Trial Outcomes & Findings for Safety and Tolerability Study of SPD489 in Preschool Children Aged 4-5 Years, Diagnosed With Attention-deficit/Hyperactivity Disorder (NCT NCT02466386)

Last Updated: 2021-03-05

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

113 participants

Primary outcome timeframe

From start of study drug administration up to follow-up (Week 53)

Results posted on

2021-03-05

Participant Flow

This study was conducted at 32 sites in United States of America from 21 August 2015 (first participant first visit) to 03 January 2020 (last participant last visit).

A total of 113 participants were enrolled and received the treatment. Out of which 69 participants completed the study. Since information from antecedent studies was exploratory in nature and was not really pivotal to the key conclusions of this study, only overall participant data was planned, analyzed and reported to avoid double-counting.

Participant milestones

Participant milestones
Measure	SPD489 Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Overall Study STARTED	113
Overall Study COMPLETED	69
Overall Study NOT COMPLETED	44

Reasons for withdrawal

Reasons for withdrawal
Measure	SPD489 Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Overall Study Adverse Event	5
Overall Study Protocol Violation	2
Overall Study Withdrawal by Subject	14
Overall Study Lost to Follow-up	5
Overall Study Lack of Efficacy	8
Overall Study Other	10

Baseline Characteristics

Safety and Tolerability Study of SPD489 in Preschool Children Aged 4-5 Years, Diagnosed With Attention-deficit/Hyperactivity Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SPD489 n=113 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Age, Continuous	4.8 Years STANDARD_DEVIATION 0.63 • n=5 Participants
Sex: Female, Male Female	33 Participants n=5 Participants
Sex: Female, Male Male	80 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	101 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 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	42 Participants n=5 Participants
Race (NIH/OMB) White	63 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to follow-up (Week 53)

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

Outcome measures

Outcome measures
Measure	SPD489 n=113 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	86 Participants

PRIMARY outcome

Timeframe: Week 52/ET

Population: Safety analysis set consisted of all participants who took at least 1 dose of investigational product. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure at the specific categories.

Sleep patterns included sleep diary data and children's sleep habits questionnaire (CSHQ), which was parent report questionnaire 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 child's sleep based on behavior within 8 different sub scales: bedtime resistance, sleep-onset delay, sleep duration, sleep anxiety, night wakings, 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, and daytime sleepiness: 8 to 24.

Outcome measures

Outcome measures
Measure	SPD489 n=102 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Bedtime Resistance: Week 52/ET	8.9 Score on scale Standard Deviation 3.04
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Sleep-onset Delay: Week 52/ET	1.6 Score on scale Standard Deviation 0.67
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Sleep Duration: Week 52/ET	3.8 Score on scale Standard Deviation 1.26
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Sleep Anxiety: Week 52/ET	5.5 Score on scale Standard Deviation 2.09
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Night Wakings: Week 52/ET	4.2 Score on scale Standard Deviation 1.59
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Parasomnias: Week 52/ET	8.6 Score on scale Standard Deviation 1.54
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Sleep-disordered Breathing: Week 52/ET	3.4 Score on scale Standard Deviation 0.74
Change From Baseline in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire (CSHQ) at Week 52/ Early Termination (ET) Daytime Sleepiness: Week 52/ET	10.1 Score on scale Standard Deviation 3.78

PRIMARY outcome

Timeframe: Week 52/ET

12-lead ECG was evaluated and recorded. ECG variables included heart rate, PR interval, QRS interval, QT interval, and corrected QT interval (QTc). The QTc was calculated using both Bazett (QTcB=QT/\[RR\]1/2) and Fridericia (QTcF=QT/\[RR\]1/3) corrections. Here, \> = represents "greater than or equal to", \< represents "lesser than" and \> represents "greater than".

Outcome measures

Outcome measures
Measure	SPD489 n=99 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) Heart Rate (< 55 Beats per minute)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) Heart Rate (> 130 Beats per minute)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) PR Interval (>= 200 millisecond [msec])	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QRS Interval (>= 90 msec)	3 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QT Interval (> = 440 msec)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QTcB Interval (> = 440 msec and < 480 msec)	5 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QTcB Interval (>= 480 msec and < 500 msec)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QTcB Interval (>= 500 msec)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QTcF Interval (> = 440 msec and < 480 msec)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QTcF Interval (>= 480 msec and < 500 msec)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) QTcF Interval (>= 500 msec)	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) ECG Interpretation	0 Participants
Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters at Week 52/ Early Termination (ET) ECG Abnormality - Rhythm	0 Participants

PRIMARY outcome

Timeframe: Week 52/ET

C-SSRS was semi-structured interview that captured the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview included definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behavior occurred. The C-SSRS contained 2 required items pertaining to suicidal ideation, 4 required items pertaining to suicidal behavior, and 1 required item pertaining to non-suicidal but self-injurious behavior. In situations where there was a positive response to the screening questions, there were 8 additional suicidal ideation items and 4 additional suicidal behavior items which were completed. Thus, there was a maximum of 19 items to be completed. Here number of participants responded as yes to suicidal ideation or behaviour were reported.

Outcome measures

Outcome measures
Measure	SPD489 n=112 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Number of Participants With a Positive Response Using Columbia Suicide Severity Rating Scale (C-SSRS) at Week 52/ Early Termination (ET)	0 Participants

PRIMARY outcome

Timeframe: Week 52/ET

Clinical laboratory evaluations included biochemistry and endocrinology, hematology, and urinalysis. Number of participants with potentially clinically significant changes in clinical laboratory values were reported.

