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CompletedNCT03327402Updated Jun 8, 2021Results posted

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

A Phase 1 interventional study of SHP465 in Attention Deficit Hyperactivity Disorder (ADHD), sponsored by Shire. Completed at 8 sites in United States. Open to participants aged 4 Years to 5 Years. Per ClinicalTrials.gov, last updated 2021-06-08.

Sponsored by Shire · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
24
Allocation
Not applicable
Ages
4 Years to 5 Years
Sex
All
01

Study summary

The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of SHP465 in children aged 4 to 5 years with ADHD after multiple daily doses of 6.25 milligram (mg) SHP465

02

Conditions studied

  • Attention Deficit Hyperactivity Disorder (ADHD)

Keywords

  • SHP465
  • ADHD
  • Hyperactivity
03

Who can participate

Ages eligible
4 Years to 5 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Male or female aged 4-5 years inclusive at the time of consent with a primary diagnosis of ADHD (any subtype) based on a detailed psychiatric evaluation using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) and has undergone nonpharmacological treatment or has a severe enough condition to consider enrollment without undergoing prior nonpharmacological treatment, based on the investigator's judgment or has never taken ADHD medication or has taken ADHD medication with unacceptable efficacy and/or tolerability.
  2. Participant's parent/legally authorized representative (LAR) must sign the informed consent form, and there must be documentation of assent (if applicable) and is willing and able to fully comply with all of the testing and requirements defined in the protocol.

  3. Participant during the screening period:

    i. Has a total score of ADHD-RS-5 >=28 for boys and >=24 for girls. ii. Has a Clinical Global Impressions-Severity of Illness (CGI-S) score >=4. iii.Functions at an age-appropriate level intellectually, as determined by the investigator.

  4. Participant has the ability to take investigational product by either swallowing the capsule whole or sprinkling the capsule contents in applesauce and ingesting the entire mixture immediately without chewing.
  5. Participant has lived with the same parent/LAR for at least 6 months.

Exclusion criteria

Exclusion Criteria:

  1. Prior enrollment or participation in the study.
  2. Documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product.
  3. Participant cannot swallow a pill and/or applesauce, or has an allergy to applesauce.
  4. Participant is currently taking or has taken ADHD medication with acceptable efficacy and tolerability.
  5. Participant has taken ADHD medication within 7 days prior to the administration of investigational product.

  6. Participant has used any medication (including over-the-counter, herbal, or homeopathic preparations) within 30 days prior to the administration of investigational product or 5 half-lives, whichever is longer, with the exception of the following:

    i. Thyroid medication ii. Intermittent use of nonsteroidal anti-inflammatory drugs or acetaminophen iii. As needed use of a beta-agonists inhaler for mild asthma or exercise induced bronchospasm iv. Over-the-counter nonsedating antihistamines for allergies. v. Participant has continuously used oral corticosteroids >=7 days in 3 months prior to investigational product dosing. If continuous use was less than (\<) 7 days, 1 month of washout prior to dosing of investigational product is required.

  7. Within 30 days prior to the administration of investigational product (IP):

    i. Participant has used an IP.

    1. If the elimination half-life of the previous study's IP was less than 6 days, then the last dose of the previous IP should be 30 days prior to the first dose of SHP465.
    2. If the elimination half-life of the previous study's IP was greater than 6 days, then the last dose of the previous IP should be 5 half-lives prior to the dose of SHP465.
  8. Glaucoma.
  9. Known family history of sudden cardiac death or ventricular arrhythmia.
  10. 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.
  11. Any clinically significant ECG or clinically significant laboratory abnormalities at the first screening visit based on the investigator's judgment. A single retest of laboratory parameters is allowed based on the investigator's judgment.
  12. Marfan's syndrome.
  13. Blood pressure >= 95th percentile for age, sex, and height at the screening visit.
  14. Height and weight \<= 5th percentile for age and sex at the first screening visit.
  15. Current abnormal thyroid function test results, defined as abnormal thyroid-stimulating hormone, thyroxine (T4), and tri-iodothyronine (T3) at the first screening visit. Treatment with a stable dose of thyroid medication for at least 3 months is permitted.
  16. History of seizures (other than infantile febrile seizures).
  17. Current, controlled (requiring medication or therapy) or uncontrolled, comorbid psychiatric disorder including but not limited to any of the following comorbid Axis I disorders and Axis II disorders.
  18. Currently considered a suicide risk in the opinion of the investigator, has previously made a suicide attempt, or has a prior history of or is currently demonstrating active suicidal ideation.
  19. History of physical, sexual, or emotional abuse.
  20. Primary sleep disorder (eg, sleep apnea, narcolepsy).
  21. Eating disorder.
04

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
24 participants (actual)

Study arms

  • Experimental
    SHP465

    Participants will receive SHP465 capsule at a dose of 6.25 mg, orally once daily for 4 weeks.

