CAH - Congenital Adrenal Hyperplasia
Conditions
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.
Interventions
DRUGNBI-74788
Capsule, administered daily.
Sponsors
Neurocrine Biosciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
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
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (50 mg QHS) NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days. | 8 |
| Cohort 2 (100 mg QHS) NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days. | 7 |
| Cohort 3 (100 mg QPM) NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days. | 8 |
| Cohort 4 (100 mg BID) NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days. | 8 |
| Total | 31 |
Baseline characteristics
| Characteristic | Cohort 1 (50 mg QHS) | Total | Cohort 2 (100 mg QHS) | Cohort 3 (100 mg QPM) | Cohort 4 (100 mg BID) |
|---|---|---|---|---|---|
| Age, Continuous Cohort 1 (50 mg QHS) | 31.1 years STANDARD_DEVIATION 9.4 | 31.1 years STANDARD_DEVIATION 9.4 | — | — | — |
| Age, Continuous Cohort 2 (100 mg QHS) | — | 32.9 years STANDARD_DEVIATION 9.7 | 32.9 years STANDARD_DEVIATION 9.7 | — | — |
| Age, Continuous Cohort 3 (100 mg QPM) | — | 30.9 years STANDARD_DEVIATION 10.5 | — | 30.9 years STANDARD_DEVIATION 10.5 | — |
| Age, Continuous Cohort 4 (100 mg BID) | — | 28.8 years STANDARD_DEVIATION 8.2 | — | — | 28.8 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Cohort 1 (50 mg QHS) Hispanic or Latino | 1 Participants | 1 Participants | — | — | — |
| Ethnicity (NIH/OMB) Cohort 1 (50 mg QHS) Not Hispanic or Latino | 7 Participants | 7 Participants | — | — | — |
| Ethnicity (NIH/OMB) Cohort 1 (50 mg QHS) Unknown or Not Reported | 0 Participants | 0 Participants | — | — | — |
| Ethnicity (NIH/OMB) Cohort 2 (100 mg QHS) Hispanic or Latino | — | 0 Participants | 0 Participants | — | — |
| Ethnicity (NIH/OMB) Cohort 2 (100 mg QHS) Not Hispanic or Latino | — | 7 Participants | 7 Participants | — | — |
| Ethnicity (NIH/OMB) Cohort 2 (100 mg QHS) Unknown or Not Reported | — | 0 Participants | 0 Participants | — | — |
| Ethnicity (NIH/OMB) Cohort 3 (100 mg QPM) Hispanic or Latino | — | 1 Participants | — | 1 Participants | — |
| Ethnicity (NIH/OMB) Cohort 3 (100 mg QPM) Not Hispanic or Latino | — | 7 Participants | — | 7 Participants | — |
| Ethnicity (NIH/OMB) Cohort 3 (100 mg QPM) Unknown or Not Reported | — | 0 Participants | — | 0 Participants | — |
| Ethnicity (NIH/OMB) Cohort 4 (100 mg BID) Hispanic or Latino | — | 0 Participants | — | — | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (100 mg BID) Not Hispanic or Latino | — | 8 Participants | — | — | 8 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (100 mg BID) Unknown or Not Reported | — | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Cohort 1 (50 mg QHS) American Indian or Alaska Native | 0 Participants | 0 Participants | — | — | — |
| Race (NIH/OMB) Cohort 1 (50 mg QHS) Asian | 1 Participants | 1 Participants | — | — | — |
| Race (NIH/OMB) Cohort 1 (50 mg QHS) Black or African American | 0 Participants | 0 Participants | — | — | — |
| Race (NIH/OMB) Cohort 1 (50 mg QHS) More than one race | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 1 (50 mg QHS) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — | — | — |
| Race (NIH/OMB) Cohort 1 (50 mg QHS) Unknown or Not Reported | 0 Participants | 0 Participants | — | — | — |
| Race (NIH/OMB) Cohort 1 (50 mg QHS) White | 7 Participants | 7 Participants | — | — | — |
| Race (NIH/OMB) Cohort 2 (100 mg QHS) American Indian or Alaska Native | — | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 2 (100 mg QHS) Asian | — | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 2 (100 mg QHS) Black or African American | — | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 2 (100 mg QHS) More than one race | — | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 2 (100 mg QHS) Native Hawaiian or Other Pacific Islander | — | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 2 (100 mg QHS) Unknown or Not Reported | — | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 2 (100 mg QHS) White | — | 7 Participants | 7 Participants | — | — |
| Race (NIH/OMB) Cohort 3 (100 mg QPM) American Indian or Alaska Native | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 3 (100 mg QPM) Asian | — | 1 Participants | — | 1 Participants | — |
| Race (NIH/OMB) Cohort 3 (100 mg QPM) Black or African American | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 3 (100 mg QPM) More than one race | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 3 (100 mg QPM) Native Hawaiian or Other Pacific Islander | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 3 (100 mg QPM) Unknown or Not Reported | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 3 (100 mg QPM) White | — | 7 Participants | — | 7 Participants | — |
| Race (NIH/OMB) Cohort 4 (100 mg BID) American Indian or Alaska Native | — | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Cohort 4 (100 mg BID) Asian | — | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Cohort 4 (100 mg BID) Black or African American | — | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Cohort 4 (100 mg BID) More than one race | — | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Cohort 4 (100 mg BID) Native Hawaiian or Other Pacific Islander | — | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Cohort 4 (100 mg BID) Unknown or Not Reported | — | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Cohort 4 (100 mg BID) White | — | 8 Participants | — | — | 8 Participants |
| Sex: Female, Male Cohort 1 (50 mg QHS) Female | 4 Participants | 4 Participants | — | — | — |
| Sex: Female, Male Cohort 1 (50 mg QHS) Male | 4 Participants | 4 Participants | — | — | — |
| Sex: Female, Male Cohort 2 (100 mg QHS) Female | — | 5 Participants | 5 Participants | — | — |
| Sex: Female, Male Cohort 2 (100 mg QHS) Male | — | 2 Participants | 2 Participants | — | — |
| Sex: Female, Male Cohort 3 (100 mg QPM) Female | — | 3 Participants | — | 3 Participants | — |
| Sex: Female, Male Cohort 3 (100 mg QPM) Male | — | 5 Participants | — | 5 Participants | — |
| Sex: Female, Male Cohort 4 (100 mg BID) Female | — | 5 Participants | — | — | 5 Participants |
| Sex: Female, Male Cohort 4 (100 mg BID) Male | — | 3 Participants | — | — | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 7 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 7 / 8 | 5 / 7 | 5 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 8 | 1 / 7 | 0 / 8 | 0 / 8 |
Outcome results
Primary
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.
Time frame: Baseline and Day 14
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (50 mg QHS) | Percent Change From Baseline to Day 14 in 17-hydroxyprogesterone (17-OHP) Morning Window Averages | -60 Percent (%) |
| Cohort 2 (100 mg QHS) | Percent Change From Baseline to Day 14 in 17-hydroxyprogesterone (17-OHP) Morning Window Averages | -58 Percent (%) |
| Cohort 3 (100 mg QPM) | Percent Change From Baseline to Day 14 in 17-hydroxyprogesterone (17-OHP) Morning Window Averages | -53 Percent (%) |
| Cohort 4 (100 mg BID) | Percent Change From Baseline to Day 14 in 17-hydroxyprogesterone (17-OHP) Morning Window Averages | -64 Percent (%) |
Secondary
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.
Time frame: Baseline and Day 14
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (50 mg QHS) | Percent Change From Baseline to Day 14 in Adrenocorticotropic Hormone (ACTH) Morning Window Averages | -54 Percent (%) |
| Cohort 2 (100 mg QHS) | Percent Change From Baseline to Day 14 in Adrenocorticotropic Hormone (ACTH) Morning Window Averages | -63 Percent (%) |
| Cohort 3 (100 mg QPM) | Percent Change From Baseline to Day 14 in Adrenocorticotropic Hormone (ACTH) Morning Window Averages | -64 Percent (%) |
| Cohort 4 (100 mg BID) | Percent Change From Baseline to Day 14 in Adrenocorticotropic Hormone (ACTH) Morning Window Averages | -66 Percent (%) |
Secondary
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.
Time frame: Baseline and Day 14
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (50 mg QHS) | Percent Change From Baseline to Day 14 in Androstenedione Morning Window Averages | -21 Percent (%) |
| Cohort 2 (100 mg QHS) | Percent Change From Baseline to Day 14 in Androstenedione Morning Window Averages | -42 Percent (%) |
| Cohort 3 (100 mg QPM) | Percent Change From Baseline to Day 14 in Androstenedione Morning Window Averages | -51 Percent (%) |
| Cohort 4 (100 mg BID) | Percent Change From Baseline to Day 14 in Androstenedione Morning Window Averages | -64 Percent (%) |