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
Phase: PHASE1
Conditions: Congenital Adrenal Hyperplasia
Sponsor: University of Texas Southwestern Medical Center

STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
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 
NCT number: NCT02574910 
IRB Approved Document date: 08-14-23 
 

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Principal Investigator: Perrin C White, MD 
Sponsor: University of Texas Southwestern Medical Center 
UTSW Protocol Number: UTSW17935/19556 
Funding Source: National Institutes of Health 
Study Drug Source: Sharp Clinical, Bethlehem, PA 18020 
IND Number: 128297 
Version: 1.27 30 August 2021 
 
Contributing investigators: 
Richard Auchus, MD, PhD; University of Michigan 
Mitchell Geffner, MD; Children’s Hospital of Los Angeles 
Deborah Merke, MD; National Institutes of Health 
 
 
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 

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1. 
INTRODUCTION AND PURPOSE ....................................................................................................... 8 
1.1. 
Synopsis ................................................................................................................................ 8 
1.2. 
Primary Outcome Measures .................................................................................................... 8 
1.2.1. 
Phase 1............................................................................................................................................8 
1.2.2. 
Phase 2............................................................................................................................................8 
1.3. 
Secondary Outcome Measures ................................................................................................. 8 
1.3.1. 
Phase 1............................................................................................................................................8 
1.3.2. 
Phase 2............................................................................................................................................8 
1.4. 
Hypotheses (Phase 2) .............................................................................................................. 8 
1.4.1. 
Primary Hypothesis .........................................................................................................................8 
1.4.2. 
Secondary Hypotheses ...................................................................................................................8 
1.5. 
Overall Rationale for the Study ................................................................................................. 9 
1.6. 
Safety endpoints .................................................................................................................... 9 
2. 
Background ................................................................................................................................... 9 
2.1. 
21-Hydroxylase Deficiency ....................................................................................................... 9 
2.1.1. 
Clinical Presentation .......................................................................................................................9 
2.1.2. 
Genetics ....................................................................................................................................... 11 
2.1.3. 
Standard of Care .......................................................................................................................... 13 
2.1.4. 
Potential Improvement in Care From This Study ........................................................................ 14 
2.2. 
Status of Study Drug ............................................................................................................. 14 
2.3. 
Previous Research on Blockade of Sex Steroids in CAH .............................................................. 14 
2.3.1. 
Testolactone and flutamide in children with CAH ....................................................................... 14 
2.3.2. 
Phase 1 Study of Abiraterone Acetate in Adult Women With CAH ............................................ 14 
2.4. 
Previous Pediatric Use of Abiraterone Acetate ......................................................................... 15 
3. 
Concise Summary of Project ......................................................................................................... 16 
3.1. 
Overview of Study Design ...................................................................................................... 16 
3.1.1. 
Phase 1 Dose-Finding .................................................................................................................. 16 
3.1.2. 
Phase 2 Double-Blind ................................................................................................................... 16 
3.2. 
Study Drug Information ......................................................................................................... 16 
3.2.1. 
Mechanism of action ................................................................................................................... 16 
3.2.2. 
Formulation ................................................................................................................................. 16 
3.2.3. 
Physical Description of Study Drug(s) .......................................................................................... 17 
3.2.4. 
Packaging and Labeling ................................................................................................................ 17 
3.2.5. 
Preparation, Handling, and Storage ............................................................................................ 17 

