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

Trial ID: 2023-509171-16-00
Protocol: NBI-74788-CAH3003
Sponsor: Neurocrine Biosciences Inc.

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Diseases & Conditions

Adrenogenital syndrome

Objectives

The primary objective of this study is to evaluate the **efficacy** of Crinecerfont (100 mg twice daily) compared with placebo in adult subjects with **Classic Congenital Adrenal Hyperplasia (CAH)**. The study aims to assess the reduction in daily glucocorticoid dosage while maintaining adrenal androgen control. Additionally, it seeks to evaluate the reduction in adrenal steroid levels following an initial 4-week treatment period. The study also aims to assess the effect of Crinecerfont on clinical endpoints associated with supraphysiologic glucocorticoid dosing, evaluate plasma concentrations of Crinecerfont and its metabolites, and assess the safety and tolerability of Crinecerfont. Furthermore, the study will evaluate an alternate dosing regimen of Crinecerfont in subjects who have not reduced their glucocorticoid dose by Month 12. These objectives are clinically relevant as they address the management of CAH, a condition that requires careful balancing of glucocorticoid therapy to avoid both under-treatment and the adverse effects of excessive dosing.

Participants

The clinical trial involves a total of **83 participants** diagnosed with **Classic Congenital Adrenal Hyperplasia (CAH)**. The study population includes both male and female subjects, all of whom are at least 18 years of age. Participants were selected based on their medically confirmed diagnosis of classic 21-hydroxylase deficiency and are required to be on a stable, supraphysiologic glucocorticoid dose regimen for at least one month prior to screening. The trial includes individuals who may be considered part of a vulnerable population. Participants' general health status is characterized by their ability to maintain stable glucocorticoid and, if applicable, fludrocortisone dosing, with specific criteria for plasma renin activity and blood pressure. Lifestyle considerations such as sodium intake are relevant for those treated with fludrocortisone. The trial ensures that female subjects of childbearing potential adhere to contraception guidelines throughout the study duration. The selection criteria ensure a focused study population to evaluate the efficacy and safety of Crinecerfont in managing CAH.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety and efficacy of **Crinecerfont** (NBI-74788) in adult subjects with **Classic Congenital Adrenal Hyperplasia (CAH)**. The trial will be conducted over an estimated period from December 2020 to August 2027. Participants will be randomly assigned to receive either Crinecerfont or a placebo, administered orally in capsule form. The primary objective is to assess the efficacy of Crinecerfont in reducing daily glucocorticoid dosage while maintaining adrenal androgen control. Secondary objectives include evaluating changes in adrenal steroid levels, clinical endpoints associated with glucocorticoid dosing, and plasma concentrations of Crinecerfont and its metabolites.

The study will begin with a screening visit to confirm eligibility, which includes criteria such as a confirmed diagnosis of classic 21-hydroxylase deficiency and stable glucocorticoid dosing. Following successful screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor efficacy and safety outcomes. Key follow-up assessments will occur at Week 4 and Week 24, with primary endpoints measured at Week 24, including the percent change from baseline in glucocorticoid daily dose. Secondary endpoints will assess changes in serum androstenedione and other metabolic parameters.

The expected duration of participant involvement is up to 72 weeks, with conditions for early termination including adverse events or withdrawal of consent. The study will conclude with an end-of-study visit to ensure participant safety and collect final data. Throughout the trial, safety and tolerability will be closely monitored to ensure the well-being of participants. The trial is categorized as a Phase III study, focusing on the potential therapeutic benefits of Crinecerfont for individuals with CAH.

Treatment

The clinical trial involves the administration of **Crinecerfont**, an investigational medication, under the product name NBI-74788. This medication is provided in the form of a **capsule** and is intended for **oral use**. The active substance, Crinecerfont, is of chemical origin and is manufactured by Neurocrine Biosciences Inc. The dosing regimen for Crinecerfont in this study is 100 mg administered twice daily (bid). The primary objective is to evaluate its efficacy in reducing daily glucocorticoid dosage while maintaining adrenal androgen control in adult subjects with Classic Congenital Adrenal Hyperplasia. The maximum treatment period for Crinecerfont is 72 weeks. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the Crinecerfont capsules in appearance but does not contain the active substance. The placebo is administered orally, following the same dosing schedule as the active treatment, to maintain the study's blinding integrity. The use of a placebo allows for the assessment of Crinecerfont's efficacy and safety by providing a baseline for comparison.

