The study has been affected significantly by the COVID pandemic, drug supply/drug amendment, low recruitment interest, and FDA approval of another drug with the same indication, so this study has not met its primary endpoint data requirements.

Children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency tend to have elevated circulating levels of androgens, which can accelerate skeletal maturation and adversely impact adult height. Additionally, these children require supraphysiologic doses of hydrocortisone to suppress secretion of adrenal androgen precursors, and this treatment can retard linear growth. This study seeks to use oral abiraterone acetate (Zytiga)as an adjunct to approved CAH therapy (oral hydrocortisone and fludrocortisone) for pre-pubescent children with classic 21-hydroxylase deficiency in order to reduce daily requirement of hydrocortisone. In this Phase 1 study, the investigators will determine the minimum effective dose of abiraterone acetate that normalizes androstenedione levels during the 7-day Treatment Period.

Congenital adrenal hyperplasia (CAH) is an inherited inability to synthesize cortisol in the adrenal gland. More than 90% of cases are cause by deficiency of steroid 21-hydroxylase (CYP21, also termed CYP21A2, P450c21), which is a cytochrome P450 enzyme located in the endoplasmic reticulum. It catalyzes conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, a precursor for cortisol, and progesterone to deoxycorticosterone, a precursor for aldosterone. Aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, shock and if untreated, death in the first few weeks of life. Because patients cannot synthesize cortisol efficiently, the adrenal cortex is stimulated by corticotropin (ACTH) and overproduces cortisol precursors. Some of these precursors are diverted to sex hormone biosynthesis, which may cause signs of androgen excess including ambiguous genitalia in newborn females, rapid postnatal growth in both sexes, and accelerated skeletal maturation and decreased adult height. Patients require supraphysiologic replacement doses of glucocorticoids to suppress the adrenocorticotropic hormone (ACTH)-driven adrenal androgen synthesis. Excessive glucocorticoids are associated with excessive weight gain and slowing of linear growth. It would be desirable in pre-pubertal children to decrease the exposure to excess glucocorticoids while avoiding the adverse effects of inappropriate exposure to androgens. Abiraterone acetate is a prodrug of abiraterone, an irreversible inhibitor of 17α hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]), a key enzyme required for testosterone synthesis. This agent indeed suppresses adrenal androgen secretion in adult women. In this Phase 1 study, the investigators will determine the minimum effective dose of abiraterone acetate that normalizes androstenedione levels during the 7-day Treatment Period.

Inclusion Criteria:

1. Pre-pubescent girls (age 2 years [12 kg minimum] to 8 years inclusive; skeletal age <10 years) or boys (age 2 years [12 kg] to 9 years inclusive; skeletal age <11 years).
2. Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B or clinical course (e.g., adrenal crisis with documented hyperkalemia and hyponatremia, at diagnosis or during a later evaluation; ambiguous genitalia in females). Documentation of one or both parents' genotypes may be required to confirm the subject's genotype.
3. Requirement for standard of care fludrocortisone (any dose) and ≥10 mg/m2/day of hydrocortisone for at least 1 month prior to the study consent.
4. Morning serum androstenedione concentrations >1.5 x Upper limit normal (ULN) after 7 days of dosing with doses of hydrocortisone required for physiologic replacement.
5. At least one parent (or other legally acceptable representative) must sign the informed consent form before the performance of any study procedures, but both parents must sign if both have parental rights. Children who are capable of providing assent (typically 10 years of age and older) must sign an assent form before the performance of any study procedures

Exclusion Criteria:

1. Evidence of central puberty: Tanner Stage >2 for breast development in girls or testicular volume >4 mL in boys, or random luteinizing hormone (LH) >0.3 milli-international units (mIU)/mL. Subjects with pubic and/or axillary hair as the only sign of puberty onset will be allowed.

2. Current or history of hepatitis from any etiology, including history of active viral hepatitis A, B, or C.

3. Patients with baseline hepatic impairment are excluded from this trial. To be eligible for this protocol, patients must meet all of the following criteria:

   AST, ALT and Total bilirubin < ULN Albumin > lower limits of normal (LLN) No evidence of ascites No evidence of encephalopathy

4. Abnormalities of liver function developing during the study

5. Abnormal renal function tests, defined as blood urea nitrogen (BUN) or creatinine >1.5 ULN for age.

6. Significant anemia (hemoglobin < 12 g/dl). If documented to be due to iron deficiency, subjects may be rescreened 3 months after this has been treated.

7. Clinically significant abnormality in the 12-lead electrocardiogram (ECG)

8. A history of a malabsorption syndrome.

9. Evidence of active malignancy.

10. Serious or uncontrolled co-existent disease, including active or uncontrolled infection. Subjects may be rescreened after resolution of any such condition.

11. Concurrent medical condition or disease other than 21-hydroxylase deficiency that may interfere with linear growth or that requires concomitant therapy that is likely to interfere with study procedures or results.

12. Asthma or other condition requiring treatment with systemic corticosteroids within the past 3 months. Asthma treatment with inhaled corticosteroids is permitted.

13. Treatment with potentially hepatotoxic medications (statins); strong inhibitors of CYP3A4 (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), or CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). CYP2C8 substrates (rosiglitazone, pioglitazone, rapaglinide) and CYP2D6 substrates (dextromethorphan, thioridazine) should be avoided

14. Treatment with medications to affect puberty or synthesis of sex steroids, including gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor blockers (e.g., flutamide, spironolactone). However, a gonadotropin releasing hormone agonist may be started during the study for treatment-emergent central puberty without disqualifying the subject

15. Treatment with growth hormone at enrollment or during the course of the study.

16. Known allergies, hypersensitivity, or intolerance to abiraterone acetate or its excipients (refer to United States Prescribing Information).

17. Has received an investigational drug within 4 weeks of the planned first dose of study drug or is currently enrolled in an investigational interventional study.

18. Any condition that, in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, or confound the protocol-specified assessments.

19. Presence or history of cataracts.

Data Safety Monitoring Board plan

4 mg dose level not reached

60 days

No subjects were enrolled at the 4 mg/kg/d dose level.

Enrollment was adversely impacted by study drug availability, requiring reformulation; by the COVID19 pandemic; by competing industry sponsored Phase 2-3 trials of tildacerfont and crinecerfont, which targeted the same outcome in the same population; and by the eventual FDA approval of crinecerfont.