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3.2.6. 
Warning Regarding the Handling of Abiraterone Acetate Tablets or Powder ............................ 17 
3.2.7. 
Drug Accountability ..................................................................................................................... 17 
3.3. 
Dosage and Administration .................................................................................................... 18 
3.3.1. 
Phase 1 Dose-Finding .................................................................................................................. 18 
3.3.2. 
Phase 2 Double-Blind ................................................................................................................... 19 
3.3.3. 
Dose Reductions .......................................................................................................................... 19 
3.3.5. 
Dose Adjustments of Study Drug for Weight Increases During Phase 2 ..................................... 20 
3.3.6. 
Treatment compliance ................................................................................................................ 20 
3.3.7. 
Missed Doses ............................................................................................................................... 20 
3.3.8. 
Missed Study Visits ...................................................................................................................... 21 
3.3.9. 
Rationales for Endpoints ............................................................................................................. 21 
3.3.10. 
Study drug dose rationale ........................................................................................................... 23 
3.3.11. 
Hydrocortisone Dose Rationale ................................................................................................... 24 
3.3.12. 
Age Rationale ............................................................................................................................... 24 
3.3.13. 
Rationale for Pharmacokinetic Sampling Scheme ....................................................................... 25 
3.3.14. 
Other Considerations................................................................................................................... 25 
3.3.15. 
Sample size .................................................................................................................................. 26 
4. 
Study Procedures......................................................................................................................... 26 
4.1. 
Phase 1, Dose Finding Study ................................................................................................... 26 
4.1.1. 
Visit 1, Up to Day -42 ................................................................................................................... 27 
4.1.2. 
Visit 2: Clinic/Laboratory Visit ..................................................................................................... 28 
4.1.3. 
Visit 3, Day 1: Clinic Visit .............................................................................................................. 29 
4.1.4. 
Visit 5, Day 8: Clinic Visit; 24h After End of Treatment Period .................................................... 30 
4.1.5. 
Visit 6, Day 21 (19-23 days): Clinic Visit; Monitoring of Washout ............................................... 31 
4.1.6. 
Phone Visit 6, Day 42 (40-44 days); Final Study Visit .................................................................. 31 
4.1.7. 
Discontinuation of Treatment in Phase 1 .................................................................................... 31 
4.2. 
Phase 2, Randomized Double-Blind Study ................................................................................ 32 
4.2.2. 
Visit 2: Clinic/laboratory Visit ...................................................................................................... 34 
4.2.3. 
Visit 3, Day 0: Clinic Visit .............................................................................................................. 35 
4.2.4. 
Phone Visit 3, Week 2 .................................................................................................................. 36 
4.2.5. 
Visit 4, Week 4: Clinic Visit .......................................................................................................... 36 
4.2.6. 
Phone Visit 4, Week 6-7............................................................................................................... 37 
4.2.7. 
Visit 5, Week 12: Clinic Visit ........................................................................................................ 37 
4.2.8. 
Phone Visit 5, Week 13-14 .......................................................................................................... 37 
4.2.9. 
Visit 6, Week 26: Clinic Visit ........................................................................................................ 37 

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4.2.10. 
Phone Visit 6, Week 27-28 .......................................................................................................... 38 
4.2.11. 
Visit 7, Week 38: Clinic Visit ........................................................................................................ 38 
4.2.12. 
Phone Visit 7, Week 39-40 .......................................................................................................... 39 
4.2.13. 
Visit 8, Week 52: Clinic Visit ........................................................................................................ 39 
4.2.14. 
Phone Visit 8, Week 53-54 .......................................................................................................... 40 
4.2.15. 
Visit 9, Week 64: Clinic Visit ........................................................................................................ 40 
4.2.16. 
Phone Visit 9, Week 65-66 .......................................................................................................... 41 
4.2.17. 
Visit 10, Week 78: Clinic Visit ...................................................................................................... 41 
4.2.18. 
Phone Visit 10, Week 77-78 ........................................................................................................ 42 
4.2.19. 
Visit 11, Week 90: Clinic Visit ...................................................................................................... 42 
4.2.20. 
Phone Visit 11, Week 91-92 ........................................................................................................ 43 
4.2.21. 
Visit 12, Week 104 Clinic Visit; End of Treatment Period ............................................................ 43 
4.2.22. 
Phone Visit 12, Week 105 ............................................................................................................ 44 
4.2.23. 
Visit 13, Week 106: Clinic/laboratory Visit; Monitoring of Washout .......................................... 44 
4.2.24. 
Phone Visit 13, Week 107 ............................................................................................................ 44 
4.2.25. 
Visit 14, Week 108: Clinic/Laboratory Visit; Monitoring of Washout ......................................... 44 
4.2.26. 
Phone Visit 14, Week 109; Final Study Visit ................................................................................ 45 
4.3. 
Evaluations .......................................................................................................................... 49 
4.3.1. 
Vital Signs..................................................................................................................................... 49 
4.3.2. 
Height and weight........................................................................................................................ 49 
4.3.3. 
Physical Examination ................................................................................................................... 49 
4.3.4. 
Clinical Laboratory Tests .............................................................................................................. 49 
4.3.6. 
ECG Evaluations ........................................................................................................................... 51 
4.4.7 
 Cataract Examinations ................................................................................................................ 51 
4.4. 
Sample Collection and Handling ................................................................................................. 51 
4.5. 
End of Study......................................................................................................................... 52 
4.5.1. 
Completion .................................................................................................................................. 52 
4.5.2. 
Unblinding ................................................................................................................................... 52 
4.5.3. 
Discontinuation of Treatment ..................................................................................................... 53 
4.5.4. 
Withdrawal from the Study ......................................................................................................... 53 
4.5.5. 
Transition of Care ........................................................................................................................ 54 
4.6. 
Subjects’ Financial Responsibility ............................................................................................ 54 
5. 
Sub-Study Procedures .................................................................................................................. 54 
5.1. 
Pharmacokinetics Evaluations.................................................................................................... 54 
5.1.1. 
Analytical Procedures ........................................................................................................ 54 