Efficacy

The efficacy of Crinecerfont (NBI-74788) in the treatment of **Classic Congenital Adrenal Hyperplasia** will be assessed through a randomized, double-blind, placebo-controlled study. The primary endpoint for evaluating efficacy is the percent change from baseline in glucocorticoid daily dose, measured in hydrocortisone equivalents adjusted for body surface area (mg/m²/day) at Week 24. Secondary endpoints include changes from baseline in serum androstenedione at Week 4, achievement of a reduction in glucocorticoid daily dose to physiologic levels by Week 24, and changes from baseline in HOMA-IR, weight, and fat mass at Week 24.

The study will involve the administration of Crinecerfont at a dosage of 100 mg twice daily, compared with a placebo, to evaluate its efficacy in reducing daily glucocorticoid dosage while maintaining adrenal androgen control. Additionally, the study will assess the reduction in adrenal steroid levels following an initial 4-week treatment period and evaluate the effect of Crinecerfont on clinical endpoints associated with supraphysiologic glucocorticoid dosing. Plasma concentrations of Crinecerfont and its metabolites will also be measured to further assess efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects must provide written informed consent.
Be a female or male at least 18 years of age.
Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency.
Be on a stable, supraphysiologic glucocorticoid dose regimen that has been stable for at least 1 month prior to screening.
If treated with fludrocortisone, dose should be stable for at least 1 month prior to screening with an upright plasma renin activity (PRA) during screening that is not greater than ULN on the subject's usual sodium intake. If PRA is >ULN, the subject must have systolic blood pressure >100 mmHg, without orthostatic hypotension, and with serum sodium and potassium in the normal range.
Female subjects of childbearing potential with fertile male partners must agree to use contraception consistently from screening until the final study visit or 30 days after the last dose of study drug, whichever is longer. A female who is not of childbearing potential must meet one of the following:

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Exclusion Criteria

Have a known or suspected diagnosis of any of the other forms of classic CAH including 11-β-hydroxylase deficiency, 17-α-hydroxylase deficiency, 3-β-hydroxysteroid dehydrogenase deficiency, P450 sidechain cleavage deficiency, or P450 oxidoreductase deficiency.
Have a history of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic therapy with oral glucocorticoids, or requiring chronic therapy with inhaled glucocorticoids that based on dose and hormone profile the investigator deems would yield significant systemic exposure interfering with study endpoints.
Have a clinically significant medical condition or chronic disease (including history of neurological, hepatic, renal, cardiovascular, gastrointestinal, significant malabsorption, hematologic, pulmonary, psychiatric, or endocrine disease [excluding CAH]) that in the opinion of the investigator would preclude the subject from participating in and completing the study or that could confound interpretation of study outcome.
History of malignancy, unless successfully treated with curative intent and considered to be cured.
Have a known history of clinically concerning cardiac arrhythmia (including long QT syndrome) or prolongation of screening (pretreatment) QT interval corrected for heart rate using Fridericia's correction (QTcF) of >450 msec (males) or >470 msec (females).
Known sensitivity (ie, hypersensitivity) or allergy to any corticotropinreleasing hormone (CRH) receptor antagonist.
Have evidence of chronic renal or liver disease Used any active investigational drug within 30 days or 5 half-lives (whichever is longer) before screening, or plans to use an investigational drug (other than the study drug) during the study.
Females who are pregnant or lactating.
Are using any excluded concomitant medication and cannot discontinue use of these medications for the duration of the study (also refer to Section 9.9.1): • Orally administered glucocorticoids for indications other than CAH. • Strong inducers of CYP3A4 or CYP2B6 except topically administered medications. • Medications that affect cortisol or glucocorticoid metabolism (eg, phenytoin, mitotane, phenobarbital, strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, cholestyramine, certain antivirals) except topically administered medications. • Aromatase inhibitors (eg, anastrozole, letrozole, testolactone).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	23 Dec 2020	6
Belgium	Not Recruiting	23 Dec 2020	4
Bulgaria	Not Recruiting	23 Dec 2020	2
Czechia	Not Recruiting	23 Dec 2020	2
France	Not Recruiting	23 Dec 2020	16
Germany	Not Recruiting	23 Dec 2020	4
Greece	Not Recruiting	23 Dec 2020	6
Italy	Not Recruiting	23 Dec 2020	36
Poland	Not Recruiting	23 Dec 2020	11
Portugal	Not Recruiting	23 Dec 2020	2