    Drug: SHP465

Interventions

  • DrugSHP465

    SHP465 capsule will be administered at a dose of 6.25 mg, orally once daily for 4 weeks. SHP465 is comprised of sulfate salts of dextroamphetamine and amphetamine, with dextroamphetamine saccharate and amphetamine aspartate monohydrate, which provide a composite enantiomer ratio of 3:1 d-amphetamine to l-amphetamine.

05

What researchers measure

Primary outcomes

  1. 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)

    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.

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

  2. Trough Plasma Drug Concentration Ctrough at Steady State (Ctrough,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  3. Time to Reach Maximum Observed Plasma Drug Concentration (Tmax) During Dosing Interval of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  4. 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

    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.

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

  5. Area Under the Concentration-Time Curve From Time Zero Predose to Five Hours Postdose (AUC0-5) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  6. Area Under the Concentration Time Curve From Time Five Hours to the Last Timepoint (AUC5-t) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  7. Area Under the Concentration-Time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  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

    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.

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

  9. Terminal Rate Constant (Lambda z) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  10. Total Body Clearance (CL/F) for Extravascular Administration of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  11. Terminal Half-life (t1/2) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  12. Apparent Volume of Distribution (Vss/F) at Steady State of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  13. 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 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.

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

  14. Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs

    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.

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

  15. Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as TEAEs

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

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

  16. Change From Baseline in Height at Final On-Treatment Assessment

    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).

    Time frame: FoTA (up to Day 30)

  17. Change From Baseline in Weight at Final On-Treatment Assessment

    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).

    Time frame: FoTA (up to Day 30)

  18. Number of Participants With Clinically Significant Changes in Clinical Laboratory Results Reported as TEAEs

    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.

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

  19. Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment

    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).

    Time frame: FoTA (up to Day 30)

  20. Length of Time Awake Per Night Assessed by PSQ at Final On-Treatment Assessment

    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).

    Time frame: FoTA (up to Day 30)

  21. Length of Time to Fall Asleep Per Night Assessed by PSQ at Final On-Treatment Assessment

    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).

    Time frame: FoTA (up to Day 30)

  22. Length of Time Sleeping Per Night Assessed by PSQ at Final On-Treatment Assessment

    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).

    Time frame: FoTA (up to Day 30)

  23. Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment

    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.

    Time frame: FoTA (up to Day 30)

  24. Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Final On-Treatment Assessment

    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).

    Time frame: FoTA (up to Day 30)

Secondary outcomes

  1. Observed Analyte Concentration at 12 Hours After Dose Administration (C12) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  2. Observed Analyte Concentration at 16 Hours After Dose Administration (C16) of Plasma d-Amphetamine and Plasma l- Amphetamine

    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.

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

  3. Observed Analyte Concentration at 24 Hours After Dose Administration (C24) of Plasma d-Amphetamine and Plasma l- Amphetamine

    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.

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

  4. Area Under the Concentration-Time Curve From Time Five Hours to Twelve Hours Postdose (AUC5-12) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

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

  5. Area Under the Concentration-Time Curve From Time Twelve Hours to Sixteen Hours Postdose (AUC12-16) of Plasma d-Amphetamine and Plasma l-Amphetamine

    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.

    Time frame: Week 4: 12, 16 hours Postdose on Day 7

  6. 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

    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.

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

06

Results

Posted Jan 29, 2020

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).

Participant flow — Overall Study
MilestoneSHP465
Started24
Rich pk sampling group12
Sparse pk sampling group12
Completed22
Not completed2
Withdrew: Withdrawal by subject1
Withdrew: Other (visit out-of-window)1

Outcome measures

PrimaryMaximum 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)

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · nanogram per milliliter (ng/mL)
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)
nanogram per milliliter (ng/mL)SHP465
d-Amphetamine31.37 ± 32.6
l-Amphetamine9.895 ± 34.7
PrimaryTrough Plasma Drug Concentration Ctrough at Steady State (Ctrough,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Predose on Day 1 and Day 28 and at 24 hours (Day 29) postdose on Day 28
Reported as:
Mean · ng/mL
Trough Plasma Drug Concentration Ctrough at Steady State (Ctrough,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine
ng/mLSHP465
d-Amphetamine7.934 ± 6.3077
l-Amphetamine3.092 ± 2.5253
PrimaryTime to Reach Maximum Observed Plasma Drug Concentration (Tmax) During Dosing Interval of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Median · hour
Time to Reach Maximum Observed Plasma Drug Concentration (Tmax) During Dosing Interval of Plasma d-Amphetamine and Plasma l-Amphetamine
hourSHP465
d-Amphetamine7.917 (5.00 to 16.3)
l-Amphetamine7.917 (5.00 to 16.3)
PrimaryArea 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