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5.1.2. 
Pharmacokinetic Parameters .............................................................................................. 54 
5.1.3. 
Pharmacodynamic Evaluations .................................................................................................... 55 
5.1.4. 
Pharmacokinetic/Pharmacodynamic Evaluations ....................................................................... 55 
5.2. 
DNA Testing ......................................................................................................................... 55 
6. 
Criteria for Inclusion of Subjects: ................................................................................................... 55 
7. 
Criteria for Exclusion of Subjects:................................................................................................... 56 
8. 
Sources of Research Material ........................................................................................................ 57 
8.1. 
History ................................................................................................................................ 57 
8.2. 
Physical examination............................................................................................................. 57 
8.3. 
Laboratory data .................................................................................................................... 58 
9. 
Recruitment Methods and Consenting Process ............................................................................... 58 
10. 
Potential Risks ......................................................................................................................... 60 
10.1. 
Study drug (abiraterone acetate) (33-35). ............................................................................ 60 
10.1.1. 
Warnings and precautions ........................................................................................................... 60 
10.1.2. 
Adverse reactions ........................................................................................................................ 61 
10.1.3. 
Post Marketing Experience .......................................................................................................... 63 
10.2. 
Drug Interactions .............................................................................................................. 63 
10.2.1. 
Drugs that Inhibit or Induce CYP3A4 Enzymes ............................................................................ 63 
10.2.2. 
Effects of Abiraterone on Drug Metabolizing Enzymes ............................................................... 64 
10.3. 
Increased Abiraterone exposure with food .......................................................................... 64 
10.4. 
Androgen blockade ........................................................................................................... 64 
10.5. 
Study procedures .............................................................................................................. 64 
10.6. 
Risks of standard of care .................................................................................................... 65 
11. 
Subject Safety and Data Monitoring ........................................................................................... 65 
11.1. 
Ensuring Adequate Conventional Therapy ............................................................................ 65 
11.1.1. 
Hydrocortisone ............................................................................................................................ 65 
11.1.2. 
Hydrocortisone Dosing During Illness ......................................................................................... 66 
11.1.3. 
Fludrocortisone ........................................................................................................................... 67 
11.2. 
Study Drug Dose Modifications and Management of Toxicity ................................................. 67 
11.2.1. 
Hypokalemia and hypertension. .................................................................................................. 67 
11.2.2. 
Management of Abnormal Liver Function Tests ......................................................................... 68 
11.3. 
Data Safety and Monitoring Board (DSMB) .............................................................................. 68 
11.3.1. 
Phase 1 Dose-Escalation .............................................................................................................. 68 
11.3.2. 
Phase 2 Double-Blind ................................................................................................................... 69 
11.4. 
Adverse Event Reporting .................................................................................................... 69 

