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Safety and Efficacy Study in Preschool Children Aged 4-5 Years With Attention-deficit/Hyperactivity Disorder (ADHD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03260205
Recruitment Status : Completed
First Posted : August 24, 2017
Results First Posted : January 18, 2020
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
Shire

Tracking Information
First Submitted Date  ICMJE August 9, 2017
First Posted Date  ICMJE August 24, 2017
Results First Submitted Date  ICMJE October 22, 2019
Results First Posted Date  ICMJE January 18, 2020
Last Update Posted Date January 18, 2020
Actual Study Start Date  ICMJE September 6, 2017
Actual Primary Completion Date October 23, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 8, 2020)
Change From Baseline in Clinician-Administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Preschool Version Total Score at Week 6 [ Time Frame: Baseline, Week 6 ]
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). Full analysis set (FAS) consisted of all participants in the safety analysis set who had at least 1 post-dose ADHD RS IV preschool version total score assessment.
Original Primary Outcome Measures  ICMJE
 (submitted: August 21, 2017)
Change From Baseline in Clinician-Administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Preschool Version Total Score at Week 6 [ Time Frame: Baseline, Week 6 ]
ADHD-RS-IV Preschool Version was adapted from the ADHD Rating Scale-IV and provides examples appropriate for the developmental level of preschool children. The ADHD-RS-IV Preschool Version is an 18-item questionnaire that requires the respondent to rate the frequency of occurrence of ADHD symptoms as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria. Each item is scored on a 4-point scale ranging from 0 (never or rarely) to 3 (very often) with total scores ranging from 0-54. The 18 items may be grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2020)
  • Clinical Global Impressions Global Improvement (CGI-I) at Week 6 [ Time Frame: Week 6 ]
    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. FAS consisted of all participants in the safety analysis set who had at least 1 post-dose ADHD RS IV preschool version total score assessment.
  • Dose Response Relationship for Change From Baseline in ADHD-RS-IV Preschool Version Total Score in Preschool Children at Week 6 [ Time Frame: Baseline, Week 6 ]
    Dose response relationship was evaluated by using the ADHD-RS Preschool Version Total Score. 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 requires 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). Dose response analysis set consisted of all participants in the safety analysis set who had at least 1 valid primary efficacy measurement on the randomized target dose level of the investigational product.
  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug administration up to follow-up (Week 7) ]
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a investigational product (IP) and that does not necessarily had a causal relationship with this treatment. TEAEs were defined as AEs that start or deteriorate on or after the date of the first dose of IP and no later than 3 days following the last dose of IP.
  • Number of Participants With Potentially Clinically Significant Changes in Vital Signs [ Time Frame: Week 6 ]
    Vital sign assessments included blood pressure (systolic and diastolic), average pulse rate. Number of participants with potentially clinically significant changes in vital signs were reported. mmHg represents millimetre of mercury in the outcome measure data.
  • Change From Baseline in Height at Week 6 [ Time Frame: Baseline, Week 6 ]
    Height was measured in inche without shoes, with the participant stood on a flat surface and with chin parallel to the floor.
  • Change From Baseline in Body Weight at Week 6 [ Time Frame: Baseline, Week 6 ]
    Body weight was measured in percentile without shoes. Body weight percentile was normalized by sex and age using the Centers for Disease Control and Prevention (CDC) growth charts. Body weight percentiles were categorized as lesser than (<) 5th, 5th to < 95th, and greater than or equal to (>=) 95th percentiles. Change from baseline in body weight at Week 6 was reported.
  • Change From Baseline in Body Mass Index (BMI) at Week 6 [ Time Frame: Baseline, Week 6 ]
    BMI was derived from height and weight. BMI percentile 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). Change from baseline in body mass index at Week 6 was reported.
  • Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values [ Time Frame: Week 6 ]
    Clinical laboratory evaluations included biochemistry and endocrinology, hematology, and urinalysis. Number of participants with potentially clinically significant changes in clinical laboratory values were reported. ULN in measure data represents upper limit of normal, mcmol/L represents to Micromoles Per Litre, > = represents greater than or equal to.
  • Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters [ Time Frame: Week 6 ]
    Number of participants with potentially clinically significant changes in ECG parameters were reported. QTcF interval represents QT Fridericia's Correction Formula interval, QTcB interval represents QTc corrected by Bazett's in measure data.
  • Children's Sleep Habits Questionnaire (CSHQ) at Week 6 [ Time Frame: Week 6 ]
    Children's Sleep Habits Questionnaire was a tool designed to screen the most common sleep problems in children, and consisted of 33 items for scoring. The instrument evaluated the child's sleep based on behavior within 8 different subscales: bedtime resistance, sleep-onset delay, sleep duration, sleep anxiety, night walkings, parasomnias, sleep-disordered breathing, and daytime sleepiness. Each item receives a score from 1 (problem occurs rarely) to 3 (problem usually occurs); therefore, a higher score is the worse outcome. Scale ranges are as follows: bedtime resistance: 6 to 18, sleep onset delay: 1 to 3, sleep duration: 3 to 9, sleep anxiety: 4 to 12, night walkings: 3 to 9, parasomnias: 7 to 21, sleep-disordered breathing: 3 to 9, daytime sleepiness: 8 to 24, and total disturbance (items from all scales): 33 to 99.
  • Number of Participants With a Positive Response Using Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Up to Week 6 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2017)
  • Clinical Global Impression- Global Improvement (CGI-I) Scale [ Time Frame: Week 6 ]
    CGI-I provides an overall assessment of global symptom improvement. It is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).
  • Dose Response Relationship in Preschool Children with Attention-deficit/Hyperactivity Disorder (ADHD) [ Time Frame: Week 6 ]
