Classic Congenital Adrenal Hyperplasia, Congenital Adrenal Hyperplasia
Conditions
Keywords
Congenital Adrenal Hyperplasia, CAH, TouCAHn, CRN04894, atumelnant
Brief summary
The purpose of this Phase 2, open-label, sequential dose cohort study is to evaluate the safety, efficacy, and pharmacokinetics (PK) of atumelnant (CRN04894) in participants with classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency.
Detailed description
This Phase 2, open-label, sequential dose cohort study will evaluate the efficacy, safety, PK, and PD of atumelnant (CRN04894) when administered for 12 weeks in participants with CAH caused by 21-hydroxylase deficiency. Up to 42 participants will be enrolled in the study.
Interventions
Atumelnant is an orally active nonpeptide melanocortin 2 receptor (MC2R) or adrenocorticotropic hormone (ACTH) antagonist.
Sponsors
Crinetics Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female participants ≥18 to 75 years of age at the time of signing the Informed Consent Form (ICF). Participants ≥16 years of age may be included in sites located in the United States 2. Classic 21-hydroxylase deficiency 3. On a stable regimen of glucocorticoid replacement (eg, hydrocortisone, prednisolone, prednisone, methylprednisolone) 4. Compliance with glucocorticoid replacement and mineralocorticoid replacement (if applicable) regimen during the Screening Period 5. Minimum total daily dose of ≥15 mg hydrocortisone (or equivalent). For Cohort 4, a mean daily dose of ≥11 mg/m²/day of hydrocortisone or hydrocortisone equivalents will be used for inclusion 6. If on estrogen therapy (any route), dose must be stable for at least 3 months prior to Screening
Exclusion criteria
1. Diagnosis of any other form of CAH other than classic 21-hydroxylase deficiency 2. Dexamethasone use within 30 days of Screening for Cohorts 1-3. In Cohort 4, dexamethasone is permitted 3. History of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic glucocorticoid therapy 4. Night shift workers or any other reason for abnormal sleep/wake cycles 5. Clinically significant unstable medical condition or chronic disease other than CAH 6. History of major surgery/surgical therapy for any cause within 4 weeks prior to Screening 7. Diabetes mellitus treated with insulin for less than 6 weeks prior to Screening, or with change in total daily insulin dose by \>15% within 6 weeks prior to Screening 8. Poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) ≥8.5%(≥69 mmol/mL), or estimated HbA1c based on fructosamine if HbA1c is not evaluable (eg, due to hemoglobinopathies) 9. Participants with hypothyroidism who are not receiving adequate hormone replacement therapy based on thyroid hormone levels measured at the time of Screening 10. History of unstable angina or acute myocardial infarction within 12 weeks prior to Screening or other clinically significant cardiac disease at the time of Screening 11. History of cancer excluding cured/treated dermal squamous or basal cell carcinoma or cervical carcinoma in situ 12. Pregnant or lactating 13. Known history of illicit drug or alcohol abuse within the last year 14. Use of antiandrogen therapy in the past 3 months (eg, spironolactone, finasteride, cyproterone acetate, flutamide) 15. Use of testosterone, androgen-containing supplements, aromatase inhibitors, or growth hormone
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Morning (Before 11:00) Serum Androstenedione (A4) PM Dosing | Baseline and Week 12 | A4 is the principal biochemical measure of disease activity in adult CAH. Blood samples were collected for the measurement of serum concentration of A4 prior to glucocorticoid administration. Baseline is defined as the last non-missing morning window value prior to or on the same day as the first dose date of atumelnant. Change from baseline was obtained by subtracting post-baseline visit value minus baseline value. |
| Change From Baseline in Morning (Before 11:00) Serum Androstenedione (A4) AM Dosing | Baseline and Week 12 | A4 is the principal biochemical measure of disease activity in adult CAH. Blood samples were collected for the measurement of serum concentration of A4 prior to glucocorticoid administration. Baseline is defined as the last non-missing morning window value prior to or on the same day as the first dose date of atumelnant. Change from baseline was obtained by subtracting post-baseline visit value minus baseline value. |
| Number of Participants Reporting of Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and Adverse Events Leading to Discontinuation Throughout the Study | From Day 1 to Up to Week 16 (End of study) | An adverse event (AE) is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. TEAEs were collected in the full analysis set which consisted of all participants who received at least one dose of study drug. A serious AE is defined by its severe clinical consequences: it is any event that results in death, is life-threatening, requires inpatient hospitalization, results in persistent disability, or requires medical intervention to prevent these outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Morning (Before 11:00) Serum 17-hydroxyprogesterone (17-OHP) PM Dosing | Baseline and Week 12 | Elevated levels of the immediate enzyme substrate 17-OHP are indicative of CAH. The secondary efficacy endpoint was change from baseline in morning serum 17-OHP at Week 12. Baseline is defined as the last non-missing morning window value prior to or on the same day as the first dose date of atumelnant. Change from baseline was analyzed using the mean at baseline and at each visit, for all participants with both baseline and the corresponding visit values. |
| Change From Baseline in Morning (Before 11:00) Serum 17-hydroxyprogesterone (17-OHP) AM Dosing | Baseline and Week 12 | Elevated levels of the immediate enzyme substrate 17-OHP are indicative of CAH. The secondary efficacy endpoint was change from baseline in morning serum 17-OHP at Week 12. Baseline is defined as the last non-missing morning window value prior to or on the same day as the first dose date of atumelnant. Change from baseline was analyzed using the mean at baseline and at each visit, for all participants with both baseline and the corresponding visit values. |
Countries
Argentina, Brazil, Germany, India, Italy, United Kingdom, United States
Participant flow
Recruitment details
This was a Phase 2, open-label, sequential dose cohort study that evaluated the safety, efficacy, and pharmacokinetics of atumelnant when administered for 12 weeks in adult participants with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21-OHD). This study included 4 dose cohorts.
Pre-assignment details
A total of 38 participants were enrolled.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 33.2 years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Multiple | 2 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White | 25 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 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 / 11 | 0 / 11 | 0 / 6 | 0 / 10 |
| other Total, other adverse events | 8 / 11 | 8 / 11 | 5 / 6 | 10 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 6 | 0 / 10 |
Outcome results
None listed