| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Attention Deficit / Hyperactivity Disorder (ADHD) |
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| E.1.1.1 | Medical condition in easily understood language |
| Attention Deficit / Hyperactivity Disorder (ADHD) |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064104 |
| E.1.2 | Term | ADHD |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX), using a composite endpoint based on the Attention Deficit/Hyperactivity Disorder (ADHD) Rating Scale – IV (ADHD-RS-IV) and Clinical Global Impressions – Severity of Illness (CGI-S) rating scale, via a randomised withdrawal design in children and adolescents diagnosed with moderately symptomatic ADHD. Children and adolescents will be treated with LDX (30, 50, or 70mg/day) for at least 6 months prior to entering a 6-week double-blind randomised (LDX or placebo) withdrawal period.
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| E.2.2 | Secondary objectives of the trial |
1. To assess secondary efficacy outcomes, including efficacy of LDX through the open-label maintenance period, using ADHD-RS-IV and the Clinical Global Impressions – Global Improvement (CGI-I).
2. To assess impact of LDX on the perception of health state preferences, quality of life, and relationship between changes in the core symptoms of ADHD and changes in functional outcomes, using the Health Utilities Index – Mark 2 (HUI-2), the Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF), and the Weiss Functional Impairment Rating Scale – Parent (WFIRS-P), respectively.
3. To evaluate long-term safety of LDX based on occurrence of treatment-emergent adverse events, specific evaluation of blood pressure and pulse, electrocardiogram results, clinical lab test results, and physical examination.
4. To monitor subject safety based on responses to the Brief Psychiatric Rating Scale for Children (BPRS-C) and the Columbia-Suicide Severity Rating Scale (C-SSRS).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject’s parent or legally authorised representative (LAR) must provide signature of informed consent, and there must be documentation of assent (if applicable) by the subject indicating that the subject is aware of the investigational nature of the study and the required procedures and restrictions in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 and applicable regulations before completing any study-related procedures.
2. Subject and parent/LAR are willing and able to comply with all the testing and requirements defined in this protocol, including oversight of morning dosing. Specifically, the parent/LAR must be available upon awakening, at approximately 7:00AM, to dispense the dose of study drug for the duration of the study.
3. Subject is a male or female aged 6-17 years inclusive at the time of consent for the antecedent study (SPD489-325).
4. Subject satisfied all entry criteria for the antecedent study (SPD489-325), and completed a minimum of 4 weeks of double-blind treatment, reached Visit 4 and completed the 1-week post-treatment washout in the antecedent study (SPD489-325), without experiencing any clinically significant AEs that would preclude exposure to LDX.
5. Subject must have a satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by medical history, physical examination findings, and clinical laboratory test results.
6. Subject has blood pressure measurements within the 95th percentile for age, gender, and height.
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| E.4 | Principal exclusion criteria |
1. Subject was terminated from SPD489-325 for non-compliance and/or experienced an SAE or AE resulting in termination from the antecedent study.
2. Subject has a current, controlled (requiring a restricted medication) or uncontrolled, comorbid psychiatric diagnosis with significant symptoms such as any severe comorbid Axis II disorder or severe Axis I disorder (such as post traumatic stress disorder, psychosis, bipolar illness, pervasive developmental disorder, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder) or other symptomatic manifestations, such as agitated states, marked anxiety, or tension that, in the opinion of the examining clinician, will contraindicate treatment with LDX or confound efficacy or safety assessments. Comorbid psychiatric diagnoses will be established at the Screening Visit (Visit -1) of the antecedent study (SPD489-325) with the screening interview of the Kiddie-SADS-Present and Lifetime – Diagnostic Interview (K SADS-PL) and additional modules if warranted by the results of the initial interview. Participation in behavioural therapy is permitted provided the subject was receiving the therapy for at least 1 month at the time of the Baseline Visit (Visit 0) of the antecedent study (SPD489-325).
3. Subject has a conduct disorder. Oppositional defiant disorder is not exclusionary.
4. Subject has any concurrent chronic or acute illness or unstable medical condition that could confound the results of safety assessments, increase risk to the subject or lead to difficulty complying with the protocol.
5. Subject is currently considered a suicide risk, has previously made a suicide attempt or has a prior history of, or is currently, demonstrating active suicidal ideation.
6. Subject is female and is pregnant or lactating.
7. Subject has glaucoma.
8. Subject has any clinically significant ECG at Visit 8 of the antecedent study (SPD489-325) or clinically significant laboratory abnormalities at Visit 7 of the antecedent study (SPD489-325).
9. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine.
10. Subject has a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine) in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision (DSM-IV-TR) ï€ criteria.
11. Subject has a history of seizures (other than infantile febrile seizures), a chronic or current tic disorder, a current diagnosis and/or a known family history of Tourette’s Disorder. Subject has a history of tics judged by the Investigator to be exclusionary.
12. Subject has a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
13. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
14. Subject is taking any medication that is excluded.
15. Subject is taking other medications that have central nervous system (CNS) effects, affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are monoamine oxidase inhibitors (during or within 14 days of investigational medicinal product administration). Stable use of bronchodilator inhalers is not exclusionary.
16. Subject has a documented allergy, hypersensitivity, or intolerance to any excipients in the investigational medicinal product(s).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for each subject is treatment failure at the end of the Randomised Withdrawal Period, defined as a 50% increase (worsening) in ADHD-RS-IV score and a greater than or equal to 2 point increase in CGI-S score at any double blind visit relative to the respective score at Visit 3R. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The change from Baseline (Visit 0 of the antecedent study, SPD489-325) of the ADHD-RS-IV at each applicable visit
• The CGI-I at each applicable visit
• The HUI-2, CHIP-CE:PRF, and WFIRS-P at each applicable visit
The long-term safety of LDX will be assessed based on TEAEs, vital signs, clinical laboratory test results, physical examination findings, and ECG measurements.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The change from Baseline (Visit 0 of the antecedent study, SPD489-325) of the ADHD-RS-IV at each applicable visit
• The CGI-I at each applicable visit (visit 7 or 8)
• The HUI-2, CHIP-CE:PRF, and WFIRS-P at each applicable visit (visit 1)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Extension of the antecedent study, SPD489-325 |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The date the final subject was examined or date the data for primary outcome was collected from the final subject’. This is Visit 9R. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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