Trial Outcomes & Findings for Safety, Tolerability and Pharmacokinetics of SHP465 in Children Aged 4 to 5 Years With Attention-Deficit/Hyperactivity Disorder (ADHD) (NCT NCT03327402)

Results Overview

Vital sign assessments included blood pressure, pulse, respiratory rate and body temperature. Any change in vital signs which were deemed clinically significant by the investigator were recorded as TEAE.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

24 participants

Primary outcome timeframe

From start of study drug administration up to follow-up (up to 5 weeks)

Results posted on

2021-06-08

Participant Flow

The study was conducted at eight centers in the United States between 13 March 2018 (first participant first visit) and 05 October 2018 (last participant last visit).

A total of 24 participants were enrolled and received the treatment. Of them 12 participants were included in the rich pharmacokinetic (PK) sampling group and 12 participants were included in the sparse PK sampling group. Overall, 22 participants completed the study.

Participant milestones

Participant milestones
Measure	SHP465 Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Overall Study STARTED	24
Overall Study Rich PK Sampling Group	12
Overall Study Sparse PK Sampling Group	12
Overall Study COMPLETED	22
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	SHP465 Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Overall Study Withdrawal by Subject	1
Overall Study Other (Visit Out-Of-Window)	1

Baseline Characteristics

Safety, Tolerability and Pharmacokinetics of SHP465 in Children Aged 4 to 5 Years With Attention-Deficit/Hyperactivity Disorder (ADHD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Age, Continuous	4.8 Years STANDARD_DEVIATION 0.41 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	12 Participants n=5 Participants
Race (NIH/OMB) White	12 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: Pharmacokinetic (PK) set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Maximum plasma drug concentration occurred at time of maximum observed concentration of plasma d-amphetamine and plasma l-amphetamine during a dosing interval were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Maximum Plasma Drug Concentration (Cmax) Occurred at the Time of Maximum Observed Concentration Sampled During a Dosing Interval (Tmax) of Plasma Dextroamphetamine (d-Amphetamine) and Plasma Levoamphetamine (l-Amphetamine) d-Amphetamine	31.37 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 32.6
Maximum Plasma Drug Concentration (Cmax) Occurred at the Time of Maximum Observed Concentration Sampled During a Dosing Interval (Tmax) of Plasma Dextroamphetamine (d-Amphetamine) and Plasma Levoamphetamine (l-Amphetamine) l-Amphetamine	9.895 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 34.7

PRIMARY outcome

Timeframe: Predose on Day 1 and Day 28 and at 24 hours (Day 29) postdose on Day 28

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Trough plasma drug concentration (predose concentrations collected at steady state) of plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Trough Plasma Drug Concentration Ctrough at Steady State (Ctrough,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	7.934 ng/mL Standard Deviation 6.3077
Trough Plasma Drug Concentration Ctrough at Steady State (Ctrough,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	3.092 ng/mL Standard Deviation 2.5253

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one post-dose PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Time to reach maximum observed plasma drug concentration of plasma d-amphetamine and plasma l-amphetamine during a dosing interval were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Time to Reach Maximum Observed Plasma Drug Concentration (Tmax) During Dosing Interval of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	7.917 hour Interval 5.0 to 16.3
Time to Reach Maximum Observed Plasma Drug Concentration (Tmax) During Dosing Interval of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	7.917 hour Interval 5.0 to 16.3

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Area under the concentration-time curve from time zero to the last quantifiable concentration of plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration-Time Curve From Time Zero to the Last Timepoint (AUC0-t) During Sample Collection of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	646.3 hournanogram per milliliter (hrng/mL) Geometric Coefficient of Variation 27.5
Area Under the Concentration-Time Curve From Time Zero to the Last Timepoint (AUC0-t) During Sample Collection of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	222.1 hournanogram per milliliter (hrng/mL) Geometric Coefficient of Variation 31.1

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5 hours Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one post-dose PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Area under the concentration time curve from time zero predose to five hours postdose of plasma d-amphetamine and plasma d-amphetamine were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration-Time Curve From Time Zero Predose to Five Hours Postdose (AUC0-5) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	109.7 hr*ng/mL Geometric Coefficient of Variation 36.1
Area Under the Concentration-Time Curve From Time Zero Predose to Five Hours Postdose (AUC0-5) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	34.53 hr*ng/mL Geometric Coefficient of Variation 40.3

