| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Attention-Deficit/Hyperactive Disorder (ADHD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Attention-Deficit/Hyperactive Disorder (ADHD) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068451 |
| E.1.2 | Term | ADHD, combined type |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068453 |
| E.1.2 | Term | ADHD, predominantly inattentive type |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068452 |
| E.1.2 | Term | ADHD, predominantly hyperactive-impulsive type |
| E.1.2 | System Organ Class | 100000004873 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064104 |
| E.1.2 | Term | ADHD |
| E.1.2 | System Organ Class | 100000004873 |
|
| 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 efficacy outcome for each subject is treatment failure during the double-blind randomised-withdrawal phase (Phase 2). The primary efficacy analysis will compare treatment failure rates between treatments (SPD503 and placebo) for all subjects who enter Phase 2 using a Cochran-Mantel-Haenszel (CMH) test stratified by age group and country. Subjects who discontinue for any reason during the randomised-withdrawal phase will be classed as treatment failures for the primary analysis. The null hypothesis states that there is no difference in treatment failure rate between SPD503 and placebo, with the 2-sided alternative of a non-zero difference between groups. |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the long-term efficacy of SPD503 using the clinician administered Attention deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) total score.
2. To assess the long-term efficacy of SPD503 using the clinician administered Global Impressions- Severity of Illness Scale (CGI-S).
3. To assess the efficacy of SPD503 using the clinician administered Clinical Global Impressions Improvement Scale (CGI-I)
4. To evaluate efficacy on ADHD functional outcomes as measured by the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P).
5. To assess the impact of treatment on the perception of health state preferences using the Health Utilities Index-Mark 2 and Mark 3 (HUI-2/3).
6. To evaluate the long-term safety of SPD503 based on treatment-emergent adverse events (TEAEs), specific evaluation of blood pressure and pulse, clinical laboratory tests, electrocardiogram (ECG) results, and results from the Columbia-Suicide Severity Rating Scale (C-SSRS). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, aged 6 to 17 years at the time of consent/assent at Screening/Visit 1.
2. Subject meets Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision (DSM IV TR) criteria for a primary diagnosis of ADHD, combined sub-type, hyperactive/impulsive sub-type, or inattentive sub-type based on a detailed psychiatric evaluation using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime version (K-SADS-PL).
3. Subject has a minimum ADHD-RS-IV total score of 32 at Enrolment/Visit 2.
4. Subject has a minimum CGI-S score of 4 at Enrolment/Visit 2.
5. Subject is able to swallow intact tablets.
|
|
| E.4 | Principal exclusion criteria |
1. Subject has a current, controlled (requiring a prohibited medication or behavioural modification program) or uncontrolled, co-morbid psychiatric diagnosis, except Oppositional Defiant Disorder (ODD), including any severe comorbid Axis II disorders or severe Axis I disorders such as Post Traumatic Stress Disorder, bipolar illness, psychosis, pervasive developmental disorder, obsessive-compulsive disorder, substance abuse disorder, or other symptomatic manifestations or lifetime history of bipolar illness, psychosis, or conduct disorder that, in the opinion of the Investigator, contraindicate SPD503 treatment or confound efficacy or safety assessments.
2. Subject is well-controlled on their current ADHD medication with acceptable tolerability and the parent/caregiver does not object to the current ADHD medication.
3. Subject has a known history or presence of structural cardiac abnormalities, serious heart rhythm abnormalities, syncope, cardiac conduction problems (e.g., clinically significant heart block), exercise related cardiac events including syncope and pre-syncope, or clinically significant bradycardia.
4. Subject with orthostatic hypotension or a known history of controlled or uncontrolled hypertension.
5. Current use of any prohibited medication or other medications, including herbal supplements, that affect blood pressure (BP) or heart rate or that have central nervous system (CNS) effects or affect cognitive performance, such as sedating antihistamines and decongestant sympathomimetics (inhaled bronchodilators are permitted) or a history of chronic use of sedating medications (i.e., antihistamines) in violation of the protocol specified washout criteria at Enrolment/Visit 2.
6. Subject is significantly overweight based on Centre for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts. Significantly overweight is defined as a BMI >95th percentile.
7. Children aged 6-12 years with a body weight of <25.0kg or adolescents aged 13-17 years with a body weight of <34.0kg or >91.0kg at Screening/Visit 1.
8. Subject has a history of alcohol or other substance abuse or dependence, as defined by DSM IV TR (with the exception of nicotine) within the last 6 months.
9. Subject 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. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator (see protocol for additional guidance).
10. History of failure to respond to an adequate trial of an alpha2-agonist for the treatment of ADHD (consisting of an appropriate dose and adequate duration of therapy in the opinion of the Investigator).
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy outcome for each subject is treatment failure during the double-blind randomised-withdrawal phase (Phase 2), defined as a >/=50% increase (worsening) in ADHD RS-IV total score at 2 consecutive Phase 2 visits (Visits 14-23/ Early Termination) relative to Visit 13 and a >/=2 point increase in CGI-S score relative to CGI-S at Visit 13 at the corresponding Phase 2 visits. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 2 consecutive Phase 2 visits (Visits 14-23/ Early Termination) |
|
| E.5.2 | Secondary end point(s) |
Time to treatment failure during the double-blind randomised-withdrawal phase (days) is a key secondary endpoint.
Other secondary endpoints are ADHD-RS-IV total scores, CGI-S scores, CGI-I scores, HUI-2/3, and WFIRS-P results.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At Phase 2 visits (Visits 14-23/ Early Termination) |
|
| 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 | No |
| 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 |
| Open label dose optimisation/maintenance phase followed by randomised withdrawal. |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of trial is defined as the safety follow-up visit, i.e. 7 days post last dose of IMP, for the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 20 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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