outcome measure. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. | FoTA (up to 330 days) | 
| Length of Time Awake Per Night and Length of Time to Fall Asleep Per Night Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) | PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last week. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. Length of time awake per night and length of time to fall asleep per night was assessed at FoTA. | FoTA (up to 330 days) | 
| Length of Time Sleeping Per Night Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) | PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last week. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. Length of time sleeping per night was assessed at FoTA. | FoTA (up to 330 days) | 
| Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment (FoTA) | CSHQ was a tool designed to screen for the most common sleep problems in children and consisted of 33 items for scoring and several extra items intended to provide administrators with other potentially useful information about respondents. The instrument evaluates the 8 different subscales: bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing, and daytime sleepiness. A 3-point scale was used for rating: usually if the sleep behavior occurs 5 to 7 times per week, sometimes for 2 to 4 times per week, and rarely for once or not at all during the week. The TSD score, which is the sum of all responses, included all items of the 8 subscales, but consisted of only 33 items because two on the bedtime resistance and sleep anxiety subscales were identical (range: 0, 99). A negative value indicates less sleep disturbance. | FoTA (up to 330 days) | 
| Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Day 330 | C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The number of participants with postive response in suicidal ideation and suicidal behavior were reported. | Day 330 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinician-administered Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) Total Score at Final On-Treatment Assessment (FoTA) | Clinician administered ADHD-RS-5, child, home version total score were analyzed. ADHD-RS-5 consists of 18 items designed to reflect current symptomatology of ADHD based on diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) criteria. Each item is scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54. The 18 items may be grouped into 2 subscales: hyperactivity/impulsivity (9 items) and inattentiveness (9 items). Higher total scores indicated higher impairment and lower scores indicated no impairment. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date). | Baseline, FoTA (up to 330 days) | 
| Clinical Global Impression of Improvement (CGI-I) at Final On-Treatment Assessment (FoTA) | CGI-I scale was performed to rate the improvement of a participant's condition on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). | FoTA (up to 330 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ADHD, SHP465, Hyperactivity