| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Attention-deficit/hyperactivity disorder (ADHD) |
|
| 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 | 23.0 |
| 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 safety objective of this study is to evaluate the comparative long-term safety of TAK-503 treatment (formerly known as SPD503) in children and adolescents aged 6 to 17 years diagnosed with ADHD for whom stimulants are not suitable, not tolerated, or shown to be ineffective:
- To demonstrate the noninferiority of TAK-503 compared with atomoxetine after 12 months of once daily (QD) treatment on psychomotor speed and attention as measured by the Cambridge automoated neuropsychological test battery (CANTAB) reaction time(RTI) task, provided assay sensitivity can be demonstrated. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary safety objectives:
- Cognitive domain, sustained attention as measured by the CANTAB Rapid Visual Information Processing (RVP) task
-Cognitive domain, Spatial Working Memory (SWM), a component of EF, as measured by the CANTAB SWM task between errors
-Cognitive domain, response control/inhibition as measured by the CANTAB Stop Signal Task (SST)
-Cognition domain, recognition memory as measured by the CANTAB Delayed Matching to Sample (DMS) task
-Sexual maturation as measured by Tanner stage
-Growth as measured by weight, height, and body mass index (BMI)
-Incidence of treatment-emergent adverse events (TEAEs)
-Vital sign and electrocardiogram (ECG) results
-Psychiatric symptoms as measured by the Brief Psychiatric Rating Scale for Children (BPRS-C) total score and factors for Depression, Anxiety, Psychomotor Excitation, Behavior Problems, Withdrawal, Thinking Disturbance, and Organicity
Please refer to protocol for further safety objectives and secondary efficacy objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
PART A
1. Subject is a male or female aged 6 to 17 years inclusive at the time of consent/assent.
2. Subject must meet DSM-5 criteria for a primary diagnosis of ADHD based on a detailed psychiatric evaluation using the Kiddie-Schedule for Affective Disorders-Present and Lifetime Version (K-SADSPL) by a trained child and adolescent psychiatrist at screening (Visit 1A).
3. Subject for whom prior stimulant therapy is not suitable, not tolerated, or shown to be ineffective as determined by investigator clinical assessment and review of the Prior Stimulant Medication Questionnaire (PSMQ) administered during screening (Visit 1A).
4. Subject has an ADHD-RS-5 total score ≥28 at baseline (Visit 2A).
5. Subject has a baseline (Visit 2A) CGI-S score ≥4.
6. Subject who is a female of childbearing potential (FOCP) and postmenarchal must have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening (Visit 1A) and a negative urine pregnancy test at baseline (Visit 2A), be nonlactating, and agree to comply with any applicable contraceptive requirements described in the protocol. Female of childbearing potential is defined as any female subject who is at least aged 9 years or younger than 9 years and postmenarchal.
7. Subject’s parent or legally authorized representative (LAR) must provide signature of informed consent. Documentation of assent (if applicable) must be provided 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 Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 and applicable regulations, before completing any study-related procedures.
8. 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 for the duration of the study to administer the IMP dose each morning when the subject awakens.
9. Subject has supine and standing blood pressure (BP) measurements less than the 95th percentile for age, sex, and height at both screening (Visit 1A) and baseline (Visit 2A).
10. Subject is functioning at an age-appropriate level intellectually, as judged by the investigator.
11. Subject is able to swallow intact tablets and capsules.
PART B
1.Female subjects of child-bearing potential must have a negative serum β-hCG pregnancy test at baseline and agree to comply with any applicable contraceptive requirements of the protocol. An FOCP is defined as any female subject who is at least aged 9 years or younger than 9 years and postmenarchal.
2.Subject has a supine and standing BP measurement less than the 95th percentile for age, sex, and height.
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|
| E.4 | Principal exclusion criteria |
PART A
1.Subject has a current, controlled (requiring medication or therapy) or uncontrolled, comorbid psychiatric disorder (except oppositional defiant disorder), including but not limited to any of the following comorbid Axis I and Axis II disorders (the K-SADS-PL should be reviewed to confirm diagnosis, if necessary):
a.Post-traumatic stress disorder (PTSD)
b.Bipolar illness, psychosis, or family history in either biological parent
c.Pervasive developmental disorder
d.Obsessive-compulsive disorder (OCD)
e.Psychosis/schizophrenia
f.Serious tic disorder or a family history of Tourette’s disorder
2.Subject is currently considered to be a suicide risk by the investigator; has made a previous suicide attempt; has a history of, or currently demonstrating, active suicidal ideation.