    Dose response relationship will be evaluated by using the ADHD-RS Preschool Version Total Score. ADHD-RS-IV Preschool Version was adapted from the ADHD Rating Scale-IV and provides examples appropriate for the developmental level of preschool children. The ADHD-RS-IV Preschool Version is an 18-item questionnaire that requires the respondent to rate the frequency of occurrence of ADHD symptoms as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria. Each item is scored on a 4-point scale ranging from 0 (never or rarely) to 3 (very often) with total scores ranging from 0-54. The 18 items may be grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17).
  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From start of study treatment up to 10 days after the last dose of investigational drug ]
    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. 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.
  • Number of Participants With Vital Sign Abnormalities Reported as Adverse Events (AEs) [ Time Frame: From start of study treatment up to 10 days after the last dose of investigational drug ]
    Vital sign assessments will include blood pressure, pulse and respiratory rate. Vital sign abnormalities are recorded and reported as AE. An 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.
  • Measurement of Height [ Time Frame: From start of study treatment, Week 6 ]
    Height should be measured in inches or centimeters without shoes with the participant standing on a flat surface and with chin parallel to the floor..
  • Measurement of Body Weight [ Time Frame: From start of study treatment up to Week 6 ]
    Weight should be measured in pounds or kilograms without shoes.
  • Number of Participants With Clinical Laboratory Abnormalities Reported as Adverse Events (AEs) [ Time Frame: From start of study treatment up to 10 days after the last dose of investigational drug ]
    Clinical laboratory evaluations include biochemistry and endocrinology, hematology, and urinalysis. Clinical laboratory abnormalities will be recorded and reported as AE. An 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.
  • Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Adverse Events (AEs) [ Time Frame: From start of study treatment up to 10 days after the last dose of investigational drug ]
    12-lead ECG will be recorded and measured with the participant in rested supine position for 5 minutes. ECG abnormalities will be recorded and reported as AE. An 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.
  • Children's Sleep Habits Questionnaire (CSHQ) [ Time Frame: Baseline up to Week 6 ]
    Children's Sleep Habits Questionnaire (CSHQ) is a parent report questionnaire designed to screen for the most common sleep problems in children, and consists 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 subscales: bedtime resistance, sleep-onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep-disordered breathing, and daytime sleepiness.
  • Columbia-Suicide Severity Rating Scale [ Time Frame: From start of study treatment up to Week 6 ]
    Columbia-Suicide Severity Rating Scale (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 interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behavior occurred. The C-SSRS contains 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 is a positive response to the screening questions, there are 8 additional suicidal ideation items and 4 additional suicidal behavior items which are completed. Thus, there is a maximum of 19 items to be completed. The assessment is done by the nature of the responses, not by a numbered scale.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study in Preschool Children Aged 4-5 Years With Attention-deficit/Hyperactivity Disorder (ADHD)
Official Title  ICMJE A Phase 3, Randomized, Double-blind, Multicenter, Parallel-group, Placebo-controlled, Fixed-Dose Safety and Efficacy Study of SPD489 Compared With Placebo in Preschool Children Aged 4-5 Years With Attention-deficit/Hyperactivity Disorder
Brief Summary The purpose of this study is to determine if an investigational treatment is effective in improving the total score on the ADHD-RS-IV Preschool Version in children 4-5 years old diagnosed with ADHD.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Attention Deficit Hyperactivity Disorder (ADHD)
Intervention  ICMJE
  • Drug: Placebo
    Placebo matching to SPD489 (Lisdexamfetamine dimesylate) capsule for 6 weeks.
  • Drug: SPD489 (Lisdexamfetamine dimesylate)
    SPD489 capsule in a 5:5:5:5:6 ratio to 5, 10, 20, 30 mg orally once daily for 6 weeks.
  • Drug: SPD489
    SPD489
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Participant will receive placebo matching to SPD489 (Lisdexamfetamine dimesylate) capsule for 6 weeks.
    Intervention: Drug: Placebo
  • Experimental: SPD489 (Lisdexamfetamine dimesylate)
    Participants will be randomized to receive SPD489 capsule in a 5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 milligram (mg) orally once daily for 6 weeks. Dosing will begin with the lowest strength of SPD489 (5 mg), and will be titrated until the randomly assigned fixed-dose is reached.
    Interventions:
    • Drug: SPD489 (Lisdexamfetamine dimesylate)
    • Drug: SPD489
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 25, 2019)
199
Original Estimated Enrollment  ICMJE
 (submitted: August 21, 2017)
195
Actual Study Completion Date  ICMJE October 23, 2018
Actual Primary Completion Date October 23, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participant is a male or female aged 4-5 years inclusive at the time of consent
  • Participant's parent(s) or legally authorized representative (LAR) must provide signature of informed consent, and there must be documentation of assent (if applicable) by the participant before completing any study related procedures.
  • Participant and parent(s)/LAR are willing and able to comply with all of the testing and requirements defined in the protocol, including oversight of morning dosing.
  • Participant must meet DSM-IV-TR criteria for a primary diagnosis of ADHD (any sub-type).
  • Participant has an ADHD-RS-IV Preschool Version Total Score at the baseline visit (Visit 0) greater than or equal to 28 for boys, and greater than or equal to 24 for girls.
  • Participant has a Clinical Global Impressions - Severity of Illness (CGI-S) score greater than or equal to 4 at the baseline visit (Visit 0).
  • Participant has a Peabody Picture Vocabulary Test standard score of greater than or equal to 70 at the screening visit (Visit -1).
  • Participant has undergone an adequate course of non-pharmacological treatment or has a severe enough condition to consider enrollment without undergoing prior non-pharmacological treatment.
  • Participant has participated in a structured group activity (e.g, preschool, sports, Sunday school) so as to assess symptoms and impairment in a setting outside the home.
  • Participant has lived with the same parent(s) or guardian for greater than or equal to 6 months.

