Clinical trial NCT03327402: Safety, Tolerability and Pharmacokinetics of SHP465 in Children Aged 4 to 5 Years With Attention-Deficit/Hyperactivity Disorder (ADHD)
Official title: A Phase 1 Open-label Study of the Safety, Tolerability, and Pharmacokinetics of d- and l-Amphetamine After Multiple Daily Doses of SHP465 6.25 mg Administered in Children Aged 4 to 5 Years With Attention-Deficit/Hyperactivity Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Keywords: SHP465
ADHD
Hyperactivity
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2017-10-31
Enrollment: 24
Sex: ALL
Minimum age (years): 4
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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


Eligibility criteria: 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:

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.

Primary outcomes:
measure: 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)
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Trough Plasma Drug Concentration Ctrough at Steady State (Ctrough,ss) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Predose on Day 1 and Day 28 and at 24 hours (Day 29) postdose on Day 28
measure: Time to Reach Maximum Observed Plasma Drug Concentration (Tmax) During Dosing Interval of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: 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
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Area Under the Concentration-Time Curve From Time Zero Predose to Five Hours Postdose (AUC0-5) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: Predose, 2, 5 hours Postdose on Day 7
measure: Area Under the Concentration Time Curve From Time Five Hours to the Last Timepoint (AUC5-t) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Area Under the Concentration-Time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: 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
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Terminal Rate Constant (Lambda z) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Total Body Clearance (CL/F) for Extravascular Administration of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Terminal Half-life (t1/2) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Apparent Volume of Distribution (Vss/F) at Steady State of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: Predose, 2, 5, 8, 12, 16, 24 hours (Day 8), 48 hours (Day 9) Postdose on Day 7
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From start of study drug administration up to follow-up (up to 5 weeks)
measure: Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs
timeFrame: From start of study drug administration up to follow-up (up to 5 weeks)
measure: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as TEAEs
timeFrame: From start of study drug administration up to follow-up (up to 5 weeks)
measure: Change From Baseline in Height at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
measure: Change From Baseline in Weight at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
measure: Number of Participants With Clinically Significant Changes in Clinical Laboratory Results Reported as TEAEs
timeFrame: From start of study drug administration up to follow-up (up to 5 weeks)
measure: Number of Participants With Overall Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
measure: Length of Time Awake Per Night Assessed by PSQ at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
measure: Length of Time to Fall Asleep Per Night Assessed by PSQ at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
measure: Length of Time Sleeping Per Night Assessed by PSQ at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
measure: Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
measure: Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Final On-Treatment Assessment
timeFrame: FoTA (up to Day 30)
Secondary outcomes:
measure: Observed Analyte Concentration at 12 Hours After Dose Administration (C12) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: 12 hours (Day 8) Postdose on Day 7
measure: Observed Analyte Concentration at 16 Hours After Dose Administration (C16) of Plasma d-Amphetamine and Plasma l- Amphetamine
timeFrame: Week 4: 16 hours (Day 8) Postdose on Day 7
measure: Observed Analyte Concentration at 24 Hours After Dose Administration (C24) of Plasma d-Amphetamine and Plasma l- Amphetamine
timeFrame: Week 4: 24 hours (Day 8) Postdose on Day 7
measure: Area Under the Concentration-Time Curve From Time Five Hours to Twelve Hours Postdose (AUC5-12) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: 5, 8, 12 hours Postdose on Day 7
measure: Area Under the Concentration-Time Curve From Time Twelve Hours to Sixteen Hours Postdose (AUC12-16) of Plasma d-Amphetamine and Plasma l-Amphetamine
timeFrame: Week 4: 12, 16 hours Postdose on Day 7
measure: 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
timeFrame: Week 4: 16, 24 hours (Day 8) Postdose on Day 7
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Preferred Research Partners
state: Arkansas
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions Inc
state: Florida
city: Evansville
country: United States
facility: Qualmedica Research, LLC
state: Indiana
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Dayton
country: United States
facility: Ohio Pediatric Research Assn Inc
state: Ohio
city: Mason
country: United States
facility: Professional Psychiatric Services (PPS)
state: Ohio
city: Mount Pleasant
country: United States
facility: Coastal Pediatric Associates
state: South Carolina
city: Memphis
country: United States
facility: Clinical Neuroscience Solutions Inc
state: Tennessee
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.