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Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1

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ClinicalTrials.gov Identifier: NCT02574910
Recruitment Status : Recruiting
First Posted : October 14, 2015
Last Update Posted : January 25, 2019
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Michigan
Children's Hospital Los Angeles
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE April 24, 2015
First Posted Date  ICMJE October 14, 2015
Last Update Posted Date January 25, 2019
Actual Study Start Date  ICMJE August 1, 2017
Estimated Primary Completion Date January 23, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 9, 2015)
Normalization of serum androstenedione level [ Time Frame: 7 days ]
The endpoint is the dose of abiraterone acetate that normalizes androstenedione to age-appropriate levels in 7/8 subjects after 7 days of treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02574910 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2015)
  • 17-hydroxyprogesterone levels [ Time Frame: 7 days ]
  • Dihydrotestosterone levels [ Time Frame: 7 days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 9, 2015)
  • Area under the plasma concentration versus time curve (AUC) of abiraterone [ Time Frame: 7 days ]
    Sparse PK will be derived from peak and trough abiraterone levels.
  • Peak Plasma Concentration (Cmax) [ Time Frame: 7 days ]
    Sparse PK will be derived from peak and trough abiraterone levels.
  • Number of adverse events [ Time Frame: 7 days ]
    Safety monitoring in Phase 1 will include liver function tests (AST, ALT, bilirubin) and possible mineralocorticoid effects (blood pressure, plasma renin).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1
Official Title  ICMJE A Phase 1 Multi-Center Study to Assess the Efficacy and Safety of Abiraterone Acetate as Adjunctive Therapy in Pre-Pubescent Children With Classic 21-Hydroxylase Deficiency
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.
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. 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Congenital Adrenal Hyperplasia
Intervention  ICMJE Drug: Abiraterone acetate
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.
Other Name: Zytiga
Study Arms  ICMJE
  • Experimental: Abiraterone acetate 1 mg/kg/d
    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.
    Intervention: Drug: Abiraterone acetate
  • Experimental: Abiraterone acetate 2 mg/kg/d
    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.
    Intervention: Drug: Abiraterone acetate
  • Experimental: Abiraterone acetate 4 mg/kg/d
    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.
    Intervention: Drug: Abiraterone acetate
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 9, 2015)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 23, 2020
Estimated Primary Completion Date January 23, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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 LH >0.3 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 > 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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 9 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Perrin C White, MD 214648-3501 perrin.white@utsouthwestern.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02574910
Other Study ID Numbers  ICMJE 112014-087
1U01HD083493-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: DSMB plan
Supporting Materials: Study Protocol
Responsible Party University of Texas Southwestern Medical Center
Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Collaborators  ICMJE
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • University of Michigan
  • Children's Hospital Los Angeles
Investigators  ICMJE
Principal Investigator: Perrin C White, MD UT Southwestern Medical Center
PRS Account University of Texas Southwestern Medical Center
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP