Trial Outcomes & Findings for Safety, Tolerability, Pharmacokinetic, and Efficacy Study of SPD489 in Preschool Children With Attention-deficit/Hyperactivity Disorder (NCT NCT02402166)

Last Updated: 2021-06-08

Results Overview

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment-emergent if it had a start date on or after, or had a start date before but increased in severity after the first dose of investigational product.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

24 participants

Primary outcome timeframe

From start of study treatment up to safety follow-up (Week 9)

Results posted on

2021-06-08

Participant Flow

The study was conducted at seven sites in the United States between 15 Apr 2015 (first participant first visit) and 30 Jun 2016 (last participant last visit).

A total of 24 participants were enrolled and received at least one dose. Overall 19 participants completed the study.

Participant milestones

Participant milestones
Measure	SPD489 Participants received 5 milligram (mg) capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Overall Study STARTED	24
Overall Study COMPLETED	19
Overall Study NOT COMPLETED	5

Reasons for withdrawal

Reasons for withdrawal
Measure	SPD489 Participants received 5 milligram (mg) capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Overall Study Adverse Event	2
Overall Study Withdrawal by Subject	2
Overall Study Lost to Follow-up	1

Baseline Characteristics

Safety, Tolerability, Pharmacokinetic, and Efficacy Study of SPD489 in Preschool Children With Attention-deficit/Hyperactivity Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SPD489 n=24 Participants Participants received 5 milligram (mg) capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Age, Continuous	4.7 years STANDARD_DEVIATION 0.48 • n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants
Sex: Female, Male Male	18 Participants n=5 Participants

PRIMARY outcome

Timeframe: From start of study treatment up to safety follow-up (Week 9)

Population: Safety analysis set consisted of all participants who had taken at least 1 dose of investigational product. Reporting groups are defined by the dose taken prior to the onset of the TEAE (Treatment Emergent Adverse Event). Number of participants analysed (N) are specific to the reporting group at the specific dose level.

Outcome measures

Outcome measures
Measure	SPD489 5 mg n=24 Participants Participants received 5 mg capsule of SPD489 orally once daily from Week 1 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 10 mg n=23 Participants Participants received 10 mg capsule of SPD489 orally once daily from Week 2 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 15 mg n=18 Participants Participants received 15 mg capsule of SPD489 orally once daily from Week 3 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 20 mg n=12 Participants Participants received 20 mg capsule of SPD489 orally once daily from Week 4 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 30 mg n=10 Participants Participants received 30 mg capsule of SPD489 orally once daily from Week 5 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 n=24 Participants Participants received 5 mg capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) at the Specified Dose Level	10 Participants	11 Participants	7 Participants	6 Participants	6 Participants	19 Participants

PRIMARY outcome

Timeframe: Baseline, Week 8/ET

Population: Safety analysis set consisted of all participants who had taken at least 1 dose of investigational product. Here number of participant analysed for the each sub-scale is specified for this endpoint.

Children's Sleep Habits Questionnaire is a tool designed to screen the most common sleep problems in children, and consists of 33 items for scoring. The instrument evaluates the child's sleep based on behavior within 8 different subscales: bedtime resistance, sleep-onset delay, sleep duration, sleep anxiety, night walkings, parasomnias, sleep-disordered breathing, and daytime sleepiness. Each item receives a score from 1 (problem occurs rarely) to 3 (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 walkings: 3 to 9, parasomnias: 7 to 21, sleep-disordered breathing: 3 to 9, daytime sleepiness: 8 to 24, and total disturbance (items from all scales): 33 to 99.

Outcome measures

Outcome measures
Measure	SPD489 5 mg n=24 Participants Participants received 5 mg capsule of SPD489 orally once daily from Week 1 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 10 mg Participants received 10 mg capsule of SPD489 orally once daily from Week 2 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 15 mg Participants received 15 mg capsule of SPD489 orally once daily from Week 3 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 20 mg Participants received 20 mg capsule of SPD489 orally once daily from Week 4 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 30 mg Participants received 30 mg capsule of SPD489 orally once daily from Week 5 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 Participants received 5 mg capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Bedtime resistance	9.9 Units on a Scale Standard Deviation 3.58	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ End of Treatment (ET) : Bedtime resistance	9.5 Units on a Scale Standard Deviation 3.26	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Sleep-onset delay	1.9 Units on a Scale Standard Deviation 0.85	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ ET : Sleep-onset delay	1.8 Units on a Scale Standard Deviation 0.92	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Sleep duration	4.5 Units on a Scale Standard Deviation 1.56	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ET : Sleep duration	4.0 Units on a Scale Standard Deviation 1.27	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Sleep anxiety	6.6 Units on a Scale Standard Deviation 2.52	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ET : Sleep anxiety	5.5 Units on a Scale Standard Deviation 1.79	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Night walkings	5.0 Units on a Scale Standard Deviation 2.10	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ET : Night wakings	4.7 Units on a Scale Standard Deviation 2.00	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Parasomnias	9.7 Units on a Scale Standard Deviation 2.03	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ET : Parasomnias	8.5 Units on a Scale Standard Deviation 1.57	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Sleep-disordered breathing	3.3 Units on a Scale Standard Deviation 0.82	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ET : Sleep-disordered breathing	3.2 Units on a Scale Standard Deviation 0.66	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Baseline : Daytime sleepiness	12.1 Units on a Scale Standard Deviation 3.43	—	—	—	—	—
Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) Week 8/ET : Daytime sleepiness	10.0 Units on a Scale Standard Deviation 3.51	—	—	—	—	—

PRIMARY outcome

Timeframe: Baseline, Week 8/ET

Population: Safety analysis set consisted of all participants who had taken at least 1 dose of investigational product.

