Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1

NCT02574910 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: STU 112014-0871U01HD083493-01
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Congenital Adrenal Hyperplasia

Outcome Measures

Primary Outcomes (1)

• Normalization of Serum Androstenedione Level

  The original primary endpoint was the dose of abiraterone acetate that normalized androstenedione to age-appropriate levels in 7/8 subjects after 7 days of treatment. However, an insufficient number of participants was enrolled to evaluate the primary endpoint. Therefore, we have instead presented the number of participants at each dose level who did normalize androstenedione to age-appropriate levels.

  7 days

Secondary Outcomes (3)

• 17-hydroxyprogestoerone Levels

  7 days

• Area Under the Plasma Concentration Versus Time Curve (AUC) of Abiraterone

  7 days

• Peak Plasma Concentration (Cmax)

  7 days

Other Outcomes (2)

• Dihydrotestosterone Levels

  7 days

• Number of Adverse Events

  7 days

Study Arms (3)

Abiraterone acetate 1 mg/kg/d

EXPERIMENTAL

Abiraterone acetate will be administered orally at a daily dose of 1 mg/kg for 7 days in addition to the standard of care treatment of hydrocortisone and fludrocortisone.

Drug: Abiraterone acetate

Abiraterone acetate 2 mg/kg/d

EXPERIMENTAL

If the 1 mg/kg/d dosing does not result in androstenedione level normalization, abiraterone acetate will be administered orally at a daily dose of 2 mg/kg for 7 days in addition to the standard of care treatment of hydrocortisone and fludrocortisone.

Drug: Abiraterone acetate

Abiraterone acetate 4 mg/kg/d

EXPERIMENTAL

If the 2 mg/kg/d dosing does not result in androstenedione level normalization, abiraterone acetate will be administered orally at a daily dose of 4 mg/kg for 7 days in addition to the standard of care treatment of hydrocortisone and fludrocortisone.

Drug: Abiraterone acetate

Interventions

Abiraterone acetate DRUG

This is a dose escalation study. Up to 3 successive cohorts of 8 subjects each will receive 7 days of 1, 2 or 4 mg/kg/d of abiraterone acetate, until 7/8 subjects have met the desired endpoint.

Also known as: Zytiga

Abiraterone acetate 1 mg/kg/d; Abiraterone acetate 2 mg/kg/d; Abiraterone acetate 4 mg/kg/d

Eligibility Criteria

• Age: 2 Years - 9 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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).
• 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.
• 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.
• Morning serum androstenedione concentrations \>1.5 x Upper limit normal (ULN) after 7 days of dosing with doses of hydrocortisone required for physiologic replacement.
• 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

You may not qualify if:

• 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.
• Current or history of hepatitis from any etiology, including history of active viral hepatitis A, B, or C.
• 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
• Abnormalities of liver function developing during the study
• Abnormal renal function tests, defined as blood urea nitrogen (BUN) or creatinine \>1.5 ULN for age.
• 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.
• Clinically significant abnormality in the 12-lead electrocardiogram (ECG)
• A history of a malabsorption syndrome.
• Evidence of active malignancy.
• Serious or uncontrolled co-existent disease, including active or uncontrolled infection. Subjects may be rescreened after resolution of any such condition.
• 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.
• Asthma or other condition requiring treatment with systemic corticosteroids within the past 3 months. Asthma treatment with inhaled corticosteroids is permitted.
• 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
• 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

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• University of Michigan: collaborator
• Children's Hospital Los Angeles: collaborator

Study Sites (4)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

National Institutes of Health

Bethesda, Maryland, 20892-1932, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Children's Medical Center

Dallas, Texas, 75235, United States

Location

Related Publications (1)

• Auchus RJ, Buschur EO, Chang AY, Hammer GD, Ramm C, Madrigal D, Wang G, Gonzalez M, Xu XS, Smit JW, Jiao J, Yu MK. Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014 Aug;99(8):2763-70. doi: 10.1210/jc.2014-1258. Epub 2014 Apr 29.

  PMID: 24780050 BACKGROUND

MeSH Terms

Conditions

Adrenal Hyperplasia, Congenital

Interventions

Abiraterone Acetate

Condition Hierarchy (Ancestors)

Adrenogenital Syndrome; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and Caveats

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.

Results Point of Contact

• Title: Dr Perrin White
• Organization: UT Southwestern Medical Center

perrin.white@utsouthwestern.edu

2146489246

Study Officials

• Perrin C White, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PROFESSOR

Study Record Dates

• First Submitted: April 24, 2015
• First Posted: October 14, 2015
• Study Start: August 1, 2017
• Primary Completion: June 3, 2023
• Study Completion: June 3, 2023
• Last Updated: November 4, 2025
• Results First Posted: November 4, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

US (4)