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Androgen Reduction in Congenital Adrenal Hyperplasia (ARCH)

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ClinicalTrials.gov Identifier: NCT03548246
Recruitment Status : Not yet recruiting
First Posted : June 7, 2018
Last Update Posted : June 7, 2018
Sponsor:
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):
University of Texas Southwestern Medical Center

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Study Start Date : September 2019
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : August 2024


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.




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 ]


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03548246


Contacts
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Contact: Perrin C White, MD 214648-3501 perrin.white@utsouthwestern.edu

Locations
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United States, California
Children's Hospital of Los Angeles Not yet recruiting
Los Angeles, California, United States, 90027
Contact: Mitchell Geffner, MD         
United States, Maryland
National Institutes of Health Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: Deborah Merke         
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, New York
North Shore/Long Island Jewish Hospital
New Hyde Park, New York, United States, 11040
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
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Principal Investigator: Perrin C White, MD UT Southwestern Medical Center

Publications:
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Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT03548246     History of Changes
Other Study ID Numbers: 042015-068
First Posted: June 7, 2018    Key Record Dates
Last Update Posted: June 7, 2018
Last Verified: May 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Hyperplasia
Adrenal Hyperplasia, Congenital
Adrenogenital Syndrome
Adrenocortical Hyperfunction
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
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
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