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

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ClinicalTrials.gov Identifier: NCT03327402
Recruitment Status : Completed
First Posted : October 31, 2017
Last Update Posted : January 3, 2019
Sponsor:
Information provided by (Responsible Party):
Shire

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

Condition or disease Intervention/treatment Phase
Attention Deficit Hyperactivity Disorder (ADHD) Drug: SHP465 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 13, 2018
Actual Primary Completion Date : October 5, 2018
Actual Study Completion Date : October 5, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Amphetamine

Arm Intervention/treatment
Experimental: SHP465
Participants will receive SHP465 capsule at a dose of 6.25 mg, orally once daily for 4 weeks.
Drug: SHP465
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.




Primary Outcome Measures :
  1. Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Area under the plasma concentration versus time curve extrapolated to infinity of d- and l-amphetamine.

  2. Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Time Point (AUC0-t) of Sample Collection of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration of d- and l-amphetamine.

  3. Area Under the Plasma Concentration Versus Time Curve From Time Zero Predose to Five Hours Postdose (AUC0-5) of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Area under the plasma concentration versus time curve from time 0 predose to 5 hours postdose of d- and l-amphetamine.

  4. Area Under the Plasma Concentration Versus Time Curve From Time Five Hours to the Last Time Point (AUC5-t) of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Area under the plasma concentration versus time curve from time 5 hours to the time of last quantifiable concentration of d- and l-amphetamine.

  5. Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Area under the plasma concentration versus time curve from time of dosing to the last measurable concentration of d- and l-amphetamine.

  6. Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval (24 Hours) at Steady State (AUCtau) of d- and l-amphetamine in Plasma [ Time Frame: Weeks 1 to 4 ]
    Area under the plasma concentration versus time curve over the dosing interval (24 hours) at steady state of d- and l-amphetamine.

  7. Total Body Clearance (CL/F) for Extravascular Administration of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Apparent total clearance of the drug from plasma after oral administration.

  8. Maximum Concentration (Cmax) Occurring at the Time of Maximum Observed Concentration Sampled During a Dosing Interval of d- and l-amphetamine in Plasma [ Time Frame: Weeks 1 to 4 ]
    Maximum observed plasma concentration of d- and l-amphetamine.

  9. Trough Plasma Concentration Ctrough at Steady State of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Trough plasma concentration (pre-dose concentrations collected at steady state) of d- and l-amphetamine.

  10. Terminal Half-life (t1/2) of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Time required for the concentration of the drug to reach half of its original value.

  11. Time of Maximum Observed Plasma Concentration (Tmax) During Dosing Interval of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Time after administration of a drug when the maximum plasma concentration in the body is reached.

  12. Apparent Volume of Distribution (Vss/F) at Steady State of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    Apparent volume of distribution at steady state after non-intravenous administration.

  13. Apparent Volume of Distribution (Vz/F) Associated With the Terminal Slope Following Extravascular Administration [ Time Frame: Weeks 1 to 4 ]
    Volume of distribution associated with the terminal slope following extravascular administration.

  14. Terminal Rate Constant (Lambda z) of d- and l-amphetamine [ Time Frame: Weeks 1 to 4 ]
    First-order elimination rate constant associated with the terminal phase of elimination of d- and l-amphetamine.

  15. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Weeks 1 up to Week 5 ]
    An adverse event (AE) is 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. Any clinically significant deviations from baseline values which are deemed clinically significant in the opinion of the investigator are to be recorded as an AE. TEAEs are 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.

  16. Number of Participants With Clinically Significant Change in Vital Signs Reported as an Adverse Event [ Time Frame: Baseline up to Week 5 ]
    Vital signs include blood pressure, pulse, respiratory rate, and body temperature.

  17. Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as an Adverse Event [ Time Frame: Baseline up to Week 5 ]
    12-lead ECG will be performed. Any clinically significant change in ECG assessment will be reported as AE.

  18. Measurement of Height [ Time Frame: Baseline up to Week 4 ]
    Height (in centimeters or inches) will be measured using a stadiometer with the participant standing on a flat surface without shoes and with the chin parallel to the floor.

  19. Measurement of Weight [ Time Frame: Baseline up to Week 4 ]
    Weight (in kilograms or pounds) will be measured using a calibrated scale. Participant should be in light clothes and without shoes.

  20. Number of Participants With Clinically Significant Change in Clinical Laboratory Results Reported as an Adverse Event [ Time Frame: Baseline up to Week 5 ]
    Clinical laboratory (biochemistry, hematology and urinalysis) results out-of-range will be assessed and if they are clinically significant will be reported as AEs.

  21. Post Sleep Questionnaire (PSQ) [ Time Frame: Baseline up to Week 4 ]
    PSQ is a 7-item questionnaire that collects 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 is done by the nature of the responses, not by a numbered scale.

  22. Children's Sleep Habits Questionnaire (CSHQ) [ Time Frame: Baseline up to Week 4 ]
    CSHQ screens for the most common sleep problems. CSHQ consists of 33 items within 8 different subscales: bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing, and daytime sleepiness.

  23. Columbia-suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to Week 4 ]
    C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The assessment is done by the nature of the responses, not by a numbered scale.



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 5 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03327402


Locations
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United States, Arkansas
Preferred Research Partners
Little Rock, Arkansas, United States, 72211
United States, Florida
Clinical Neuroscience Solutions Inc
Orlando, Florida, United States, 32801
United States, Indiana
Qualmedica Research, LLC
Evansville, Indiana, United States, 47715
United States, Ohio
University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States, 44106
Ohio Pediatric Research Assn Inc
Dayton, Ohio, United States, 45414
Professional Psychiatric Services (PPS)
Mason, Ohio, United States, 45040
United States, South Carolina
Coastal Pediatric Associates
Mount Pleasant, South Carolina, United States, 29464
United States, Tennessee
Clinical Neuroscience Solutions Inc
Memphis, Tennessee, United States, 38119
Sponsors and Collaborators
Shire
Investigators
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Study Director: Shire Director Shire

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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT03327402     History of Changes
Other Study ID Numbers: SHP465-112
First Posted: October 31, 2017    Key Record Dates
Last Update Posted: January 3, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shire:
SHP465
ADHD
Hyperactivity

Additional relevant MeSH terms:
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Amphetamine
Disease
Attention Deficit Disorder with Hyperactivity
Hyperkinesis
Pathologic Processes
Attention Deficit and Disruptive Behavior Disorders
Neurodevelopmental Disorders
Mental Disorders
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Central Nervous System Stimulants
Physiological Effects of Drugs
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Uptake Inhibitors