Evaluation of Tildacerfont in Reducing Supraphysiologic Glucocorticoid Use in Adults with Classic Congenital Adrenal Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the mean absolute change in **glucocorticoid** use in adult subjects with **Classic Congenital Adrenal Hyperplasia** over a 24-week, double-blind, placebo-controlled treatment period. This is clinically relevant as it aims to assess the potential of tildacerfont to reduce the need for supraphysiologic doses of glucocorticoids, which are commonly used in managing this condition, thereby potentially minimizing associated side effects and improving patient outcomes.

Secondary objectives include:

• Evaluating the effect of tildacerfont in reducing glucocorticoid use to near-physiologic levels while maintaining androgen control in subjects with congenital adrenal hyperplasia.
• Assessing the effect of tildacerfont in reducing cardiovascular risk in these subjects.

The clinical trial involves a total of **46 participants** diagnosed with **Classic Congenital Adrenal Hyperplasia**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on a documented historical diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, confirmed by genetic mutation in CYP21A2 and/or elevated 17-hydroxyprogesterone levels. All participants are currently undergoing treatment with glucocorticoids such as hydrocortisone, prednisone, or dexamethasone, and have been on a stable, supraphysiologic dose of glucocorticoid replacement for at least one month prior to screening. For those with the salt-wasting form of the condition, a stable dose of mineralocorticoid replacement for at least one month is also required. The trial includes a vulnerable population, and all participants have provided written informed consent, indicating their understanding of the study procedures and willingness to comply with the protocol. Lifestyle considerations such as diet and physical activity are 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 **Tildacerfont** in reducing supraphysiologic glucocorticoid use in adult subjects with **Classic Congenital Adrenal Hyperplasia**. The trial is categorized as a Phase IIb study and is expected to span a duration from July 2020 to October 2028. Participants will be involved in the study for a maximum treatment period of 310 days. The primary objective is to assess the mean absolute change in glucocorticoid dose over a 24-week treatment period. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and safety, and an end-of-study visit to evaluate the final outcomes.

Participants will be randomly assigned to receive either Tildacerfont or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study. The inclusion criteria require participants to be adults aged 18 years or older with a documented diagnosis of Classic Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency. They must have been on a stable, supraphysiologic dose of glucocorticoid replacement for at least one month prior to screening. The study will exclude individuals who do not meet these criteria or who have conditions that could interfere with the study outcomes.

The sequence of study visits is structured to ensure comprehensive monitoring and data collection. The initial screening visit will involve assessments to confirm the diagnosis and eligibility. Follow-up visits will occur at regular intervals to monitor the glucocorticoid dose, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will focus on evaluating the primary and secondary endpoints, including the absolute change in glucocorticoid dose and improvements in cardiovascular risk factors. Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or choose to withdraw consent.

The clinical trial involves the administration of **Tildacerfont**, an investigational medicinal product, in the form of a tablet. Tildacerfont is a new chemical entity developed by Spruce Biosciences, Inc. The active substance, Tildacerfont, is chemically synthesized and is administered orally. The maximum daily dose is 200 mg, with a total maximum dose of 434,000 mg over a treatment period of 310 days. The trial aims to evaluate the efficacy and safety of Tildacerfont in reducing supraphysiologic glucocorticoid use in adult subjects with classic congenital adrenal hyperplasia.

**Prednisolone** is used as a comparator treatment in the study. It is available in tablet form and is administered orally. The maximum daily dose of Prednisolone is 15 mg, with a total maximum dose of 32,550 mg over the same treatment period of 310 days. Prednisolone is a chemically synthesized glucocorticoid and is included in the trial to provide a standard-of-care comparison for the investigational product.

Additionally, **Hydrocortisone** is utilized as an auxiliary treatment. It is also provided in tablet form and administered orally. The maximum daily dose for Hydrocortisone is 60 mg, with a total maximum dose of 130,200 mg over 310 days. Hydrocortisone is a chemically synthesized corticosteroid, serving as a supportive treatment to manage adrenal insufficiency in the study participants.

A placebo, identical in appearance to the Tildacerfont tablet but devoid of the active substance, is used to maintain the double-blind nature of the trial. The placebo is administered orally, following the same dosing schedule as the investigational product, to ensure blinding and unbiased assessment of the treatment effects.

Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment schedule. This monitoring is crucial for maintaining the integrity of the trial data and ensuring accurate evaluation of the investigational product's efficacy and safety.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the treatment of adult subjects with **classic congenital adrenal hyperplasia**. The primary endpoint is the absolute change from baseline in glucocorticoid dose, measured in hydrocortisone equivalents, at Week 24. This will provide a quantitative measure of the reduction in glucocorticoid use, which is a key objective of the study.

Secondary endpoints include the proportion of subjects with a baseline glucocorticoid dose of ≤35 mg hydrocortisone equivalents (HCe) who achieve a glucocorticoid dose of ≤11 mg/m²/day in HCe and androstenedione (A4) levels ≤1.2 times baseline or ≤ the upper limit of normal (ULN) at Week 24. Additionally, the proportion of subjects achieving a glucocorticoid dose of ≤11 mg/m²/day in HCe and A4 levels ≤1.2 times baseline or A4 ≤ ULN at Week 24 will be assessed. Another secondary endpoint is the proportion of subjects showing improvement in at least one cardiovascular risk factor at Week 24.

The efficacy parameters will be collected and analyzed at the specified timepoint of Week 24, using appropriate measurement tools and validated scales to ensure accuracy and reliability of the data. The study is designed as a randomized, double-blind, placebo-controlled trial, which will help in minimizing bias and ensuring the validity of the efficacy assessments.