Exclusion Criteria:

  • Participant is required to or anticipates the need to take any prohibited medications or medications that have central nervous system (CNS) effects or have an effect on performance. Stable use of bronchodilator inhalers is not exclusionary.
  • Participant has taken another investigational product or has taken part in a clinical study within 30 days prior to the screening visit (Visit -1).
  • Participant is well-controlled on his/her current ADHD medication with acceptable tolerability.
  • Participant has a concurrent chronic or acute illness, disability, or other condition that might confound the results of safety assessments or may increase risk to the participant..
  • Participant has glaucoma.
  • Participant has failed to fully respond to an adequate course of amphetamine therapy.
  • Participant has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product.
  • Participant has a known family history of sudden cardiac death or ventricular arrhythmia.
  • Participant has a blood pressure measurement greater than or equal to 95th percentile for age, sex, and height at the screening visit (Visit -1) or the baseline visit (Visit 0) or history of moderate or severe hypertension.
  • Participant has a known history of symptomatic cardiovascular disease, unexplained syncope, exertional chest pain,advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems.
  • Participant has any clinically significant clinical laboratory abnormalities at the screening visit (Visit -1) or electrocardiogram (ECG) at screening visit (Visit-1) or baseline visit (Visit 0) based on investigator judgment.
  • Participant has current abnormal thyroid function, defined as abnormal thyroid stimulating hormone (TSH) and thyroxine (T4) at the screening visit (Visit -1). Treatment with a stable dose of thyroid medication for at least 3 months is permitted.
  • Participant has a current, controlled (requiring medication or therapy) or uncontrolled, co-morbid psychiatric disorder including but not limited to any of the below co-morbid Axis I disorders and Axis II disorders:

    i. post-traumatic stress disorder or adjustment disorder ii. bipolar illness, psychosis, or a family history of these disorders iii. pervasive developmental disorder iv. obsessive-compulsive disorder (OCD) v. psychosis/schizophrenia vi. a serious tic disorder, or a family history of Tourette's disorder vii. Participant is 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.

viii. a history of physical, sexual, or emotional abuse ix. any other disorder or agitated state that in the opinion of the investigator, contraindicates SPD489 or lisdexamfetamine dimesylate treatment or confound efficacy or safety assessments.

  • Participant has initiated behavioral therapy within 1 month of the baseline visit (Visit 0). Participant may not initiate behavioral therapy during the study.
  • Participant has a height less than equal to (<=) 5th percentile for age and sex at the screening visit (Visit -1).
  • Participant has a weight <= 5th percentile for age and sex at the screening visit (Visit -1).
  • Participant lives with anyone who currently abuses stimulants or cocaine.
  • Participant has a history of seizures (other than infantile febrile seizures).
  • Participant is taking any medication that is excluded per the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Years to 5 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03260205
Other Study ID Numbers  ICMJE SPD489-347
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers
Responsible Party Shire
Study Sponsor  ICMJE Shire
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Shire
PRS Account Shire
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP