Efficacy and Safety Evaluation of Apremilast in Pediatric Patients with Active Oral Ulcers Associated with Behçet's Disease: A Phase 3, Multicenter, Double-blind Study

The primary objective of this study is to estimate the **efficacy** of apremilast in pediatric subjects aged 2 to less than 18 years with oral ulcers associated with Behçet's Disease (BD). This is clinically relevant as Behçet's Disease is a chronic condition characterized by recurrent oral ulcers, which can significantly impact the quality of life and overall health of affected children. Evaluating the efficacy of apremilast could provide a therapeutic option to manage these symptoms effectively.

Secondary objectives include:

• Estimating other measures of the efficacy of apremilast for oral ulcers in pediatric subjects.
• Estimating the efficacy of apremilast in the treatment of genital ulcers in pediatric subjects with oral ulcers.
• Estimating the efficacy of apremilast for overall BD-related disease activity in pediatric subjects with oral ulcers.
• Estimating the effect of apremilast on BD manifestations other than oral and genital ulcers in pediatric subjects with oral ulcers.
• Estimating the effect of apremilast on health-related quality of life (HRQoL) in pediatric subjects with oral ulcers.
• Estimating the safety and tolerability of apremilast in pediatric subjects with oral ulcers.
• Characterizing the pharmacokinetics of apremilast in pediatric subjects with oral ulcers.
• Evaluating the taste and acceptability of apremilast tablet and liquid formulations in pediatric subjects with oral ulcers.
• Estimating the worsening of BD requiring protocol-prohibited medication in pediatric subjects with oral ulcers.

The clinical trial involves a total of **28 participants** diagnosed with **Behcet's disease**, specifically focusing on oral ulcers associated with this condition. The study population comprises both male and female subjects aged from 2 to less than 18 years. Participants were selected based on their diagnosis of Behcet's disease, meeting the ISGBD criteria, and having experienced oral ulcers at least three times within the 12 months prior to the screening visit. Additionally, subjects must have had at least two oral ulcers at both the screening visit and on day one of the trial. The trial includes individuals who have previously undergone treatment with at least one non-biologic therapy for Behcet's disease and are candidates for systemic therapy for oral ulcers. The trial population is considered vulnerable due to the pediatric age range. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **apremilast** in pediatric subjects aged 2 to less than 18 years with active oral ulcers associated with **Behçet's disease**. The trial consists of a parallel group study followed by an active treatment phase. The estimated duration of the trial is from September 2021 to July 2028, with a maximum treatment period of 52 weeks for each participant. The study involves the administration of apremilast in the form of film-coated tablets or oral solution, with a placebo group for comparison.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of Behçet's disease, and history of oral ulcers. Following randomization, participants will attend regular follow-up visits to monitor the number of oral ulcers, pain levels, and overall disease activity. The primary endpoint is the area under the curve for the number of oral ulcers from baseline to week 12. Secondary endpoints include changes in pain, complete response rates for oral and genital ulcers, and various safety assessments.

The expected length of participant involvement is up to 52 weeks, with an additional 30-day post-treatment safety follow-up phase. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, the need for protocol-prohibited medications due to worsening of Behçet's disease, or withdrawal of consent by the participant or their guardian. The trial aims to provide comprehensive data on the efficacy and safety of apremilast in the pediatric population affected by Behçet's disease.

The clinical trial involves the administration of **Apremilast**, a chemical compound, as the experimental medication. Apremilast is provided in two pharmaceutical forms: **film-coated tablets** and **oral solution**. The film-coated tablets are administered orally with a maximum daily dose of 60 mg, and the oral solution is also administered orally with a maximum daily dose of 12 ml. The treatment period for both forms is up to 52 weeks. The active substance in Apremilast is chemically derived and is identified by the synonym CC-10004. The sponsor product code for Apremilast is AMG 407, and it is manufactured by Amgen Inc. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** as a non-experimental treatment. The placebo is designed to match the film-coated tablets and oral suspension forms of Apremilast, with dosages of 10 mg, 20 mg, and 30 mg for the tablets, and 5 mg/ml for the oral suspension. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo does not contain any active substance and serves as a comparator to evaluate the efficacy and safety of Apremilast in the treatment of oral ulcers associated with Behçet's Disease in pediatric subjects.

The efficacy of **Apremilast** in the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the area under the curve (AUC) for the number of oral ulcers from baseline (week 0) to week 12. Secondary endpoints include the number of oral ulcers from baseline to week 12, change in the pain of oral ulcers as measured by a visual analog scale (VAS) from baseline to week 12, and the complete response rate for oral ulcers, defined as the proportion of subjects who are oral ulcer-free at week 12. Additional secondary endpoints involve the proportion of subjects at week 12 whose number of oral ulcers is reduced by 50% or more from baseline, and the complete response rate for genital ulcers at week 12.

Further assessments include changes in disease activity as measured by Behçet’s Disease Current Activity (BDCAF) scores, the proportion of subjects with new-onset or recurrence of Behçet’s-related manifestations, and changes in quality of life as measured by the Short Form Survey (SF-10). Safety and tolerability will be monitored through adverse events, clinical laboratory tests, vital signs, and physical examinations from the signing of informed consent through week 52 and the 30-day post-treatment safety follow-up phase. Plasma concentrations of Apremilast will be summarized by visit and dosing regimen from week 2 to week 52. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the therapeutic impact of Apremilast on pediatric subjects with oral ulcers associated with Behçet's Disease.