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · hour*nanogram per milliliter (hr*ng/mL)
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
hour*nanogram per milliliter (hr*ng/mL)SHP465
d-Amphetamine646.3 ± 27.5
l-Amphetamine222.1 ± 31.1
PrimaryArea Under the Concentration-Time Curve From Time Zero Predose to Five Hours Postdose (AUC0-5) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5 hours Postdose on Day 7
Reported as:
Geometric mean · hr*ng/mL
Area Under the Concentration-Time Curve From Time Zero Predose to Five Hours Postdose (AUC0-5) of Plasma d-Amphetamine and Plasma l-Amphetamine
hr*ng/mLSHP465
d-Amphetamine109.7 ± 36.1
l-Amphetamine34.53 ± 40.3
PrimaryArea Under the Concentration Time Curve From Time Five Hours to the Last Timepoint (AUC5-t) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · hr*ng/mL
Area Under the Concentration Time Curve From Time Five Hours to the Last Timepoint (AUC5-t) of Plasma d-Amphetamine and Plasma l-Amphetamine
hr*ng/mLSHP465
d-Amphetamine549.9 ± 30.3
l-Amphetamine194.1 ± 34.1
PrimaryArea Under the Concentration-Time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · hr*ng/mL
Area Under the Concentration-Time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Plasma d-Amphetamine and Plasma l-Amphetamine
hr*ng/mLSHP465
d-Amphetamine646.3 ± 27.5
l-Amphetamine222.1 ± 31.1
PrimaryArea Under the Concentration-Time Curve Over the Dosing Interval (24 Hours) at Steady State (AUCtau,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · hr*ng/mL
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
hr*ng/mLSHP465
d-Amphetamine520.6 ± 29.8
l-Amphetamine171.0 ± 32.9
PrimaryTerminal Rate Constant (Lambda z) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · per hour
Terminal Rate Constant (Lambda z) of Plasma d-Amphetamine and Plasma l-Amphetamine
per hourSHP465
d-Amphetamine0.06639 ± 15.5
l-Amphetamine0.05632 ± 15.3
PrimaryTotal Body Clearance (CL/F) for Extravascular Administration of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · Liter per hour (L/hr)
Total Body Clearance (CL/F) for Extravascular Administration of Plasma d-Amphetamine and Plasma l-Amphetamine
Liter per hour (L/hr)SHP465
d-Amphetamine5.618 ± 29.8
l-Amphetamine5.703 ± 32.9
PrimaryTerminal Half-life (t1/2) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Median · hour
Terminal Half-life (t1/2) of Plasma d-Amphetamine and Plasma l-Amphetamine
hourSHP465
d-Amphetamine9.911 (8.42 to 14.1)
l-Amphetamine12.16 (9.71 to 15.6)
PrimaryApparent Volume of Distribution (Vss/F) at Steady State of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
Reported as:
Geometric mean · liter
Apparent Volume of Distribution (Vss/F) at Steady State of Plasma d-Amphetamine and Plasma l-Amphetamine
literSHP465
d-Amphetamine90.09 ± 34.3
l-Amphetamine109.4 ± 35.6
PrimaryNumber 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 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.

Time frame:
From start of study drug administration up to follow-up (up to 5 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
ParticipantsSHP465
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)11
PrimaryNumber of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs

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.

Time frame:
From start of study drug administration up to follow-up (up to 5 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs
ParticipantsSHP465
Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs1
PrimaryNumber of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as TEAEs

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

Time frame:
From start of study drug administration up to follow-up (up to 5 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as TEAEs
ParticipantsSHP465
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as TEAEs0
PrimaryChange From Baseline in Height at Final On-Treatment Assessment

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).

Time frame:
FoTA (up to Day 30)
Reported as:
Mean · centimeter (cm)
Change From Baseline in Height at Final On-Treatment Assessment
centimeter (cm)SHP465
Change From Baseline in Height at Final On-Treatment Assessment1.601 ± 1.5073
PrimaryChange From Baseline in Weight at Final On-Treatment Assessment

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).

