Androgen Reduction in Congenital Adrenal Hyperplasia (ARCH)

• ClinicalTrials.gov Identifier: NCT03548246
• Recruitment Status: Withdrawn
• First Posted: June 7, 2018
• Last Update Posted: February 1, 2023
• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Institutes of Health Clinical Center (CC); University of Michigan; Children's Hospital Los Angeles; Feinstein Institute for Medical Research
• Information provided by (Responsible Party): Perrin C White, MD, University of Texas Southwestern Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Congenital Adrenal Hyperplasia	Drug: Abiraterone acetate; Drug: Placebo; Drug: Hydrocortisone; Drug: Fludrocortisone	Phase 2

Detailed Description:

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. This Phase 2 will determine if, over 24 months, this treatment retards bone age advancement and thus improves adult height prognosis. The present study is the first clinical trial to explore the utility of abiraterone acetate as a means for decreasing daily requirements for glucocorticoids in pre-pubertal children with 21-hydroxylase deficiency.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 1-2 Multi-Center Study to Assess the Efficacy and Safety of Abiraterone Acetate as Adjunctive Therapy in Pre-Pubescent Children With Classic 21-Hydroxylase Deficiency
• Estimated Study Start Date: January 2023
• Estimated Primary Completion Date: January 2026
• Estimated Study Completion Date: January 2026

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Daily placebo, plus usual maintenance treatment with hydrocortisone and fludrocortisone.	Drug: Placebo; Daily placebo for 2 years.; Drug: Hydrocortisone; Hydrocortisone will be administered at a starting dose of 7-9 mg/M2/d and adjusted as necessary based on 17-hydroxyprogesterone and ACTH levels.; Drug: Fludrocortisone; Fludrocortisone will be administered at the dose the subject was taking a study entry and adjusted as necessary to keep plasma renin in the high normal range.
Experimental: Abiraterone acetate; Abiraterone acetate administered daily in dose determined in Phase 1, plus usual maintenance treatment with hydrocortisone and fludrocortisone..	Drug: Abiraterone acetate; Daily oral abiraterone acetate for 2 years. The dose will be specified based on pharmacodynamic data from Phase 1.; Other Name: Zytiga; Drug: Hydrocortisone; Hydrocortisone will be administered at a starting dose of 7-9 mg/M2/d and adjusted as necessary based on 17-hydroxyprogesterone and ACTH levels.; Drug: Fludrocortisone; Fludrocortisone will be administered at the dose the subject was taking a study entry and adjusted as necessary to keep plasma renin in the high normal range.

Outcome Measures

Primary Outcome Measures :

1. Bone age advancement [ Time Frame: 104 weeks ]
   Advancement from baseline in radiographically determined skeletal maturation

Secondary Outcome Measures :

1. Weight [ Time Frame: 104 weeks ]
   Change from baseline, determined every 6 months.
2. Body mass index Z-score [ Time Frame: 104 weeks ]
   Change from baseline, determined every 6 months.
3. Predicted adult height [ Time Frame: 104 weeks ]
   Derived from height and radiographically determined skeletal maturation, determined every 6 months
4. Hydrocortisone dose required to normalize androstenedione levels [ Time Frame: 104 weeks ]
   Hydrocortisone dose (measured as milligrams per meter squared body surface area, per day) will be adjusted in a blinded manner every 3 months by the treating physician to maintain serum androstenedione in the normal range, with increases as necessary to maintain ACTH < 5 times the upper limit of the reference range.
5. Number of adverse events [ Time Frame: 104 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 9 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Pre-pubescent girls (age 2 years [12 kg] to 8 years inclusive; skeletal age ≤9 years) or boys (age 2 years [12 kg] to 9 years inclusive; skeletal age ≤10 years).
• Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B, or by clinical course.
• 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 ULN after 7 days of dosing with doses of hydrocortisone required for physiologic replacement.
• Informed consent .

Exclusion Criteria:

• Evidence of central puberty: Tanner Stage >2 for breast development in girls or testicular volume >4 mL in boys, or random LH >0.3 mIU/mL.
• Current or history of hepatitis from any etiology.
• Abnormal liver function tests (transaminases>3X ULN).
• Abnormal renal function tests (BUN or creatinine >1.5 ULN).
• Significant anemia (hemoglobin < 12 g/dl).
• Clinically significant ECG abnormality
• A history of a malabsorption syndrome.
• Evidence of active malignancy.
• Co-existent disease that may interfere with linear growth or that requires concomitant therapy that is likely to interfere with study procedures or results.
• Treatment with potentially hepatotoxic medications, CYP2D6, strong inhibitors or inducers of CYP3A4
• Treatment with medications to affect puberty or synthesis of sex steroids, including gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor blockers
• Treatment with growth hormone
• Known allergies, hypersensitivity, or intolerance to abiraterone acetate or its excipients.

Contacts and Locations

Locations

United States, California

Children's Hospital of Los Angeles

Los Angeles, California, United States, 90027

United States, Maryland

National Institutes of Health

Bethesda, Maryland, United States, 20892

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Texas

Children's Medical Center

Dallas, Texas, United States, 75235

Sponsors and Collaborators

University of Texas Southwestern Medical Center

National Institutes of Health Clinical Center (CC)

University of Michigan

Children's Hospital Los Angeles

Feinstein Institute for Medical Research

Investigators

• Principal Investigator: Perrin C White, MD; UT Southwestern Medical Center

More Information

Publications:

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.

• Responsible Party: Perrin C White, MD, Professor of Medicine, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03548246
• Other Study ID Numbers: 042015-068
• First Posted: June 7, 2018
• Last Update Posted: February 1, 2023
• Last Verified: January 2023

• 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; Pathologic Processes; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Gonadal Disorders; Hydrocortisone; Fludrocortisone; Abiraterone Acetate; Anti-Inflammatory Agents; Antineoplastic Agents; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 Enzyme Inhibitors