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

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03525886
• Collaborator: (none)
• Enrollment: 18
• Locations: 6
• Arms: 4
• Actual Duration (Months): 23.9
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
CAH - Congenital Adrenal Hyperplasia	Drug: NBI-74788	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 10, 2018
• Actual Primary Completion Date: Apr 7, 2020
• Actual Study Completion Date: Apr 7, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline to Day 14 in 17-hydroxyprogesterone (17-OHP) Morning Window Averages [Baseline and Day 14]

   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.

Secondary Outcome Measures

1. Percent Change From Baseline to Day 14 in Androstenedione Morning Window Averages [Baseline and Day 14]

   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.

2. Percent Change From Baseline to Day 14 in Adrenocorticotropic Hormone (ACTH) Morning Window Averages [Baseline and Day 14]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Be in good general health.

2. Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH.

3. Be on a stable regimen of steroidal treatment for CAH that is expected to remain stable throughout the study.

4. 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.

5. Subjects of childbearing potential must have a negative pregnancy test at screening and negative urine pregnancy test at baseline.

6. Have a negative urine drug (for illegal drugs) and alcohol breath test at screening and baseline.

7. 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.

8. Be willing to provide authorization for access to personal health information in conjunction with US Health Insurance Portability and Accountability Act (HIPAA).

Exclusion Criteria:

1. Have a clinically significant unstable medical condition or chronic disease, or malignancy.

2. Had a medically significant illness within 30 days of screening.

3. Have a known or suspected differential diagnosis of any of the other known forms of classic CAH.

4. Have a history that includes bilateral adrenalectomy, hypopituitarism, or other condition requiring daily therapy with orally administered glucocorticoids.

5. Are pregnant or lactating females.

6. Have a history of epilepsy or serious head injury.

7. Have a known history of long QT syndrome or cardiac tachy-arrhythmia.

8. Have hypersensitivity to any corticotropin releasing hormone antagonists.

9. Test positive at screening for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), or have a history of a positive result.

10. Have a recent history (≤1 year) of alcohol or drug abuse, or current evidence of substance dependence or abuse criteria.

11. Used any anticoagulants or antiplatelet therapies within 30 days before screening.

12. Have an active bleeding disorder.

13. 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.

14. Have a blood loss ≥550 mL or donated blood within 56 days or donated plasma within 7 days before baseline.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neurocrine Clinical Site	Aurora	Colorado	United States	80045
2	Neurocrine Clinical Site	Indianapolis	Indiana	United States	46202
3	Neurocrine Clinical Site	Ann Arbor	Michigan	United States	48109
4	Neurocrine Clinical Site	Minneapolis	Minnesota	United States	55454
5	Neurocrine Clinical Site	Philadelphia	Pennsylvania	United States	19104
6	Neurocrine Clinical Site	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Neurocrine Biosciences

Investigators

• Study Director: Clinical Development Lead, Neurocrine Biosciences

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 14, 2019

More Information

Additional Information:

• Study website

Publications

• Auchus RJ, Sarafoglou K, Fechner PY, Vogiatzi MG, Imel EA, Davis SM, Giri N, Sturgeon J, Roberts E, Chan JL, Farber RH. Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2022 Feb 17;107(3):801-812. doi: 10.1210/clinem/dgab749.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT03525886
• Other Study ID Numbers: NBI-74788-CAH2001
• First Posted: May 16, 2018
• Last Update Posted: May 3, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction; Hyperplasia

Study Results

Participant Flow

Recruitment Details

The study followed a sequential cohort design with four NBI-74788 dosing regimens, each administered for 14 consecutive days. There was ~2-week period to evaluate safety and tolerability data before proceeding from Cohort 1 to Cohort 2. Subjects who previously completed the study in Cohort 1 or 2 (and had no safety concerns) could reenroll into Cohorts 3 and/or 4 (in addition to new subjects); 18 unique subjects participated. First subject enrolled: 4/10/2018; Last subject completed: 4/7/2020

Arm/Group Title	Cohort 1 (50 mg QHS)	Cohort 2 (100 mg QHS)	Cohort 3 (100 mg QPM)	Cohort 4 (100 mg BID)
Arm/Group Description	NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days.	NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days.
Period Title: Cohort 1 (50 mg QHS)
STARTED	8	0	0	0
COMPLETED	8	0	0	0
NOT COMPLETED	0	0	0	0
Period Title: Cohort 1 (50 mg QHS)
STARTED	0	7	0	0
COMPLETED	0	7	0	0
NOT COMPLETED	0	0	0	0
Period Title: Cohort 1 (50 mg QHS)
STARTED	0	0	8	0
COMPLETED	0	0	8	0
NOT COMPLETED	0	0	0	0
Period Title: Cohort 1 (50 mg QHS)
STARTED	0	0	0	8
COMPLETED	0	0	0	8
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1 (50 mg QHS)	Cohort 2 (100 mg QHS)	Cohort 3 (100 mg QPM)	Cohort 4 (100 mg BID)	Total
Arm/Group Description	NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days.	NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days.	Total of all reporting groups
Overall Participants	8	7	8	8	31
Age (years) [Mean (Standard Deviation) ]
Cohort 1 (50 mg QHS)	31.1 (9.4)	31.1 (9.4)
Cohort 2 (100 mg QHS)	32.9 (9.7)	32.9 (9.7)
Cohort 3 (100 mg QPM)	30.9 (10.5)	30.9 (10.5)
Cohort 4 (100 mg BID)	28.8 (8.2)	28.8 (8.2)
Sex: Female, Male (Count of Participants)
Female	4 50%	4 57.1%
Male	4 50%	4 57.1%
Female	5 62.5%	5 71.4%
Male	2 25%	2 28.6%
Female	3 37.5%	3 42.9%
Male	5 62.5%	5 71.4%
Female	5 62.5%	5 71.4%
Male	3 37.5%	3 42.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 12.5%	1 14.3%
Not Hispanic or Latino	7 87.5%	7 100%
Unknown or Not Reported	0 0%	0 0%
Hispanic or Latino	0 0%	0 0%
Not Hispanic or Latino	7 87.5%	7 100%
Unknown or Not Reported	0 0%	0 0%
Hispanic or Latino	1 12.5%	1 14.3%
Not Hispanic or Latino	7 87.5%	7 100%
Unknown or Not Reported	0 0%	0 0%
Hispanic or Latino	0 0%	0 0%
Not Hispanic or Latino	8 100%	8 114.3%
Unknown or Not Reported	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%
Asian	1 12.5%	1 14.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%
Black or African American	0 0%	0 0%
White	7 87.5%	7 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%
Asian	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%
Black or African American	0 0%	0 0%
White	7 87.5%	7 100%
More than one race	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%
Asian	1 12.5%	1 14.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%
Black or African American	0 0%	0 0%
White	7 87.5%	7 100%
More than one race	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%
Asian	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%
Black or African American	0 0%	0 0%
White	8 100%	8 114.3%
More than one race	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline to Day 14 in 17-hydroxyprogesterone (17-OHP) Morning Window Averages
Description	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.
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set, which includes all enrolled participants who received at least one dose of study drug and have at least one PD parameter measurement at baseline and at least one PD parameter measurement at the Day 14 visit.

Arm/Group Title	Cohort 1 (50 mg QHS)	Cohort 2 (100 mg QHS)	Cohort 3 (100 mg QPM)	Cohort 4 (100 mg BID)
Arm/Group Description	NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days.	NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days.
Measure Participants	8	7	8	8
Median (Inter-Quartile Range) [Percent (%)]	-60	-58	-53	-64

2. Secondary Outcome

Title	Percent Change From Baseline to Day 14 in Androstenedione Morning Window Averages
Description	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.
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set, which includes all enrolled participants who received at least one dose of study drug and have at least one PD parameter measurement at baseline and at least one PD parameter measurement at the Day 14 visit.

Arm/Group Title	Cohort 1 (50 mg QHS)	Cohort 2 (100 mg QHS)	Cohort 3 (100 mg QPM)	Cohort 4 (100 mg BID)
Arm/Group Description	NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days.	NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days.
Measure Participants	8	7	8	8
Median (Inter-Quartile Range) [Percent (%)]	-21	-42	-51	-64

3. Secondary Outcome

Title	Percent Change From Baseline to Day 14 in Adrenocorticotropic Hormone (ACTH) Morning Window Averages
Description	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.
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set, which includes all enrolled participants who received at least one dose of study drug and have at least one PD parameter measurement at baseline and at least one PD parameter measurement at the Day 14 visit.

Arm/Group Title	Cohort 1 (50 mg QHS)	Cohort 2 (100 mg QHS)	Cohort 3 (100 mg QPM)	Cohort 4 (100 mg BID)
Arm/Group Description	NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.	NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days.	NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days.
Measure Participants	8	7	8	8
Median (Inter-Quartile Range) [Percent (%)]	-54	-63	-64	-66

Adverse Events

Time Frame	Up to 7 weeks
Arm/Group Title	Cohort 1 (50 mg QHS)		Cohort 2 (100 mg QHS)		Cohort 3 (100 mg QPM)		Cohort 4 (100 mg BID)
Arm/Group Description	NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.		NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days.		NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days.		NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days.
All Cause Mortality
	Cohort 1 (50 mg QHS)		Cohort 2 (100 mg QHS)		Cohort 3 (100 mg QPM)		Cohort 4 (100 mg BID)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/7 (0%)		0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Cohort 1 (50 mg QHS)		Cohort 2 (100 mg QHS)		Cohort 3 (100 mg QPM)		Cohort 4 (100 mg BID)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Hepatobiliary disorders
Cholelithiasis	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1 (50 mg QHS)		Cohort 2 (100 mg QHS)		Cohort 3 (100 mg QPM)		Cohort 4 (100 mg BID)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)		5/7 (71.4%)		5/8 (62.5%)		5/8 (62.5%)
Gastrointestinal disorders
Dyspepsia	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Gastrointestinal pain	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Nausea	1/8 (12.5%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
General disorders
Chest discomfort	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Fatigue	1/8 (12.5%)		0/7 (0%)		1/8 (12.5%)		1/8 (12.5%)
Feeling abnormal	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Malaise	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Peripheral swelling	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Pyrexia	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		1/8 (12.5%)
Infections and infestations
Localised infection	1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/8 (0%)
Nasopharyngitis	0/8 (0%)		0/7 (0%)		0/8 (0%)		2/8 (25%)
Upper respiratory tract infection	3/8 (37.5%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Urinary tract infection	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Viral infection	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Injury, poisoning and procedural complications
Contusion	2/8 (25%)		0/7 (0%)		0/8 (0%)		0/8 (0%)
Skin abrasion	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Investigations
Hepatic enzyme increased	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Joint swelling	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Muscle fatigue	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Myalgia	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Nervous system disorders
Dizziness	1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/8 (0%)
Headache	3/8 (37.5%)		1/7 (14.3%)		0/8 (0%)		1/8 (12.5%)
Tremor	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Psychiatric disorders
Insomnia	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		1/8 (12.5%)
Agitation	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Anxiety	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Panic attack	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Reproductive system and breast disorders
Metrorrhagia	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Ovulation pain	1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Oropharyngeal pain	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Hair growth abnormal	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Hyperhidrosis	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Vascular disorders
Hot flush	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Hypertension	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Generally, the PI has the right to publish results provided such publication does not violate confidentiality or IP provisions within the contract with the Sponsor. Prior to submission for publication or presentation of results, the PI must provide the Sponsor time for review. The Sponsor can request the PI to withhold or remove information from all publications. For a multi-center study, any publication of results by the PI shall not be made before the first multi-center publication.