A Phase 3 Study of Viloxazine ER Capsules in Korean Children and Adolescents With ADHD

A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter, Bridging Clinical Trial to Evaluate the Efficacy and Safety of Viloxazine Extended-Release (ER) Capsules (AK-D101) in Korean Children and Adolescents (6-17 Years of Age) With Attention-Deficit/Hyperactivity Disorder (ADHD)

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter bridging clinical trial designed to evaluate the efficacy and safety of viloxazine extended-release capsules (AK-D101) compared with placebo in Korean children and adolescents aged 6 to 17 years with attention-deficit/hyperactivity disorder (ADHD). Eligible participants will be randomized in a 1:1 ratio to receive AK-D101 or placebo once daily for 8 weeks. Randomization will be stratified by study site and age group (children aged 6 to 11 years and adolescents aged 12 to 17 years). The primary efficacy endpoint is the change from baseline to Week 8, End of Treatment, in the Korean ADHD Rating Scale, 5th Edition (K-ARS-5) Total Score.

This study is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 bridging clinical trial in Korean children and adolescents aged 6 to 17 years with ADHD. At Screening, written informed consent will be obtained from the participant's parent or legal representative, and assent will be obtained from the participant, as applicable, before any study-specific procedures are performed. Eligibility will be assessed at Screening and confirmed at Baseline.

Eligible participants will be stratified by study site and age group, defined as children aged 6 to 11 years and adolescents aged 12 to 17 years, and randomized in a 1:1 ratio to the AK-D101 group or placebo group through an Interactive Web Response System (IWRS). The study is double-blind; participants, investigators, site personnel, sponsor personnel, CRO personnel, and other personnel involved in study conduct or interpretation will remain blinded to treatment assignment.

Participants will receive the investigational product once daily in the morning for a total of 8 weeks. Treatment will start at 100 mg once daily. During the titration period of up to 3 weeks, the dose may be increased by 100 mg weekly at the investigator's discretion based on tolerability and response, up to a maximum dose of 400 mg once daily. At the end of titration, the maintenance dose will be determined as 200 mg, 300 mg, or 400 mg and will be continued for at least 5 weeks. To maintain blinding, placebo-treated participants will undergo mock titration using the same procedures.

Participants will visit the study site weekly from Visit 3 to Visit 6 for efficacy and safety assessments. Visits 7 and 9 will be conducted as phone-call visits to assess investigational product administration, concomitant medications or therapies, and adverse events. Visits 8, 10, and 11 will be on-site visits for efficacy and/or safety assessments. Visit 10 at Week 8/Day 56 is the End of Treatment visit. Visit 11 at Week 9/Day 63 is the End of Study visit for final safety follow-up. Participants who discontinue investigational product before completing the planned 56-day treatment period or withdraw early will undergo an Early Termination visit, with procedures corresponding to the End of Treatment visit, and will be followed until End of Study whenever feasible.

Pharmacokinetic assessments will be conducted in participants who consent to PK blood sampling. PK blood sampling will be performed at two blood sampling visits, Visit 3 and one of Visit 6, Visit 8, or Visit 10, according to the protocol-defined schedule.

Inclusion Criteria

1. Korean male or female subjects who are ≥6 and ≤17 years of age at the time of written informed consent.

2. Subjects with a primary diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), confirmed by the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) at Visit 1 (Screening).

3. Subjects with a Korean ADHD Rating Scale, 5th Edition (K-ARS-5) Total Score of ≥28 at Visit 1 (Screening) and Visit 2 (Baseline).

4. Subjects with a Clinical Global Impression-Severity (CGI-S) score of ≥4 at Visit 1 (Screening) and Visit 2 (Baseline).

5. Subjects who meet the following body weight criteria at Visit 1 (Screening):

   • 6 to 11 years of age: ≥20 kg.
   • 12 to 17 years of age: ≥35 kg.

6. Subjects who agree not to initiate or take any ADHD medication other than the investigational medicinal product during the study. Subjects who are taking ADHD medication at Visit 1 (Screening) but whose ADHD symptoms are not adequately controlled with their current ADHD medication, as demonstrated by meeting Inclusion Criterion 3, may participate if they meet all other inclusion/exclusion criteria and have discontinued ADHD medication at least 7 days before Visit 2 (Baseline).