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11.4.1. 
Definitions ................................................................................................................................... 69 
11.4.2. 
Management of Adverse Events, Serious Adverse Events and Special Reporting Situations ..... 71 
11.4.3. 
Recording of Adverse Events, Serious Adverse Events and Special Reporting Situations .......... 71 
11.4.4. 
Maintenance of Safety Information ............................................................................................ 72 
11.4.5. 
FDA Reporting Requirements ...................................................................................................... 72 
11.4.6. 
Transmission Methods: ............................................................................................................... 72 
11.4.7. 
Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), Pregnancies, and 
Special Reporting Situations ........................................................................................................................ 72 
11.4.8. 
Contacting Sponsor Regarding Safety ......................................................................................... 73 
12. 
Procedures to Maintain Confidentiality....................................................................................... 73 
12.1. 
Privacy of Personal Data .................................................................................................... 73 
12.2. 
Disclosure to Outside Entities ............................................................................................. 74 
13. 
Potential Benefits ..................................................................................................................... 74 
14. 
Biostatistics ............................................................................................................................. 75 
14.1. 
General Considerations ......................................................................................................... 75 
14.2. 
Subject Information .............................................................................................................. 75 
14.3. 
Sample Size Determination .................................................................................................... 75 
14.3.1. 
Phase 1 Dose-Finding .................................................................................................................. 75 
14.3.2. 
Phase 2 Double-Blind ................................................................................................................... 75 
14.4. 
Pharmacokinetic and Pharmacodynamic Analyses (Phase 1) ...................................................... 75 
14.4.1. 
Pharmacokinetic analysis ............................................................................................................ 76 
14.4.2. 
Pharmacodynamic Analyses ........................................................................................................ 76 
14.5. 
Outcome Analyses ................................................................................................................ 76 
14.5.1. 
Bone age ...................................................................................................................................... 76 
14.5.2. 
Hydrocortisone dosing ................................................................................................................ 76 
14.5.3. 
Physical Examination ................................................................................................................... 77 
14.5.4. 
Vital Signs..................................................................................................................................... 77 
14.5.5. 
Clinical Laboratory Tests .............................................................................................................. 77 
14.5.6. 
DNA Analyses ............................................................................................................................... 77 
14.6. 
Safety Analyses ................................................................................................................. 77 
14.6.1. 
Adverse Events ............................................................................................................................ 78 
14.6.2. 
Cardiac Function Tests ................................................................................................................. 78 
15. 
ADMINISTRATIVE REQUIREMENTS ................................................................................... 78 
15.1. 
Protocol Amendments ....................................................................................................... 78 
15.2. 
Regulatory Documentation ................................................................................................ 79 

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15.2.1. 
Required Pre-study Documentation ............................................................................................ 79 
15.3. 
Subject Identification, Enrollment, and Screening Logs .......................................................... 79 
15.4. 
Source Documentation ...................................................................................................... 80 
15.5. 
Data Reporting ................................................................................................................. 80 
15.6. 
Data Quality Assurance/Quality Control ............................................................................... 80 
15.7. 
Record Retention .............................................................................................................. 81 
15.8. 
Monitoring ....................................................................................................................... 81 
15.9. 
Study Completion/Termination ........................................................................................... 82 
15.9.1. 
Study Completion ........................................................................................................................ 82 
15.9.2. 
Study Termination ....................................................................................................................... 82 
15.10. 
On-Site Audits................................................................................................................... 82 
15.11. 
Use of Information and Publication ..................................................................................... 82 
 
 
 