Outcome measures

Outcome measures
Measure	SPD489 n=104 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Eosinophils/Leukocytes: Greater than (>)10%	12 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Hematocrit: Less than (<) 0.3	2 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Leukocytes: <3 × 10^9/Liter (L)	1 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Leukocytes: >16 × 10^9/L	1 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Lymphocytes/leukocytes: >70%	1 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Neutrophils: <1 × 10^9/L	1 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Neutrophils/leukocytes: <30%	15 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Hematology: Platelets: <75 × 10^9/L	1 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Biochemistry and Endocrinology: Glucose: <3.05 Millimole per liter (mmol/L)	2 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Biochemistry and Endocrinology: Glucose: >8.88 mmol/L	2 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Biochemistry and Endocrinology: Potassium: >5.5 mmol/L	1 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Biochemistry and Endocrinology: Protein: >90 gram per liter (g/L)	1 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Biochemistry and Endocrinology: Thyrotropin: < Lower limit of normal (LLN)	7 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Urinalysis: Ketones: Positive value (excluding trace)	15 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Urinalysis: Occult blood: Positive value (excluding trace)	2 Participants
Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values at Week 52/ Early Termination (ET) Urinalysis: Protein: Positive value (excluding trace)	30 Participants

PRIMARY outcome

Timeframe: Week 52/ET

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

Vital sign assessments included blood pressure, pulse and respiratory rate. Number of participants with potentially clinically significant changes in vital signs were reported.

Outcome measures

Outcome measures
Measure	SPD489 n=113 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Number of Participants With Potentially Clinically Significant Changes in Vital Signs at Week 52/ Early Termination (ET)	0 Participants

PRIMARY outcome

Timeframe: Week 52/ET

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

BMI was derived from height and weight. BMI was normalized by sex and age using the CDC growth charts. BMI percentiles were categorized as: Underweight (BMI \< 5th percentile); Healthy weight (BMI 5th percentile up to \< 85th percentile); Overweight (BMI 85th percentile \< 95th percentile); Obese (BMI \>= 95th percentile). Number of participants with shift from baseline in BMI percentile categories at Week 52/ET was reported.

Outcome measures

Outcome measures
Measure	SPD489 n=113 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Number of Participants With Shift From Baseline in Body Mass Index (BMI) Percentiles at Week 52/Early Termination (ET) Underweight: Week 52/ET	8 Participants
Number of Participants With Shift From Baseline in Body Mass Index (BMI) Percentiles at Week 52/Early Termination (ET) Healthy Weight: Week 52/ET	78 Participants
Number of Participants With Shift From Baseline in Body Mass Index (BMI) Percentiles at Week 52/Early Termination (ET) Overweight: Week 52/ET	12 Participants
Number of Participants With Shift From Baseline in Body Mass Index (BMI) Percentiles at Week 52/Early Termination (ET) Obese: Week 52/ET	3 Participants

SECONDARY outcome

Timeframe: Week 52/ET

Population: Full analysis set consisted of all participants in the safety analysis set who took at least 1 post-dose ADHD-RS-IV Preschool Version Total Score assessment during the study. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

CGI-I was an overall assessment of global symptom improvement by evaluation of the participant's condition severity and improvement over time. Scoring was done based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), where higher score reported worse condition. The scoring was elaborated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.

Outcome measures

Outcome measures
Measure	SPD489 n=87 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Clinical Global Impressions Global Improvement (CGI-I) at Week 52/ Early Termination (ET)	2.0 Score on a scale Standard Deviation 0.91

SECONDARY outcome

Timeframe: Week 52/ET

ADHD-RS-IV Preschool Version was adapted from the ADHD Rating Scale-IV and provided examples appropriate for the developmental level of preschool children. The ADHD-RS-IV Preschool Version was an 18-item questionnaire that required the respondent to rate the frequency of occurrence of ADHD symptoms as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria. Each item was 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 were grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17).

Outcome measures

Outcome measures
Measure	SPD489 n=87 Participants Participants received 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Change From Baseline in Clinician-Administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Preschool Version Total Score at Week 52/ Early Termination (ET)	-24.2 Score on a scale Standard Deviation 13.34

Adverse Events

Total

Serious events: 0 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Total n=113 participants at risk Participants received 5 mg of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Gastrointestinal disorders Vomiting	5.3% 6/113 • Number of events 7 • From start of study drug administration up to follow-up (Week 53)
General disorders Pyrexia	9.7% 11/113 • Number of events 12 • From start of study drug administration up to follow-up (Week 53)
Infections and infestations Influenza	8.8% 10/113 • Number of events 10 • From start of study drug administration up to follow-up (Week 53)
Infections and infestations Nasopharyngitis	7.1% 8/113 • Number of events 11 • From start of study drug administration up to follow-up (Week 53)
Infections and infestations Pharyngitis streptococcal	8.0% 9/113 • Number of events 11 • From start of study drug administration up to follow-up (Week 53)
Infections and infestations Upper respiratory tract infection	7.1% 8/113 • Number of events 15 • From start of study drug administration up to follow-up (Week 53)
Investigations Weight decreased	6.2% 7/113 • Number of events 7 • From start of study drug administration up to follow-up (Week 53)
Metabolism and nutrition disorders Decreased appetite	15.9% 18/113 • Number of events 21 • From start of study drug administration up to follow-up (Week 53)
Psychiatric disorders Affect lability	6.2% 7/113 • Number of events 8 • From start of study drug administration up to follow-up (Week 53)
Psychiatric disorders Initial insomnia	5.3% 6/113 • Number of events 7 • From start of study drug administration up to follow-up (Week 53)
Respiratory, thoracic and mediastinal disorders Cough	6.2% 7/113 • Number of events 14 • From start of study drug administration up to follow-up (Week 53)

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