7. Subjects considered suitable for participation in the clinical trial by the investigator based on clinical laboratory tests, vital signs, and ECG assessments, meeting all of the following criteria:

   • Clinical laboratory tests: Results are within the normal range or, if outside the normal range, are not considered clinically significant. However, eGFR must be ≥30 mL/min/1.73 m², AST and ALT must be <3 × upper limit of normal (ULN), and total bilirubin must be <2 × ULN.
   • Vital signs: Blood pressure, pulse rate, respiratory rate, and body temperature are within the normal range or, if outside the normal range, are not considered clinically significant.
   • 12-lead ECG: No clinically significant abnormal findings.

8. Subjects whose legally authorized representative(s), or parent(s), and the subject, as applicable, voluntarily agree to participate in this clinical trial and provide written informed consent/assent.

Exclusion Criteria:

1. Subjects who are currently taking viloxazine, who previously took viloxazine for the treatment of ADHD but discontinued it due to adverse reactions or lack of efficacy, or who have a history of allergic reaction, hypersensitivity*, or intolerance to viloxazine extended-release capsules or any of their excipients.

   *Hypersensitivity-related excipients: lactose, sucrose, Yellow No. 5 (Sunset Yellow FCF), and Yellow No. 203 (Quinoline Yellow WS).

2. Subjects who, at Screening according to the MINI-KID, are diagnosed with a psychiatric disorder other than ADHD as the primary diagnosis, or who have a comorbid psychiatric disorder secondary to ADHD that, in the opinion of the investigator, may interfere with treatment adherence to the investigational medicinal product or affect study results. However, subjects with a history of Major Depressive Disorder may be eligible if no episode has occurred within 6 months prior to the Screening visit.

3. Subjects with a history of diagnosis of significant central nervous system (CNS) disease or neuromuscular disease, including:

   • CNS diseases, such as brain tumors, inflammatory CNS diseases, epilepsy, or cerebrovascular diseases.
   • Neuromuscular diseases with childhood onset, such as Duchenne muscular dystrophy or myasthenia gravis.
   • History of seizures, seizure-like symptoms, such as syncope, myoclonus, or severe muscle spasms, family history of seizure disorders in first-degree relatives, parents or siblings, and/or febrile convulsions.
   • Other CNS or neuromuscular diseases that, in the investigator's medical judgment, may affect participation in the clinical trial.

4. Subjects with a history of diagnosis of medically significant systemic disease.

5. Subjects with a history of suicidal plan/intent, suicidal ideation, or one or more suicide attempts within 6 months prior to the Screening visit.

6. Subjects whose BMI exceeds the 95th percentile for age and sex at the Screening visit.

7. Subjects who have taken any of the following medications within the specified period prior to the first dose of investigational medicinal product at Visit 2 (Baseline):

   • Monoamine oxidase inhibitors (MAOIs) within 14 days prior to the randomization visit.
   • CYP1A2 substrate drugs, such as theophylline, melatonin, olanzapine, or duloxetine, within 7 days prior to the randomization visit.

8. Pregnant or breastfeeding females, or females of childbearing potential, defined as those with confirmed menarche, with a positive pregnancy test result at the Baseline visit.

9. Females of childbearing potential, defined as those with confirmed menarche, who do not agree to use adequate contraception during the study period and for 4 weeks after the last dose of the investigational medicinal product.

   (*) Adequate contraception includes sexual abstinence, hormonal contraceptives without known drug interactions, intrauterine hormone-releasing systems, such as a levonorgestrel intrauterine system (IUS), intrauterine devices (IUDs), and surgical sterilization, including bilateral tubal ligation, salpingectomy, and vasectomy. However, periodic abstinence methods, such as calendar, symptothermal, or post-ovulation methods, use of spermicides alone, lactational amenorrhea method, double barrier methods, simultaneous use of female and male condoms, and withdrawal are not considered acceptable contraception.

10. Subjects with food allergies, intolerances, dietary restrictions, or special diets that, in the investigator's judgment, may make the subject unsuitable for participation in this clinical trial.

11. Subjects who have received or used any other investigational medicinal product or medical device within 30 days prior to Visit 1 (Screening).

12. Subjects who are otherwise considered by the investigator to be unsuitable for participation in this clinical trial.