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1. 
INTRODUCTION AND PURPOSE 
1.1. 
Synopsis 
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 (reviewed in (1-3)). Supraphysiologic doses of hydrocortisone are required to suppress 
secretion of adrenal androgen precursors, and this treatment can retard linear growth. 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 (4;5). Phase 1 of this 
study is designed to determine the minimal dose of abiraterone acetate dispersed tablets formulated 
from Active Pharmaceutical Ingredient (API)) needed to decrease serum androstenedione to age-
appropriate levels in pre-pubescent children with classic 21-hydroxylase deficiency in order to reduce 
daily requirement of hydrocortisone in these patients. Phase 2 will determine if, over 24 months, this 
treatment retards bone age advancement and thus improves adult height prognosis. Phase 1 and Phase 
2 will determine safety and tolerability in a pediatric population over the short and long term, 
respectively. 
1.2. 
Primary Outcome Measures 
1.2.1. 
Phase 1 
The minimal dose of abiraterone acetate required to suppress excess androgens as indicated by a 
normalization of androstenedione in pre-pubescent children with classic 21-hydroxylase deficiency on 
physiologic replacement doses of hydrocortisone. 
1.2.2. 
Phase 2 
Retardation of bone age advancement in growing pre-pubescent children with classic 21-hydroxylase 
deficiency during treatment with abiraterone acetate for 24 months. 
1.3. 
Secondary Outcome Measures  
1.3.1. 
Phase 1 
The pharmacokinetic (PK) profile of abiraterone. 
1.3.2. 
Phase 2 
Changes in height, weight, body mass index (Z-score for age, predicted adult height, laboratory 
parameters and hydrocortisone dose after treatment with abiraterone acetate; the safety profile of 
abiraterone acetate after multiple dosing in this patient population. 
1.4. 
Hypotheses (Phase 2) 
1.4.1. 
Primary Hypothesis 
Abiraterone acetate retards the advancement of skeletal maturity (bone age) over the study period in 
pre-pubescent children with classic 21-hydroxylase deficiency.  
1.4.2. 
Secondary Hypotheses 
• Abiraterone acetate reduces the daily requirement of hydrocortisone to normalize 
androstenedione concentrations in pre-pubescent children with classic 21-hydroxylase 
deficiency. 

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• Abiraterone acetate is associated with less weight gain than placebo. 
• Abiraterone acetate is associated with lower age-adjusted BMI Z-score than placebo. 
• Abiraterone acetate is associated with higher predicted adult height (adjusted for midparental 
height) than placebo. 
1.5. 
Overall Rationale for the Study 
As noted, children with 21-hydroxylase deficiency require supraphysiologic replacement doses of 
glucocorticoids to suppress adrenocorticotropic hormone (ACTH)-driven adrenal androgen synthesis (3). 
Excessive glucocorticoids are associated with excessive weight gain and slowing of linear growth (6). 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. 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.   See section 2.2 for approved 
indications for abiraterone acetate.  
 
1.6. 
Safety endpoints 
The potential benefits to the subjects would be some retardation in bone age advancement and thus 
improvement in adult height, and avoidance of supraphysiologic glucocorticoid dosing, which itself 
carries many risks including reduced linear growth, excessive weight gain, and abnormal glucose 
tolerance (also see Section 13). The main risks to abiraterone acetate are abnormal liver function tests, 
which should be avoidable with periodic monitoring. Patients taking abiraterone acetate who have 
normally functioning adrenal glands secrete increased amounts of deoxycorticosterone, an active 
mineralocorticoid, and consequently are at risk of developing signs of mineralocorticoid excess such as 
hypertension or heart failure (see Sections 10.1.1.1 and 11.2.1), but patients with 21-hydroxylase 
deficiency are unable to synthesize this steroid and are not at risk for these problems. Cataracts were 
observed in preclinical studies in rats but have not been seen in other nonhuman species including 
monkeys, and have not been observed at an increased rate in clinical trials. Subjects will have yearly 
ophthalmologic exams to monitor for this problem.  
2. 
BACKGROUND 
2.1. 
21-Hydroxylase Deficiency  
2.1.1. 
Clinical Presentation 
Congenital adrenal hyperplasia (CAH) is an inherited inability to synthesize cortisol in the adrenal gland 
(Figure 1).  
 
More than 90% of cases are caused by deficiency of steroid 21-hydroxylase (CYP21, also termed 
CYP21A2, P450c21); in this protocol we will generally use the terms CAH and 21-hydroxylase deficiency 
interchangeably. CYP21 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. Thus, patients with 21-hydroxylase 
deficiency cannot synthesize cortisol efficiently, and so the adrenal cortex is stimulated by corticotropin 

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(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 and rapid postnatal growth in both sexes.  Concomitant aldosterone deficiency may lead to salt 
wasting with consequent failure to thrive, hypovolemia and shock.  
 
There is a range of phenotypes. A severely affected form with a concurrent severe defect in 
aldosterone biosynthesis ("salt wasting" type) and a form with less impairment of aldosterone 
biosynthesis ("simple virilizing" type), are together termed “classic” 21-hydroxylase deficiency. A mild 
"nonclassic" form may be asymptomatic or associated with signs of postnatal androgen excess (1;2). 
Classic 21-hydroxylase deficiency is detected in approximately 1/16,000 births in most populations 
(reviewed in (7)). The nonclassic form occurs in approximately 0.2 percent in the general Caucasian 
population. 
 