PRIMARY outcome

Timeframe: Week 4: 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Area under the concentration time curve from time five hours to the time of last quantifiable concentration of plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration Time Curve From Time Five Hours to the Last Timepoint (AUC5-t) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	549.9 hr*ng/mL Geometric Coefficient of Variation 30.3
Area Under the Concentration Time Curve From Time Five Hours to the Last Timepoint (AUC5-t) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	194.1 hr*ng/mL Geometric Coefficient of Variation 34.1

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Area under the concentration-time curve from time of dosing to the last measurable concentration of plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration-Time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	646.3 hr*ng/mL Geometric Coefficient of Variation 27.5
Area Under the Concentration-Time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	222.1 hr*ng/mL Geometric Coefficient of Variation 31.1

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Area under the concentration-time curve over the dosing interval (24 hours) at steady state of plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration-Time Curve Over the Dosing Interval (24 Hours) at Steady State (AUCtau,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	520.6 hr*ng/mL Geometric Coefficient of Variation 29.8
Area Under the Concentration-Time Curve Over the Dosing Interval (24 Hours) at Steady State (AUCtau,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	171.0 hr*ng/mL Geometric Coefficient of Variation 32.9

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure at the specific categories. Sparse PK sampling group were excluded from the PK analysis.

Terminal Rate Constant of plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=12 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Terminal Rate Constant (Lambda z) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	0.06639 per hour Geometric Coefficient of Variation 15.5
Terminal Rate Constant (Lambda z) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	0.05632 per hour Geometric Coefficient of Variation 15.3

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Apparent total clearance of the plasma drug concentration of plasma d- amphetamine and plasma l-amphetamine after oral dose administration were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Total Body Clearance (CL/F) for Extravascular Administration of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	5.618 Liter per hour (L/hr) Geometric Coefficient of Variation 29.8
Total Body Clearance (CL/F) for Extravascular Administration of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	5.703 Liter per hour (L/hr) Geometric Coefficient of Variation 32.9

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure at the specific categories. Sparse PK sampling group were excluded from the PK analysis.

Time required for the plasma drug concentration to reach half of its original value of plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=12 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Terminal Half-life (t1/2) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	9.911 hour Interval 8.42 to 14.1
Terminal Half-life (t1/2) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	12.16 hour Interval 9.71 to 15.6

PRIMARY outcome

Timeframe: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected.Here, number of participants analyzed signifies participants who were evaluable for this outcome measure at the specific categories. Sparse PK sampling group were excluded from the PK analysis.

Apparent volume of distribution at steady state of plasma d-amphetamine and plasma l-amphetamine after oral dose administration were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=12 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Apparent Volume of Distribution (Vss/F) at Steady State of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	90.09 liter Geometric Coefficient of Variation 34.3
Apparent Volume of Distribution (Vss/F) at Steady State of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	109.4 liter Geometric Coefficient of Variation 35.6

PRIMARY outcome

Timeframe: From start of study drug administration up to follow-up (up to 5 weeks)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily had 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 (IP) and no later than 3 days following the last dose of IP.

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	11 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to follow-up (up to 5 weeks)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

Vital sign assessments included blood pressure, pulse, respiratory rate and body temperature. Any change in vital signs which were deemed clinically significant by the investigator were recorded as TEAE.

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs	1 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to follow-up (up to 5 weeks)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

12-lead ECG were evaluated. Any change in ECG assessments which are deemed clinically significant by the investigator were reported as TEAE.

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as TEAEs	0 Participants

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Height (in centimeters) was measured using a stadiometer with the participant standing on a flat surface without shoes and with the chin parallel to the floor. Final on-treatment assessment (FoTA) was defined as the last valid assessment obtained after baseline and while on IP (on or before 2 days after the last dose date).

Outcome measures

Outcome measures
Measure	SHP465 n=22 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Change From Baseline in Height at Final On-Treatment Assessment	1.601 centimeter (cm) Standard Deviation 1.5073

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

Weight (in kilograms) was measured using a calibrated scale. Participant should be in light clothes and without shoes. FoTA was defined as the last valid assessment obtained after baseline and while on IP (on or before 2 days after the last dose date).