Time frame:
FoTA (up to Day 30)
Reported as:
Mean · kilogram (kg)
Change From Baseline in Weight at Final On-Treatment Assessment
kilogram (kg)SHP465
Change From Baseline in Weight at Final On-Treatment Assessment-0.305 ± 0.4268
PrimaryNumber of Participants With Clinically Significant Changes in Clinical Laboratory Results Reported as TEAEs

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.

Time frame:
From start of study drug administration up to follow-up (up to 5 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Changes in Clinical Laboratory Results Reported as TEAEs
ParticipantsSHP465
Number of Participants With Clinically Significant Changes in Clinical Laboratory Results Reported as TEAEs0
PrimaryNumber of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment

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).

Time frame:
FoTA (up to Day 30)
Reported as:
Count of participants · Participants
Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment
ParticipantsSHP465
FoTA: Overall quality of sleep - Very poor0
FoTA: Overall quality of sleep - Poor4
FoTA: Overall quality of sleep - Average6
FoTA: Overall quality of sleep - Good11
FoTA: Overall quality of sleep - Very Good3
PrimaryLength of Time Awake Per Night Assessed by PSQ at Final On-Treatment Assessment

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).

Time frame:
FoTA (up to Day 30)
Reported as:
Mean · minutes
Length of Time Awake Per Night Assessed by PSQ at Final On-Treatment Assessment
minutesSHP465
Length of Time Awake Per Night Assessed by PSQ at Final On-Treatment Assessment10.1 ± 9.86
PrimaryLength of Time to Fall Asleep Per Night Assessed by PSQ at Final On-Treatment Assessment

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).

Time frame:
FoTA (up to Day 30)
Reported as:
Mean · minutes
Length of Time to Fall Asleep Per Night Assessed by PSQ at Final On-Treatment Assessment
minutesSHP465
Length of Time to Fall Asleep Per Night Assessed by PSQ at Final On-Treatment Assessment19.8 ± 11.75
PrimaryLength of Time Sleeping Per Night Assessed by PSQ at Final On-Treatment Assessment

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).

Time frame:
FoTA (up to Day 30)
Reported as:
Mean · hours
Length of Time Sleeping Per Night Assessed by PSQ at Final On-Treatment Assessment
hoursSHP465
Length of Time Sleeping Per Night Assessed by PSQ at Final On-Treatment Assessment9.1 ± 1.41
PrimaryTotal Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment

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.

Time frame:
FoTA (up to Day 30)
Reported as:
Mean · Units on scale
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment
Units on scaleSHP465
FoTA: Total Sleep Disturbance Score45.4 ± 8.21
FoTA: Bedtime Resistance10.1 ± 3.71
FoTA: Sleep Onset Delay1.4 ± 0.58
FoTA: Sleep Duration4.3 ± 1.68
FoTA: Sleep Anxiety6.2 ± 2.41
FoTA: Night Wakings4.1 ± 0.90
FoTA: Parasomnias8.9 ± 2.12
FoTA: Sleep Disordered Breathing3.2 ± 0.82
FoTA: Daytime Sleepiness10.6 ± 3.02
PrimaryNumber of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Final On-Treatment Assessment

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).

Time frame:
FoTA (up to Day 30)
Reported as:
Count of participants · Participants
Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Final On-Treatment Assessment
ParticipantsSHP465
Suicidal Ideation0
Suicidal Behavior0
SecondaryObserved Analyte Concentration at 12 Hours After Dose Administration (C12) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: 12 hours (Day 8) Postdose on Day 7
Reported as:
Geometric mean · ng/mL
Observed Analyte Concentration at 12 Hours After Dose Administration (C12) of Plasma d-Amphetamine and Plasma l-Amphetamine
ng/mLSHP465
d-Amphetamine24.59 ± 31.1
l-Amphetamine8.059 ± 33.2
SecondaryObserved Analyte Concentration at 16 Hours After Dose Administration (C16) of Plasma d-Amphetamine and Plasma l- Amphetamine

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.

Time frame:
Week 4: 16 hours (Day 8) Postdose on Day 7
Reported as:
Geometric mean · ng/mL
Observed Analyte Concentration at 16 Hours After Dose Administration (C16) of Plasma d-Amphetamine and Plasma l- Amphetamine
ng/mLSHP465
d-Amphetamine20.53 ± 39.0
l-Amphetamine6.957 ± 40.7
SecondaryObserved Analyte Concentration at 24 Hours After Dose Administration (C24) of Plasma d-Amphetamine and Plasma l- Amphetamine

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.

