ARCH: Androgen Reduction in Congenital Adrenal Hyperplasia

Sponsor
University of Texas Southwestern Medical Center (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT03548246
Collaborator
National Institutes of Health Clinical Center (CC) (NIH), University of Michigan (Other), Children's Hospital Los Angeles (Other), Feinstein Institute for Medical Research (Other)
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Study Details

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
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
Anticipated Enrollment :
54 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
Anticipated Study Start Date :
Jan 1, 2023
Anticipated Primary Completion Date :
Jan 1, 2026
Anticipated Study Completion Date :
Jan 1, 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 Names:
  • 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 [104 weeks]

      Advancement from baseline in radiographically determined skeletal maturation

    Secondary Outcome Measures

    1. Weight [104 weeks]

      Change from baseline, determined every 6 months.

    2. Body mass index Z-score [104 weeks]

      Change from baseline, determined every 6 months.

    3. Predicted adult height [104 weeks]

      Derived from height and radiographically determined skeletal maturation, determined every 6 months

    4. Hydrocortisone dose required to normalize androstenedione levels [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 [104 weeks]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    2 Years to 9 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Site City State Country Postal Code
    1 Children's Hospital of Los Angeles Los Angeles California United States 90027
    2 National Institutes of Health Bethesda Maryland United States 20892
    3 University of Michigan Ann Arbor Michigan United States 48109
    4 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    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:
    Jun 7, 2018
    Last Update Posted:
    Dec 20, 2021
    Last Verified:
    Dec 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Dec 20, 2021