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Change From Baseline in Weight at Final On-Treatment Assessment	-0.305 kilogram (kg) Standard Deviation 0.4268

PRIMARY outcome

Timeframe: From start of study drug administration up to follow-up (up to 5 weeks)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

Clinical laboratory tests included biochemistry, endocrinology, hematology and urinalysis. Any change in clinical laboratory results which are deemed clinically significant by the investigator were reported as TEAE.

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Number of Participants With Clinically Significant Changes in Clinical Laboratory Results Reported as TEAEs	0 Participants

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

The PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collected 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. FoTA was defined as the last valid assessment obtained after baseline and while on IP (on or before 2 days after the last dose date).

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment FoTA: Overall quality of sleep - Very poor	0 Participants
Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment FoTA: Overall quality of sleep - Poor	4 Participants
Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment FoTA: Overall quality of sleep - Average	6 Participants
Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment FoTA: Overall quality of sleep - Good	11 Participants
Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment FoTA: Overall quality of sleep - Very Good	3 Participants

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

The PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collected 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 while on IP (on or before 2 days after the last dose date).

Outcome measures

Outcome measures
Measure	SHP465 n=14 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Length of Time Awake Per Night Assessed by PSQ at Final On-Treatment Assessment	10.1 minutes Standard Deviation 9.86

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

The PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collected 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 while on IP (on or before 2 days after the last dose date).

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Length of Time to Fall Asleep Per Night Assessed by PSQ at Final On-Treatment Assessment	19.8 minutes Standard Deviation 11.75

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product.

The PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collected 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 while on IP (on or before 2 days after the last dose date).

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Length of Time Sleeping Per Night Assessed by PSQ at Final On-Treatment Assessment	9.1 hours Standard Deviation 1.41

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety set consisted of all enrolled participants who had taken at least one dose of investigational product. FoTA was defined as the last valid assessment obtained after baseline and while on IP (on or before 2 days after the last dose date).

The CSHQ was a validated, retrospective, parent-reported sleep screening tool. The questionnaire consisted of 35 items that yield a TSD score, as well as 8 subscale scores, including bedtime resistance, sleep duration, parasomnias, sleep disordered breathing, night wakings, daytime sleepiness, sleep anxiety, and sleep onset delay. Each item receives a score from 1 (meaning the problem occurs rarely) to 3 (meaning the problem usually occurs); therefore, a higher score is the worse outcome. Scale ranges are as follows: Bedtime Resistance: 6 to 18, Sleep Onset Delay: 1 to 3, Sleep Duration: 3 to 9, Sleep Anxiety: 4 to 12, Night Wakings: 3 to 9, Parasomnias: 7 to 21, Disordered Breathing: 3 to 9, Daytime Sleepiness: 8 to 24, and Total Disturbance (items from all scales): 33 to 99. A negative value indicated less sleep disturbance.

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Total Sleep Disturbance Score	45.4 Units on scale Standard Deviation 8.21
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Bedtime Resistance	10.1 Units on scale Standard Deviation 3.71
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Sleep Onset Delay	1.4 Units on scale Standard Deviation 0.58
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Sleep Duration	4.3 Units on scale Standard Deviation 1.68
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Sleep Anxiety	6.2 Units on scale Standard Deviation 2.41
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Night Wakings	4.1 Units on scale Standard Deviation 0.90
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Parasomnias	8.9 Units on scale Standard Deviation 2.12
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Sleep Disordered Breathing	3.2 Units on scale Standard Deviation 0.82
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment FoTA: Daytime Sleepiness	10.6 Units on scale Standard Deviation 3.02

PRIMARY outcome

Timeframe: FoTA (up to Day 30)

Population: Safety Set consisted of all enrolled participants who had taken at least one dose of investigational product.

C-SSRS was a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts (suicidal ideation) and suicidal behaviors during the assessment period needed to be determine if a suicide-related thought or behavior were occurred. The assessment was done by the nature of the responses, not by a numbered scale. FoTA was defined as the last valid assessment obtained after baseline and while on IP (on or before 2 days after the last dose date).