Time frame:
Week 4: 24 hours (Day 8) Postdose on Day 7
Reported as:
Geometric mean · ng/mL
Observed Analyte Concentration at 24 Hours After Dose Administration (C24) of Plasma d-Amphetamine and Plasma l- Amphetamine
ng/mLSHP465
d-Amphetamine11.16 ± 28.5
l-Amphetamine4.186 ± 32.7
SecondaryArea Under the Concentration-Time Curve From Time Five Hours to Twelve Hours Postdose (AUC5-12) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: 5, 8, 12 hours Postdose on Day 7
Reported as:
Geometric mean · hr*ng/mL
Area Under the Concentration-Time Curve From Time Five Hours to Twelve Hours Postdose (AUC5-12) of Plasma d-Amphetamine and Plasma l-Amphetamine
hr*ng/mLSHP465
d-Amphetamine195.2 ± 32.6
l-Amphetamine61.88 ± 34.4
SecondaryArea Under the Concentration-Time Curve From Time Twelve Hours to Sixteen Hours Postdose (AUC12-16) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: 12, 16 hours Postdose on Day 7
Reported as:
Geometric mean · hr*ng/mL
Area Under the Concentration-Time Curve From Time Twelve Hours to Sixteen Hours Postdose (AUC12-16) of Plasma d-Amphetamine and Plasma l-Amphetamine
hr*ng/mLSHP465
d-Amphetamine89.68 ± 31.7
l-Amphetamine29.92 ± 34.4
SecondaryArea Under the Concentration-Time Curve From Time Sixteen Hours to Twenty-Four Hours Postdose (AUC16-24) of Plasma d-Amphetamine and Plasma l-Amphetamine

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.

Time frame:
Week 4: 16, 24 hours (Day 8) Postdose on Day 7
Reported as:
Geometric mean · hr*ng/mL
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
hr*ng/mLSHP465
d-Amphetamine122.1 ± 31.3
l-Amphetamine43.44 ± 34.0

Adverse events

Collected over From start of study drug administration up to follow-up (up to 5 weeks). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
SHP4650/24 (0%)0/24 (0%)2/24 (8.3%)
Most frequent other events
Most frequent other events
EventSHP465
Affect labilityPsychiatric disorders2/24

Baseline characteristics

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

Age, Continuous
Age, Continuous(Years)SHP465
Mean4.8 ± 0.41
Sex: Female, Male
Sex: Female, Male(Participants)SHP465
Female8
Male16
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)SHP465
Hispanic or Latino0
Not Hispanic or Latino24
Unknown or Not Reported0
Race (NIH/OMB)
Race (NIH/OMB)(Participants)SHP465
American Indian or Alaska Native0
Asian0
Native Hawaiian or Other Pacific Islander0
Black or African American12
White12
More than one race0
Unknown or Not Reported0
07

Study locations

8 sites
  • Preferred Research Partners
    Little Rock, Arkansas 72211, United States
  • Clinical Neuroscience Solutions Inc
    Orlando, Florida 32801, United States
  • Qualmedica Research, LLC
    Evansville, Indiana 47715, United States
  • University Hospitals Cleveland Medical Center
    Cleveland, Ohio 44106, United States
  • Ohio Pediatric Research Assn Inc
    Dayton, Ohio 45414, United States
  • Professional Psychiatric Services (PPS)
    Mason, Ohio 45040, United States
  • Coastal Pediatric Associates
    Mount Pleasant, South Carolina 29464, United States
  • Clinical Neuroscience Solutions Inc
    Memphis, Tennessee 38119, United States
08

References and documents

Publications

  • Ilic K, Kugler AR, Yan B, McNamara N. Pharmacokinetics, Safety, and Tolerability of SHP465 Mixed Amphetamine Salts After Administration of Multiple Daily Doses in Children Aged 4-5 Years with Attention-Deficit/Hyperactivity Disorder. CNS Drugs. 2022 Jan;36(1):71-81. doi: 10.1007/s40263-021-00870-5. Epub 2021 Nov 26. PubMed 34826114 ↗

Study documents

  • Study protocol · Sep 15, 2017
  • Statistical analysis plan · Apr 2, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting information: Study protocol, Sap, Icf, Csr

09

Registry details

Key details

Study ID
NCT03327402
Lead sponsor
Shire
Responsible party
Sponsor
First posted
Oct 31, 2017
Start date
Mar 13, 2018
Primary completion
Oct 5, 2018
Completion
Oct 5, 2018
Results posted
Jan 29, 2020
Last update
Jun 8, 2021

Study contacts

Study Director
study director · Takeda

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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