Figure 1 Pathways of steroid biosynthesis in 21-hydroxylase deficiency. Enzymes are indicated by their 
activities rather than by systematic names. Steroids that are typically increased in this disorder are 
denoted by upward-pointing arrows. Aromatase and 5α-reductase are located mainly in extra-adrenal 
sites.  
 
Approximately 75 percent of classic 21-hydroxylase deficiency patients cannot adequately 
synthesize aldosterone.  Since aldosterone regulates urinary sodium resorption, untreated individuals 
excrete excessive sodium and develop hypovolemia and hyperreninemia. They cannot excrete 
potassium efficiently and are prone to hyperkalemia, especially in infancy. Cortisol deficiency contributes 
to poor cardiac function, poor vascular response to catecholamines, decreased glomerular filtration, and 

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increased secretion of antidiuretic hormone (reviewed in (8)).  Thus, cortisol and aldosterone deficiency 
together cause hyponatremic dehydration and shock in inadequately treated patients.  
 
Excess 17-OHP, 17-hydroxypregnenolone, and progesterone are further metabolized to 
dehydroepiandrosterone and androstenedione. Once secreted, these substances are further 
metabolized to active androgens (testosterone and dihydrotestosterone). Adrenal secretion of excess 
androgen precursors does not significantly affect male sexual differentiation. In affected female fetuses, 
androgens inhibit the formation of separate vaginal and urethral canals and cause clitoral enlargement, 
fusion of the labial folds, and rostral migration of the urethral/vaginal perineal orifice (reviewed in (9)). 
Thus, severely affected girls typically have ambiguous or male appearing external genitalia with perineal 
hypospadias and chordee, but without palpable testes.  
 
Most importantly for the present study, in inadequately treated patients, postnatal chronic 
exposure to high levels of sex hormones promotes rapid somatic growth (predominantly an androgen 
effect) and advanced skeletal age leading to premature epiphyseal fusion (predominantly an effect of 
extragonadal aromatization of androgens to estrogens )(10). Pubic and axillary hair may develop early. 
Clitoral growth may continue in girls. Young boys may have penile growth despite small testes, since the 
androgens are adrenal in origin. Chronic exposure to androgens may activate the hypothalamic-
pituitary-gonadal axis causing centrally-mediated precocious puberty (2). Linear growth is affected even 
with close therapeutic monitoring. Based on meta-analysis of data from over 30 centers, adult heights 
in classic patients average 1.4 standard deviations below the population mean, or 1.0 standard 
deviations below expectations adjusted for parental heights (6). Both under-treatment and over-
treatment put patients at risk for short stature, the former owing to premature epiphyseal closure 
induced by sex steroids, and the latter to glucocorticoid-induced inhibition of growth (11). The present 
study will test whether pharmacologic blockade of sex steroid biosynthesis will improve growth 
expectations in children with CAH. 
 
2.1.2. 
Genetics 
We will discuss the genetics of this disorder because it is relevant to subject selection. Steroid 
21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations in the CYP21 
(CYP21A2) gene, which is located on chromosome 6p21.3 along with a pseudogene, CYP21P (CYP21A1P) 
(reviewed in (1;2)). Although CYP21 and CYP21P are 98 percent identical in nucleotide sequence, the 
latter has accumulated several mutations that totally inactivate its gene product (Figure 2). Other 
mutations in CYP21P affect pre-mRNA splicing or amino acid sequence. Most mutations causing 21-
hydroxylase deficiency arise from two types of recombination between CYP21 and CYP21P. 

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Approximately 75 percent represent 
deleterious mutations found in the 
pseudogene that are transferred to 
CYP21 during mitosis by a process 
termed gene conversion. About 20 
percent are meiotic recombinations 
that delete a 30 kilobase gene segment 
encompassing the 3' end of the CYP21P 
pseudogene, all of the adjacent C4B 
complement gene, and the 5' end of 
CYP21. This produces a non-functional 
chimeric 
pseudogene. 
Over 
165 
additional mutations comprise the 
remaining 5 percent (12). In patients, 1 
to 2 percent of affected alleles are de 
novo mutations not carried by either 
parent (1). Moreover, many patients 
carry more than one mutation on each 
allele because of the high rate of gene 
conversion. It is therefore important to 
ascertain 
parental 
genotypes 
for 
prenatal counseling and to set phase on 
detected mutations (i.e., determine 
which mutations are on each allele).  
 