Outcome measures

Outcome measures
Measure	SHP465 n=24 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Final On-Treatment Assessment Suicidal Ideation	0 Participants
Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Final On-Treatment Assessment Suicidal Behavior	0 Participants

SECONDARY outcome

Timeframe: Week 4: 12 hours (Day 8) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis

Observed analyte concentration of plasma d-amphetamine and plasma l-amphetamine at 12 hours after dose administration were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Observed Analyte Concentration at 12 Hours After Dose Administration (C12) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	24.59 ng/mL Geometric Coefficient of Variation 31.1
Observed Analyte Concentration at 12 Hours After Dose Administration (C12) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	8.059 ng/mL Geometric Coefficient of Variation 33.2

SECONDARY outcome

Timeframe: Week 4: 16 hours (Day 8) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis

Observed analyte concentration of plasma d-amphetamine and plasma l-amphetamine at 16 hours after dose administration were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Observed Analyte Concentration at 16 Hours After Dose Administration (C16) of Plasma d-Amphetamine and Plasma l- Amphetamine d-Amphetamine	20.53 ng/mL Geometric Coefficient of Variation 39.0
Observed Analyte Concentration at 16 Hours After Dose Administration (C16) of Plasma d-Amphetamine and Plasma l- Amphetamine l-Amphetamine	6.957 ng/mL Geometric Coefficient of Variation 40.7

SECONDARY outcome

Timeframe: Week 4: 24 hours (Day 8) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis

Observed analyte concentration of plasma d-amphetamine and plasma l-amphetamine at 24 hours after dose administration were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Observed Analyte Concentration at 24 Hours After Dose Administration (C24) of Plasma d-Amphetamine and Plasma l- Amphetamine d-Amphetamine	11.16 ng/mL Geometric Coefficient of Variation 28.5
Observed Analyte Concentration at 24 Hours After Dose Administration (C24) of Plasma d-Amphetamine and Plasma l- Amphetamine l-Amphetamine	4.186 ng/mL Geometric Coefficient of Variation 32.7

SECONDARY outcome

Timeframe: Week 4: 5, 8, 12 hours Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis

Area under the concentration-time curve from time five hours to twelve hours postdose (AUC5-12) in plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method.Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration-Time Curve From Time Five Hours to Twelve Hours Postdose (AUC5-12) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	195.2 hr*ng/mL Geometric Coefficient of Variation 32.6
Area Under the Concentration-Time Curve From Time Five Hours to Twelve Hours Postdose (AUC5-12) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	61.88 hr*ng/mL Geometric Coefficient of Variation 34.4

SECONDARY outcome

Timeframe: Week 4: 12, 16 hours Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Area under the concentration-time curve from time twelve hours to sixteen hours postdose (AUC12-16) in plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration-Time Curve From Time Twelve Hours to Sixteen Hours Postdose (AUC12-16) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	89.68 hr*ng/mL Geometric Coefficient of Variation 31.7
Area Under the Concentration-Time Curve From Time Twelve Hours to Sixteen Hours Postdose (AUC12-16) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	29.92 hr*ng/mL Geometric Coefficient of Variation 34.4

SECONDARY outcome

Timeframe: Week 4: 16, 24 hours (Day 8) Postdose on Day 7

Population: PK set consisted of all participants in the safety set for whom at least one PK blood sample was collected. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Sparse PK sampling group were excluded from the PK analysis.

Area under the concentration-time curve from time sixteen hours to twenty-four hours postdose (AUC16-24) in plasma d-amphetamine and plasma l-amphetamine were evaluated using rich sampling collection method. Values displayed do not necessarily reflect the actual precision obtained.

Outcome measures

Outcome measures
Measure	SHP465 n=11 Participants Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Area Under the Concentration-Time Curve From Time Sixteen Hours to Twenty-Four Hours Postdose (AUC16-24) of Plasma d-Amphetamine and Plasma l-Amphetamine d-Amphetamine	122.1 hr*ng/mL Geometric Coefficient of Variation 31.3
Area Under the Concentration-Time Curve From Time Sixteen Hours to Twenty-Four Hours Postdose (AUC16-24) of Plasma d-Amphetamine and Plasma l-Amphetamine l-Amphetamine	43.44 hr*ng/mL Geometric Coefficient of Variation 34.0

Adverse Events

SHP465

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	SHP465 n=24 participants at risk Participants aged 4-5 years received SHP465 capsule at a dose of 6.25 milligram (mg) orally once daily for 4 weeks.
Psychiatric disorders Affect lability	8.3% 2/24 • Number of events 2 • From start of study drug administration up to follow-up (up to 5 weeks)

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