| 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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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064104 |
| E.1.2 | Term | ADHD |
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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 efficacy of LDX administered as a daily morning dose (30, 50, and 70mg/day) compared to placebo over the course of seven weeks. The study will enrol children and adolescents (6-17 years of age inclusive) diagnosed with moderately symptomatic ADHD.
The primary measure of efficacy will be the clinician-administered ADHD rating scale IV (ADHD RS IV).
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| E.2.2 | Secondary objectives of the trial |
The key secondary objective is to assess the efficacy of LDX compared to placebo using a global clinical measure of improvement, the Clinical Global Impressions – Global Improvement (CGI-I).
The other secondary objectives are:
1. To assess LDX compared to placebo using the Conners’ Parent Rating Scale – Revised
2. To assess LDX compared to placebo using the Health Utilities Index – Mark 2 (HUI-2) and the Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP CE:PRF), respectively.
3. To assess the relationship of change in the core symptoms of ADHD with the changes in functional outcomes, as assessed by the Weiss Functional Impairment Rating Scale Parent (WFIRS-P), in subjects treated with LDX compared to placebo.
4. To evaluate the safety of LDX based on occurrence of TEAE’s, BP and pulse, ECG results, clinical laboratory test results and physical examination findings.
5. To assess the safety and efficacy of CONCERTA XL compared to placebo.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The subject cannot be randomised before all inclusion criteria (including test results) are confirmed.
Subjects meeting all of the criteria listed below will be included in the study.
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.
4. Subject must meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD based on a detailed psychiatric evaluation.
5. Subject must have a Baseline ADHD-RS-IV total score greater than or equal to 28.
6. Subject, who is a female of child-bearing potential (FOCP), must have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to comply with any applicable contraceptive requirements of the protocol
7. Subject has blood pressure measurements within the 95th percentile for age, gender, and height at Screening and Baseline.
8. Subject is functioning at an age-appropriate level intellectually, as deemed by the study investigator.
9. Subject is able to swallow a capsule.
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| E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria are met at Screening or at Baseline (if reassessed).
1. Subject has failed to respond to more than one adequate course (dose and duration) of stimulant therapy. One course must have been a long-acting formulation.
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, anorexia nervosa, 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 CONCERTA XL or confound efficacy or safety assessments. Comorbid psychiatric diagnoses will be established 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. Subjects may continue participating in behavioural therapy during this study as long as they have been receiving the therapy for at least 1 month at the time of the Baseline Visit.
3. Subject has a conduct disorder. Oppositional defiant disorder (ODD) is not exclusionary.
4. Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition that might confound the results of safety assessments conducted in the study or that might increase risk to the subject. Similarly, the subject will be excluded if he or she has any additional condition(s) that, in the Investigator’s opinion, would prohibit the subject from completing the study or would not be in the best interest of the subject. The additional condition(s) would include any significant illness or unstable medical condition that could lead to difficulty complying with the protocol. Mild, stable asthma is not exclusionary.
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 weighs less than 22.7kg (50lbs).
9. Subject is significantly overweight based on Centre for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts at Screening. Significantly overweight is defined as a BMI >97th percentile for this study.
10. Subject has a positive urine drug result at Screening (with the exception of subject’s current ADHD therapy).
11. Subject has current abnormal thyroid function, defined as abnormal thyroid stimulating hormone (TSH) at Screening. Treatment with a stable dose of thyroid medication for at least 3 months is permitted.
12. Subject has any clinically significant electrocardiogram (ECG) or laboratory abnormalities at Screening and/or Baseline.
13. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or methylphenidate.
14. Subject has a documented allergy, hypersensitivity, or intolerance to any excipients in the test or reference products.
15. Subject has a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine) in accordance with DSM-IV-TR criteria.
16. Subject has a history of seizures (other than infantile febrile seizures), a tic disorder, or a current diagnosis and/or a known family history of Tourette’s Disorder.
17. 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.
18. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
19. Subject is taking any medication that is excluded.
20. 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 test or reference product administration). Stable use of bronchodilator inhalers is not exclusionary.
21. Subject is well controlled on their current ADHD medication with acceptable tolerability.
22. Subject has taken another investigational product or taken part in a clinical trial within 30 days prior to Screening.
23. Subject has a pre-existing severe gastrointestinal tract narrowing (pathologic or iatrogenic).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for this study is defined as the change from Baseline score of the ADHD RS IV total score at Endpoint, defined as the last post-randomisation treatment week (up to Visit 7/ET) at which a valid ADHD-RS-IV total score is observed.
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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 | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 4 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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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| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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