3.Subject has a substance abuse disorder as defined by DSM-5 criteria or has been suspected of a substance abuse or dependence disorder (except nicotine) within the past 6 months.
4.Subject has a clinically important abnormality on the urine drug and alcohol screen (except for the subject’s current ADHD stimulant, if applicable) at screening (Visit 1A).
5.Subject has been physically, sexually, and/or emotionally abused.
6.Subject has any other disorder that as judged by the investigator could contraindicate TAK-503 or confound the results of the safety and efficacy assessments.
7.Subject has any condition or illness including any clinically significant abnormal laboratory value at screening (Visit 1A) or, if the laboratory test was repeated, at baseline (Visit 2A) that, as judged by the investigator, would be an inappropriate risk to the subject and/or could confound the interpretation of study results.
8.Subject has current abnormal thyroid function, defined as abnormal thyroid-stimulating hormone and thyroxine at screening (Visit 1A). Treatment with a stable dose of thyroid medication for ≥3 months before screening will be permitted.
9.Subject has a known history or presence of: malignancy (except nonmelanoma skin cancer), pregnancy, and/or a developmental delay or abnormality associated with growth or sexual maturation delays that are not related to ADHD.
10.Children aged 6 to 12 years with a body weight <25.0 kg or adolescents aged ≥13 years with a body weight <34.0 kg at screening (Visit 1A) or baseline (Visit 2A).
11.Subject is significantly overweight based on the Centers for Disease Control (CDC) BMI-for-age sex-specific charts at screening (Visit 1A) or baseline (Visit 2A). For this study, significantly overweight will be defined as a BMI that is greater than the 95th percentile.
12.Subject has a known history or presence of: structural cardiac abnormalities, serious heart rhythm abnormalities, syncope, cardiac conduction problems (eg, clinically significant heart block or QT interval prolongation), bradycardia, or exercise-related cardiac events including syncope and presyncope.
13.Subject has clinically significant ECG findings, as judged by the investigator, at baseline (Visit 2A).
14.Subject has orthostatic hypotension* or a known history of hypertension.
(*Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 minutes of standing from supine.)
15.Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
16.Subject is currently using any medication that violates protocol-specified washout criteria at baseline (Visit 2A), including any ADHD medication or other prohibited medications such as herbal supplements, medications that affect BP or heart rate (HR) or medications 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 (ie, antihistamines).
17.Subject has a medical condition except ADHD that requires treatment with any medication that affects the CNS.
18.Subject is female and pregnant or currently lactating.
19.Subject has taken another investigational product or participated in a clinical study within 30 days before screening (Visit 1A).
20.Subject does not tolerate or has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to guanfacine hydrochloride, atomoxetine, or any TAK-503 or atomoxetine drug product component.
see protocol for further part A exclusion criteria
PART B
1.Subject failed screening, voluntarily withdrew, or was discontinued from Study Part A for protocol nonadherence, subject noncompliance, or TEAE or SAE.
2.Subject had any clinically significant TEAE during Study Part A that, as judged by the investigator, would preclude exposure to TAK-503.
3. Subject has a clinically important abnormality on the urine drug and/or alcohol screen at screening.
Please refer to protocol for further part B exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary safety endpoint will be the change from baseline in the CANTAB RTI task. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Various time points throughout the study |
|
| E.5.2 | Secondary end point(s) |
Secondary safety endpoints will include the following:
-CANTAB tasks: RVP, SWM between errors, DMS, and SST
-Tanner stage, weight, height, BMI
-Vital signs (BP and pulse) and ECG results
-BPRS-C total score and scales for Depression, Anxiety, Psychomotor Excitation, Behavior Problems, Withdrawal, Thinking Disturbance, and Organicity
-C-SSRS
-Specified UKU side effect rating scale items: Asthenia/Lassitude/Increased
Fatigability, Sleepiness/Sedation, Increased Duration of Sleep, and Orthostatic
Dizziness
-PDSS
Secondary efficacy endpoints will include the following:
-ADHD-RS-5 total score and subscale scores for hyperactivity/impulsivity and
inattention domains
-CGI-I, calculated from CGI-S
-CHIP-CE:PRF
-C3PS Total Score and scores for Learning Problems and Executive Functioning subscales |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Various time points throughout the study |
|
| 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 | No |
| 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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 34 |
| 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 |
| Austria |
| Sweden |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Belgium |
| Portugal |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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