The C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors. 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 interview was initiated with 5 (yes/no) questions, presented in ascending order of severity, about suicidal ideation. The most severe type of ideation was rated for frequency, duration, controllability, deterrents, and reason. If the answer to the first 2 ideation questions was "yes," the clinician asked questions 3-5. Active suicidal ideation included any participant who answered "yes" to questions 2-5. If the answers to ideation questions 1 and 2 were "No," then the clinician proceeded to 5 (yes/no) questions that addressed suicidal behavior, which was categorized as actual attempt, interrupted attempt, aborted attempt, preparatory acts or behaviors, and completed suicide.

Outcome measures

Outcome measures
Measure	SPD489 5 mg n=24 Participants Participants received 5 mg capsule of SPD489 orally once daily from Week 1 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 10 mg Participants received 10 mg capsule of SPD489 orally once daily from Week 2 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 15 mg Participants received 15 mg capsule of SPD489 orally once daily from Week 3 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 20 mg Participants received 20 mg capsule of SPD489 orally once daily from Week 4 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 30 mg Participants received 30 mg capsule of SPD489 orally once daily from Week 5 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 Participants received 5 mg capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Number of Participants With Suicide Related Behavior Assessed by Columbia-Suicide Severity Rating Scale Questionnaire (C-SSRS)	1 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, FoTA

Population: Full analysis set consisted of all participants in the safety analysis set who had at least 1 post-dose ADHD-RS-IV Preschool Version total score assessment.

The ADHD-RS-IV Preschool Version is an 18-item questionnaire that requires the respondent to rate the frequency of occurrence of ADHD symptoms as defined by Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV-TR) criteria. Each item is scored on a 4-point scale ranging from 0 (never or rarely) to 3 (very often) with total scores ranging from 0-54. The 18 items may be grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17). Data presented here was analysed at Final on-Treatment Assessment (FoTA).

Outcome measures

Outcome measures
Measure	SPD489 5 mg n=24 Participants Participants received 5 mg capsule of SPD489 orally once daily from Week 1 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 10 mg Participants received 10 mg capsule of SPD489 orally once daily from Week 2 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 15 mg Participants received 15 mg capsule of SPD489 orally once daily from Week 3 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 20 mg Participants received 20 mg capsule of SPD489 orally once daily from Week 4 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 30 mg Participants received 30 mg capsule of SPD489 orally once daily from Week 5 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 Participants received 5 mg capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Change From Baseline in Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Preschool Version Total Score at FoTA (Final on Treatment Assessment) Baseline	43.6 Units on a Scale Standard Deviation 5.54	—	—	—	—	—
Change From Baseline in Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Preschool Version Total Score at FoTA (Final on Treatment Assessment) FoTA	-26.1 Units on a Scale Standard Deviation 14.37	—	—	—	—	—

SECONDARY outcome

Timeframe: FoTA

Population: Full analysis set consisted of all participants in the safety analysis set who had at least 1 post-dose ADHD-RS-IV Preschool Version total score assessment.

CGI-I was performed to rate the severity of a participant's condition on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse). Data presented here was analysed at Final on-Treatment Assessment (FoTA). Improved is defined as a score of "very much improved" or "much improved".

Outcome measures

Outcome measures
Measure	SPD489 5 mg n=24 Participants Participants received 5 mg capsule of SPD489 orally once daily from Week 1 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 10 mg Participants received 10 mg capsule of SPD489 orally once daily from Week 2 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 15 mg Participants received 15 mg capsule of SPD489 orally once daily from Week 3 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 20 mg Participants received 20 mg capsule of SPD489 orally once daily from Week 4 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 30 mg Participants received 30 mg capsule of SPD489 orally once daily from Week 5 up to Week 8 based on the investigator's assessment of participants' response and tolerability.	SPD489 Participants received 5 mg capsule of SPD489 orally once daily and titrated up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 8 weeks.
Number of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I)	20 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Visit 7 [Dose Maintenance Phase] at pre-dose, and 1, 2, 3, 4, 6, and 8 h post-dose

Population: The PK set consisted all participants in the safety analysis set for whom the primary PK data were considered sufficient and interpretable. PK assessments were performed only during the Dose Maintenance Period (2 weeks) for SPD 489 10, 15 and 30 mg reporting groups.

AUC 0-last is the area under the concentration-time curve from time zero to the time of the last quantifiable concentration of SPD489 in plasma. Pharmacokinetic (PK) parameters were compared against the study NRP104-201 (NCT00557011) to observe and compare the effects of SPD489.