Evaluation of ALKS 2680 Efficacy and Safety in Idiopathic Hypersomnia: A Phase 2 Randomized, Double-Blind, Dose-Range-Finding Study

The primary objective of this study is to evaluate the **efficacy** of ALKS 2680 in the treatment of **Excessive Daytime Sleepiness (EDS)** in subjects with **Idiopathic Hypersomnia (IH)**. This is clinically relevant as EDS significantly impacts the quality of life and daily functioning of individuals with IH, and effective treatment options are limited.

Secondary objectives include:

• Evaluating the efficacy of ALKS 2680 for the treatment of EDS in subjects with IH.
• Assessing the **safety** and **tolerability** of ALKS 2680 in subjects with IH.

The clinical trial investigating the efficacy of ALKS 2680 for the treatment of **Excessive Daytime Sleepiness** in subjects with **Idiopathic Hypersomnia** includes a total of 81 participants. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on their ability to understand and comply with protocol requirements, including lifestyle considerations and adherence to specific guidelines. The trial includes individuals who meet the diagnostic criteria for Idiopathic Hypersomnia as per ICSD-3-TR guidelines, confirmed by diagnostic evaluations conducted within the previous 10 years. The study population is characterized by a diverse group, including vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across different demographics. Participants' general health status is not specified, but adherence to primary therapy for conditions such as Obstructive Sleep Apnea, if applicable, is required throughout the study.

The clinical trial is a **Phase 2**, randomized, parallel-group, double-blind, dose-range-finding study designed to evaluate the safety and efficacy of **ALKS 2680** in subjects with **Idiopathic Hypersomnia**. The primary objective is to assess the efficacy of ALKS 2680 in treating excessive daytime sleepiness in this population. The trial will involve the administration of ALKS 2680 in tablet form, with doses ranging from 10 mg to 18 mg, and a placebo group for control. The maximum treatment period is set at 8 weeks, with the trial expected to conclude by December 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on diagnostic criteria for idiopathic hypersomnia, as per ICSD-3-TR guidelines. This will be followed by baseline assessments and randomization into treatment groups. Subsequent visits will occur at regular intervals to monitor safety and efficacy, including assessments of the **Epworth Sleepiness Scale** and **Idiopathic Hypersomnia Severity Scale**. Safety evaluations will include monitoring of treatment-emergent adverse events, clinical laboratory assessments, vital signs, safety ECGs, and the **Columbia-Suicide Severity Rating Scale** (C-SSRS).

The expected length of participant involvement is approximately 8 weeks, with conditions for early termination including non-compliance with protocol requirements, adverse events, or withdrawal of consent. The trial is not categorized as low intervention, and the investigational product is not currently authorized for use in the study population. The study will adhere to strict protocol requirements, including lifestyle considerations, adherence to contraception guidance, and compliance with actigraphy and diary requirements. Participants receiving treatment for obstructive sleep apnea must adhere to their primary therapy throughout the study.

The clinical trial involves the administration of **ALKS 2680**, a chemical compound developed by Alkermes, Inc. The experimental medication is provided in the form of a **tablet** and is intended for **oral use**. The study includes three different dosage regimens of ALKS 2680. The first regimen involves a maximum daily dose of 10 mg, with a total maximum dose of 1190 mg over a treatment period of 8 weeks. The second regimen allows for a maximum daily dose of 18 mg, with a total maximum dose of 1638 mg over the same period. The third regimen involves a maximum daily dose of 14 mg, with a total maximum dose of 1414 mg over 8 weeks. Each dosage is administered once daily, and participant compliance is monitored throughout the study duration.

In addition to the experimental medication, a **placebo** is used as a comparator treatment to match ALKS 2680. The placebo is designed to mimic the appearance of the ALKS 2680 tablet but contains no active substance. The placebo is administered under the same conditions as the experimental drug to ensure blinding and maintain the integrity of the study. The use of a placebo allows for the assessment of the efficacy and safety of ALKS 2680 in treating **Excessive Daytime Sleepiness** in subjects with **Idiopathic Hypersomnia**. Compliance with the placebo regimen is also monitored to ensure accurate and reliable study results.

The efficacy of **ALKS 2680** in the treatment of **Idiopathic Hypersomnia** will be assessed through a Phase 2, randomized, parallel-group, double-blind, dose-range-finding study. The primary endpoint for evaluating efficacy is the change in the Epworth Sleepiness Scale (ESS) from baseline to Week 8, measured by dose level. Secondary endpoints include the change in the Idiopathic Hypersomnia Severity Scale (IHSS) from baseline to Week 8, also assessed by dose level. Additional secondary endpoints involve the evaluation of treatment-emergent adverse events (TEAEs), clinical laboratory assessments, vital signs, safety electrocardiograms (ECGs), and the Columbia-Suicide Severity Rating Scale (C-SSRS).

Data collection will occur at specified timepoints, with the primary and secondary endpoints being measured at baseline and Week 8. The ESS and IHSS are validated scales used to quantify sleepiness and hypersomnia severity, respectively. These scales will be administered to participants to capture patient-reported outcomes. The analysis will focus on the comparison of changes in these scales from baseline to the end of the treatment period, stratified by the dose level of ALKS 2680 administered. The study aims to provide a comprehensive evaluation of the drug's efficacy in reducing excessive daytime sleepiness in subjects with idiopathic hypersomnia.