Evaluation of Crinecerfont (NBI-74788) Efficacy and Safety in Pediatric Patients with Classic Congenital Adrenal Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of crinecerfont, compared with placebo, in reducing adrenal steroid levels during a glucocorticoid-stable period in pediatric subjects with Classic Congenital Adrenal Hyperplasia (CAH). This is clinically relevant as it aims to manage the hormonal imbalances associated with CAH, potentially improving patient outcomes by stabilizing adrenal steroid production without altering glucocorticoid therapy.

Secondary objectives include: - Evaluating the efficacy of crinecerfont in reducing daily glucocorticoid dosage while maintaining adrenal androgen control. - Assessing the effect of crinecerfont on clinical endpoints associated with supraphysiologic glucocorticoid dosing and androgen excess. - Evaluating plasma concentrations of crinecerfont and its metabolites. - Assessing the safety and tolerability of crinecerfont. These objectives aim to provide a comprehensive understanding of crinecerfont's therapeutic potential and safety profile in managing CAH.

The clinical trial involves a total of **58 participants** diagnosed with **Classic Congenital Adrenal Hyperplasia (CAH)** due to 21-hydroxylase deficiency. The study population comprises both male and female subjects aged between 2 to 17 years, with a minimum body weight of 10 kg. Participants are required to be on a stable regimen of glucocorticoid treatment for CAH and must have elevated adrenal androgens. The trial population was selected based on their ability to adhere to study procedures and return for follow-up visits. Additionally, if participants are treated with fludrocortisone, the dose should be stable for at least one month prior to screening. The study includes a vulnerable population, and lifestyle considerations such as sodium intake are monitored to ensure plasma renin activity remains within specified limits. The trial aims to evaluate the efficacy of crinecerfont in reducing adrenal steroid levels during a glucocorticoid-stable period.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety and efficacy of **crinecerfont** (NBI-74788) in pediatric subjects with **Classic Congenital Adrenal Hyperplasia (CAH)**. The trial will be conducted over a period of 52 weeks, followed by an open-label treatment phase. Participants will be randomly assigned to receive either crinecerfont or a placebo, with the primary objective being to assess the efficacy of crinecerfont in reducing adrenal steroid levels during a glucocorticoid-stable period. The primary endpoint is the change from baseline in serum androstenedione at Week 4, with secondary endpoints including changes in serum 17-hydroxyprogesterone and glucocorticoid dose at specified intervals.

The study will commence with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and a medically confirmed diagnosis of classic CAH due to 21-hydroxylase deficiency. Participants must be on a stable glucocorticoid regimen and meet specific adrenal androgen levels. Following the screening, participants will undergo regular follow-up visits to monitor safety and efficacy outcomes, with assessments including blood tests and clinical evaluations. The end-of-study visit will conclude the trial, providing a comprehensive evaluation of the participant's response to the treatment.

Participant involvement is expected to last for the entire 52-week duration of the trial, with conditions for early termination including non-compliance with study procedures or adverse events that may compromise participant safety. The trial is structured to ensure rigorous monitoring and data collection, adhering to the highest standards of clinical research methodology.

The clinical trial involves the administration of **Crinecerfont** (NBI-74788), an investigational medication developed by Neurocrine Biosciences Inc. The active substance, crinecerfont, is of chemical origin. The trial utilizes two pharmaceutical forms of the medication: an **oral solution** and a **capsule**. The oral solution is designated with the sponsor product code MFS-74788-103 and is specifically formulated for pediatric use. The capsule form, identified by the sponsor product code MFS-74788-101, is not a pediatric formulation. Both forms are administered via the oral route. The maximum treatment period for both formulations is 52 weeks. The dosage and frequency of administration are determined based on the study protocol, with compliance monitored throughout the trial.

In addition to the experimental medication, the study includes the use of a placebo to maintain the double-blind design. The placebo is available in two forms: a placebo for oral capsules and a placebo for oral solution. These placebo forms are used to match the respective active formulations of crinecerfont, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the active medication, with the same dosing schedule and monitoring procedures applied to ensure consistency and reliability of the trial results.

The efficacy of **crinecerfont** in the clinical trial will be assessed by evaluating its impact on adrenal steroid levels in pediatric subjects with Classic Congenital Adrenal Hyperplasia (CAH). The primary endpoint for efficacy assessment is the change from baseline in serum androstenedione levels at Week 4. Secondary endpoints include the change from baseline in serum 17-hydroxyprogesterone at Week 4 and the percent change from baseline in glucocorticoid dose at Week 28.

Measurements of these endpoints will be conducted using validated laboratory tests to ensure accuracy and reliability. The trial is designed as a randomized, double-blind, placebo-controlled study, followed by an open-label treatment phase. The schedule for collecting efficacy data includes specific timepoints, notably at Week 4 and Week 28, to capture changes in the relevant biomarkers and treatment dosages. This structured approach allows for a comprehensive evaluation of the therapeutic potential of crinecerfont in managing CAH symptoms.