Correlations 
between 
CYP21 genotype and phenotype 
have been studied in various 
ethnic and racial groups (13)(and 
reviewed 
in 
(1;2)). 
CYP21 
mutations can be grouped into 
three categories according to the 
level 
of 
enzymatic 
activity 
predicted 
from 
in 
vitro 
mutagenesis 
and 
expression. 
Group A consists of mutations 
such as deletions or nonsense 
mutations that totally ablate 
enzyme activity; these are most 
often associated with salt-wasting 
disease. Group B consists mainly 
of 
the 
missense 
mutation 
Ile172Asn (I172N,999T>A), which 
Figure 2. Genetics of 21-hydroxylase deficiency. A, Diagram of the chromosomal 
region on 6p21.3 containing the 21-hydroxylase genes.  CYP21P and CYP21 are the
steroid 21-hydroxylase pseudogene and active gene, respectively. C4A and C4B 
encode the fourth component of serum complement. STK19  encodes a 
serine/threonine kinase 
, and STK19P is the corresponding truncated pseudogene. On the opposite 
chromosomal strand, TNXB encodes tenascin-X and TNXA is the corresponding 
truncated pseudogene. A bar delineates the 30 kb region that is deleted in 
approximately 20 percent of 21-hydroxylase deficiency chromosomes. 
B, illustration of unequal crossing-over events causing deletions of CYP21 
C, Diagram of CYP21. Numbered boxes represent exons; a 1 kb scale is indicated.
The positions of  mutations normally found in CYP21P are shown; any of these 
can be transferred to CYP21 in gene conversion events. Recombinant enzymes 
carrying each missense mutation have been expressed in cultured cells. The 
percent of normal activity seen in each mutant enzyme is denoted by the
position of each mutation on a vertical scale, with the mutations most severely 
affecting activity at the bottom of the figure. Mutations are: P30L, Pro30Leu;
a6g, mutation in intron 2 activating a cryptic splice site; Δ8nt, 8 nucleotide 
deletion; I172N, Ile172Asn; I236N,V237E, and M239K are a cluster of three
mutations invariably inherited together, Ile236Asn, Val237Glu, Met239Lys; 
V281L, Val281Leu; +1nt, single nucleotide insertion; Q318X, nonsense mutation 
of Gln318; R356W, Arg356Trp; P453S, Pro453Ser.  

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yields an enzyme with 1 to 2 percent normal activity. This permits some aldosterone synthesis and is 
characteristic of patients with simple virilizing disease. A mutation in the second intron (nucleotide 656A 
to G, transferred from CYP21P by gene conversion, 655A/C>G) comprises 25 percent of all classic 21-
hydroxylase deficiency alleles and usually results in abnormally spliced mRNA transcripts. However, a 
small amount of the mRNA is normally spliced, and thus this mutation is associated with both salt-
wasting and simple virilizing disease. This is the only mutation in Group A1. 
The final group of mutations includes Val281Leu (V281L, 1683G>T) and Pro30Leu (P30L, 89C>T), 
which produce enzymes retaining 20 to 60 percent of normal activity; these are associated with 
nonclassic disease. However, if the P30L mutation is present as part of a larger gene conversion 
encompassing at least the first 167 bases of the CYP21A1P/CYP21A2 promoter, it is associated with 
simple virilizing disease. Such gene conversions will be classified as mutation group B for purposes of this 
study (14).When 21-hydroxylase deficiency phenotype is quantitated using 17-OHP levels or scores for 
signs of androgen excess or salt wasting, 80 to 90 percent of phenotypic variation is accounted for by 
CYP21 genotype (i.e., allelic variation). Compound heterozygotes for two different CYP21 mutations 
usually have a phenotype compatible with the milder of the gene defects, and are therefore classified 
into groups A, A1, B or C depending on the more mildly affected allele.  
 
