A Phase 4 study to Assess the Safety and Efficacy of Guanfacine Hydrochloride Prolonged release (SPD503) in Children and Adolescents aged 6 to 17 Years with ADHD

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04]

Trial duration

20 Nov 2019 → 2 Sep 2025

Decision date (initial)

2023-05-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2022-502630-71-00

EudraCT number

2018-000821-29

ClinicalTrials.gov

NCT04085172

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

-The primary safety objective of this study is to evaluate the comparative long-term safety of TAK-503 (formerly known as SPD503) treatment 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 evaluate TAK-503 compared with atomoxetine after 12 months of once daily (QD) treatment on psychomotor speed and attention as measured by the Cambridge automated neuropsychological test battery (CANTAB) reaction time (RTI) task, using the mixed-effects model for repeated measures (MMRM). The effect of TAK-503 on cognition will be assessed and interpreted on the totality of the data.

Secondary objectives 9

1. Secondary safety objectives: Cognitive domain, sustained attention as measured by the CANTAB Rapid Visual Information Processing (RVP) task
2. Cognitive domain, Spatial Working Memory (SWM), a component of EF, as measured by CANTAB SWM task between errors
3. Cognitive domain, response control/inhibition as measured by the CANTAB Stop Signal Task (SST)
4. Cognition domain, recognition memory as measured by the CANTAB Delayed Matching to Sample (DMS) task
5. Sexual maturation as measured by Tanner stage
6. Growth as measured by weight, height, and body mass index (BMI)
7. Incidence of treatment-emergent adverse events (TEAEs)
8. Vital sign and electrocardiogram (ECG) results
9. 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

Conditions and MedDRA coding

Attention-deficit/hyperactivity disorder (ADHD)

Study design 10 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to ais qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitmetn?commitmen=5). These IPDs will be provided in a secure research environment following approval of a data request, and under the terms of the data sharing agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Part A: 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) 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 within 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.
12. Part B: Female subjects of child-bearing potential must have a negative serum β-hCG pregnancy test if a screening visit is conducted and/or a negative urine 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.
13. Subject has a supine and standing BP measurement within the 95th percentile for age, sex, and height.

Exclusion criteria 23

1. Part A: 1. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, comorbid psychiatric disorder (except oppositional defiant XML File Identifier: vAaVBCyckZCLfd3o3k7JrBRTHw8= Page 44/57 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. 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. 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. 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. 5. Subject has been physically, sexually, and/or emotionally abused.
6. 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. 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. 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. 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. 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. 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. 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. 13. Subject has clinically significant ECG findings, as judged by the investigator, at baseline (Visit 2A).
14. 14. Subject has orthostatic hypotension or a known history of hypertension.
15. 15. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
16. 16. Subject is currently using any medication that violates protocolspecified 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. 17. Subject has a medical condition except ADHD that requires treatment with any medication that affects the CNS.
18. 18. Subject is female and pregnant or currently lactating.
19. 19. Subject has taken another investigational product or participated in a clinical study within 30 days before screening (Visit 1A).
20. 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.
21. Part B: 1. Subject failed screening, voluntarily withdrew, or was discontinued from Study Part A for protocol nonadherence, subject noncompliance, or TEAE or SAE.
22. 2. Subject had any clinically significant TEAE during Study Part A that, as judged by the investigator, would preclude exposure to TAK-503.
23. 3. Subject has a clinically important abnormality on the urine drug and/or alcohol screen at screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary safety endpoint will be the change from baseline in the CANTAB RTI task.

Secondary endpoints 11

1. Secondary safety endpoints: -CANTAB tasks: RVP, SWM between errors, DMS, and SST
2. Tanner stage, weight, height, BMI
3. Vital signs (BP and pulse) and ECG results
4. BPRS-C total score and scales for Depression, Anxiety, Psychomotor Excitation, Behavior Problems, Withdrawal, Thinking Disturbance, and Organicity
5. C-SSRS
6. Specified UKU side effect rating scale items: Asthenia/Lassitude/Increased Fatigability, Sleepiness/Sedation, Increased Duration of Sleep, and Orthostatic Dizziness
7. PDSS
8. Secondary efficacy endpoints: -ADHD-RS-5 total score and subscale scores for hyperactivity/impulsivity and inattention domains
9. CGI-I, calculated from CGI-S
10. CHIP-CE:PRF
11. C3PS Total Score and scores for Learning Problems and Executive Functioning subscales

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 5

Placebo 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Steven Johnson

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Steven Johnson

Third parties 6

Locations

5 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 100 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications