Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NBI-74788 in Adults With Congenital Adrenal Hyperplasia

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multiple-dose, dose-escalation study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NBI-74788 in up to 30 adult female and male subjects (18 to 50 years of age) with a documented medical diagnosis of classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH). The study will include a sequential-cohort design with four NBI-74788 dosing regimens, with each regimen administered for 14 days.

Official Title
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A Phase 2, Open-Label, Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NBI-74788 in Adult Subjects With Congenital Adrenal Hyperplasia

Conditions
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CAH - Congenital Adrenal Hyperplasia

Intervention / Treatment
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* Drug: NBI-74788


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be in good general health. Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH. Be on a stable regimen of steroidal treatment for CAH that is expected to remain stable throughout the study. Subjects of childbearing potential must be instructed on the proper use of barrier methods of contraception and agree to use hormonal or two forms of nonhormonal contraception (dual contraception) consistently from screening until the final study visit or a prespecified window after the last dose of study drug, whichever is longer. Subjects of childbearing potential must have a negative pregnancy test at screening and negative urine pregnancy test at baseline. Have a negative urine drug (for illegal drugs) and alcohol breath test at screening and baseline. Be willing and able to adhere to the study regimen and study procedures described in the protocol and informed consent/assent form, including all requirements at the study center and return for the follow-up visit. Be willing to provide authorization for access to personal health information in conjunction with US Health Insurance Portability and Accountability Act (HIPAA). Exclusion Criteria: Have a clinically significant unstable medical condition or chronic disease, or malignancy. Had a medically significant illness within 30 days of screening. Have a known or suspected differential diagnosis of any of the other known forms of classic CAH. Have a history that includes bilateral adrenalectomy, hypopituitarism, or other condition requiring daily therapy with orally administered glucocorticoids. Are pregnant or lactating females. Have a history of epilepsy or serious head injury. Have a known history of long QT syndrome or cardiac tachy-arrhythmia. Have hypersensitivity to any corticotropin releasing hormone antagonists. Test positive at screening for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), or have a history of a positive result. Have a recent history (≤1 year) of alcohol or drug abuse, or current evidence of substance dependence or abuse criteria. Used any anticoagulants or antiplatelet therapies within 30 days before screening. Have an active bleeding disorder. Used any other investigational drug within 30 days before initial screening, or plans to use an investigational drug (other than the study drug) during the study. Have a blood loss ≥550 mL or donated blood within 56 days or donated plasma within 7 days before baseline.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (50 mg QHS)<br>NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days. | Drug: NBI-74788<br>* Capsule, administered daily.<br>|
| Experimental: Cohort 2 (100 mg QHS)<br>NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days. | Drug: NBI-74788<br>* Capsule, administered daily.<br>|
| Experimental: Cohort 3 (100 mg QPM)<br>NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days. | Drug: NBI-74788<br>* Capsule, administered daily.<br>|
| Experimental: Cohort 4 (100 mg BID)<br>NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days. | Drug: NBI-74788<br>* Capsule, administered daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Day 14 in 17-hydroxyprogesterone (17-OHP) Morning Window Averages | Percent changes in 17-OHP were assessed through the collection of samples from 0600 hours to 1000 hours both prior to study drug administration (i.e., at baseline) and after 14 days of study drug dosing. The 3 samples collected during this morning window at each visit were averaged and used to determine the percent change from baseline. | Baseline and Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Day 14 in Androstenedione Morning Window Averages | Percent changes in androstenedione were assessed through the collection of samples from 0600 hours to 1000 hours prior to study drug administration (baseline) and after 14 days of study drug dosing. The 3 samples collected at each visit during this morning window were averaged and used to determine the change and percent change from baseline. | Baseline and Day 14 | 
| Percent Change From Baseline to Day 14 in Adrenocorticotropic Hormone (ACTH) Morning Window Averages | Percent changes in ACTH were assessed through the collection of samples from 0600 hours to 1000 hours prior to study drug administration (baseline) and after 14 days of study drug dosing. The 3 samples collected at each visit during this morning window were averaged and used to determine the change and percent change from baseline. | Baseline and Day 14 |