A MULTICENTER, DOUBLE-BLIND, RANDOMIZED STUDY TO EVALUATE THE EFFECTS OF TASIMELTEON VS. PLACEBO IN TREATING PEDIATRIC INSOMNIA

The primary objective is to evaluate the efficacy of tasimelteon administered daily compared to placebo on sleep latency in participants, as measured by daily diary. This endpoint is clinically relevant as sleep latency represents a core manifestation of insomnia disorder in the pediatric population and its reduction is associated with improved sleep initiation and overall sleep architecture.

The secondary objectives include:

• Evaluation of tasimelteon efficacy on nighttime subjective sleep parameters including sleep quality, wake time, and total sleep time as measured by daily sleep diary, as well as assessment using Patient Global Impression of Change scale (PGI-C) and Clinical Global Impression of Change scale (CGI-C).

• Assessment of tasimelteon efficacy on daytime functioning measured by improvement in Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) and Sheehan Disability Scale for Pediatrics and Adolescents (SDS-P/A).

• Evaluation of the impact of sleep improvement on behavior as measured by the Aberrant Behavior Checklist (ABC).

• Determination of tasimelteon efficacy as measured by improvements in actigraphy parameters.

• Characterization of the pharmacokinetics of an age-appropriate oral formulation of tasimelteon in 2-year-old participants.

• Evaluation of the safety and tolerability of repeated doses of tasimelteon in pediatric participants with insomnia disorder.

The clinical trial enrolled a total of **370 participants** diagnosed with **insomnia disorder**. The study population comprised both **male** and **female** subjects between **2 and 17 years of age**, representing a **pediatric** cohort. Participants were required to have a confirmed clinical diagnosis of insomnia disorder with reported **sleep latency** of at least 1 hour on average 4 nights per week for a minimum of 3 months prior to screening. The selection process involved screening using a Daily Sleep Diary, where participants demonstrated sleep latency of at least 1 hour on average 4 nights per week and at least 3 nights per week in each of the 4 weeks preceding randomization. The sleep disturbance could not be attributed to another medication. Both the legal guardian and child were required to be willing and able to comply with study requirements. Participants were expected to complete the Post-Sleep Questionnaire of the Daily Sleep Diary for an average of 5 out of 7 nights during the screening period. This trial involved a **vulnerable population** due to the pediatric age range of the enrolled subjects.

This is a multicenter, double-blind, randomized clinical trial designed to evaluate the efficacy of **tasimelteon** compared to **placebo** in treating pediatric patients with **insomnia disorder**. The study is classified as a **Phase 3** trial. The trial will employ a randomized controlled design where participants will be allocated to receive either tasimelteon or placebo in a blinded manner. The placebo liquid formulation will be indistinguishable from tasimelteon and will be administered in the same way to maintain blinding integrity. Tasimelteon will be administered as an oral suspension at a maximum daily dose of 0.7 mg/kg, with a maximum total dose of 20 mg, over a maximum treatment period of 12 months.

The primary objective of the trial is to evaluate the efficacy of tasimelteon administered daily compared to placebo on **sleep latency** in participants, as measured by daily diary. The **primary endpoint** is sleep latency as measured by daily sleep diary. Secondary endpoints include nighttime subjective sleep parameters measured by daily sleep diary, **Patient Global Impression of Change scale** (PGI-C), **Clinical Global Impression of Change scale** (CGI-C), **Caregiver Global Impression of Change scale** (CaGI-C), **Epworth Sleepiness Scale for Children and Adolescents** (ESS-CHAD), **Sheehan Disability Scale for Pediatrics and Adolescents** (SDS-P/A), **Aberrant Behavior Checklist** (ABC), actigraphy parameters, and tasimelteon pharmacokinetics in 2-year-old participants.

Eligible participants are male or female between 2 and 17 years of age, inclusive, at the screening visit. Principal inclusion criteria include a confirmed clinical diagnosis of insomnia disorder, reported sleep latency of at least 1 hour on average 4 nights per week for at least 3 months prior to screening, and sleep latency of at least 1 hour on average 4 nights per week and at least 3 nights per week in each of the 4 weeks preceding randomization by sleep diary. The sleep disturbance must not be a result of another medication. Participants must complete the required Post-Sleep Questionnaire of the Daily Sleep Diary for an average of 5 out of 7 nights during screening. Informed consent from the legal guardian and assent as required must be obtained. Both guardian and child must be willing and able to comply with study requirements and restrictions.

The trial is expected to commence recruitment in December 2025 and is estimated to conclude in January 2028, resulting in an overall trial duration of approximately 25 months. Participants will undergo a screening visit (Visit 1) to assess eligibility, followed by a series of follow-up visits during the treatment period to monitor efficacy and safety parameters. The end-of-study visit will complete the participant's involvement in the trial. The expected length of participant involvement includes the screening period, a treatment period of up to 12 months, and final assessments at the end-of-study visit. Conditions that may lead to early termination from the study include non-compliance with study requirements, adverse events, withdrawal of consent by the legal guardian, or at the discretion of the investigator if continuation is deemed not in the best interest of the participant.

The experimental medication **tasimelteon** is administered as a **suspension for oral suspension**. The active substance is tasimelteon, a chemical compound manufactured by Vanda Pharmaceuticals. The medication is administered via the **oral route** on a daily basis. The **maximum daily dose** is 0.7 mg/kg body weight, with a **maximum total dose** not exceeding 20 mg per administration. The **maximum treatment period** is 12 months. Participant compliance is monitored through daily diary recordings completed by participants or caregivers.

The comparator treatment consists of a **placebo** in liquid formulation. The placebo is formulated to be indistinguishable from the tasimelteon suspension in appearance, taste, and texture. The placebo is administered using the same **route of administration**, **dosing schedule**, and **frequency** as the active treatment to maintain blinding throughout the study. The placebo contains no active pharmaceutical ingredient and serves as the control arm for evaluating the efficacy of tasimelteon.

Efficacy will be assessed using the primary endpoint of **sleep latency** as measured by daily sleep diary. Secondary efficacy endpoints include nighttime subjective sleep parameters measured by daily sleep diary, Patient Global Impression of Change scale (PGI-C), Clinical Global Impression of Change scale (CGI-C), Caregiver Global Impression of Change scale (CaGI-C), Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), Sheehan Disability Scale for Pediatrics and Adolescents (SDS-P/A), Aberrant Behavior Checklist (ABC), and actigraphy parameters. Additionally, **tasimelteon pharmacokinetics** will be evaluated in 2-year-old participants. The treatment period will extend for 12 weeks. Participants will be required to complete the Post-Sleep Questionnaire of the Daily Sleep Diary for an average of 5 out of 7 nights during the screening period to ensure adequate baseline data collection for efficacy assessment.