2.1.3. 
Standard of Care  
Patients with classic 21-hydroxylase deficiency require chronic glucocorticoid treatment to inhibit 
excessive secretion of CRH and ACTH by the hypothalamus and pituitary and reduce elevated adrenal 
sex steroids (reviewed in (3)). In children, the preferred drug is hydrocortisone (i.e., cortisol itself) in 
maintenance doses of 10 to 15 mg/M2/day in three divided doses.  Hydrocortisone’s short half-life 
minimizes growth suppression and other adverse side effects of longer acting, more potent 
glucocorticoids such as prednisone and dexamethasone. Because of the short half-life, a single daily dose 
of hydrocortisone is ineffective in regulating adrenocortical secretion. There is divergence of opinion 
regarding whether to administer three equal doses over the day, or provide more hydrocortisone in the 
morning (the time of the normal diurnal ACTH and cortisol peaks) or the evening, to attempt to suppress 
the morning ACTH peak. There appears to be little difference between such regimens in practice (15). 
Stress doses of up to 100 mg/M2/day are given during adrenal crises and life-threatening situations.  
 
Even maintenance doses exceed physiologic cortisol secretion (7 to 9 mg/M2/day in neonates 
and 6 to 8 mg/M2/day in children and adolescents (16)).  Treatment efficacy is best monitored by 
measuring 17-OHP and androstenedione levels at a consistent time in relation to medication dosing. 
Children should also have an annual bone age x-ray and careful monitoring of linear growth. The goal is 
to use the lowest glucocorticoid dose that adequately suppresses adrenal androgens and maintains 
normal growth and weight gain, generally <17 mg/M2/24h of hydrocortisone (11).  One should not strive 
to normalize 17-OHP since this often requires excessive glucocorticoid doses. Rather, 17-OHP levels 
should be partially suppressed to the range of 100 to 1200 ng/dl (3 to 30 nmol/L). Androstenedione and 
testosterone levels (the latter useful only in women and pre-pubertal children) should be maintained at 
a level appropriate for age and sex. 
 

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In addition to glucocorticoid treatment, children with the salt wasting form of 21-hydroxylase 
deficiency require mineralocorticoid (fludrocortisone acetate, usually 0.05 to 0.2 mg daily but up to 0.4 
mg daily in sick neonates) and infants often require sodium chloride supplements.  Blood pressure and 
plasma renin activity or direct renin assays may be used to monitor mineralocorticoid and sodium 
replacement. Hypertension, edema, tachycardia and suppressed plasma renin signify overtreatment 
with mineralocorticoids. Excessive fludrocortisone may also retard growth. 
 
2.1.4. 
Potential Improvement in Care From This Study 
Pharmacologic blockade of sex steroid synthesis in prepubertal children with 21-hydroxylase deficiency 
would retard skeletal maturation and afford more years in which such children could grow. Moreover, if 
glucocorticoid dosing could be reduced to a level sufficient to prevent adrenal insufficiency (but not itself 
suppress secretion of adrenal androgen precursors) this would minimize glucocorticoid-related linear 
growth retardation. The overall effect would be improved adult height. 
 
2.2. 
Status of Study Drug 
Abiraterone acetate tablet formulations (ZYTIGA® brand and several generics) in combination with 
prednisone/prednisolone (hereafter referred to as prednisone) have been approved for the treatment 
of men with metastatic castration-resistant prostate cancer (mCRPC). See section 3.2 for details. 
 
2.3. 
Previous Research on Blockade of Sex Steroids in CAH 
2.3.1. 
Testolactone and flutamide in children with CAH 
The hypothesis that blockade of sex steroid synthesis or action might permit glucocorticoid doses to be 
decreased in CAH patients has been previously tested. A four-drug regimen consisting of low dose 
hydrocortisone, fludrocortisone, testolactone (an aromatase inhibitor to minimize estrogen-induced 
skeletal maturation), and flutamide (an androgen receptor blocker) reduced the rate of bone age 
advancement and slowed weight and height velocity, compared with a standard regimen of higher dose 
hydrocortisone and fludrocortisone (17). No serious adverse effects were observed. This experimental 
therapy is not currently recommended as standard of care (3). 
 
2.3.2. 
Phase 1 Study of Abiraterone Acetate in Adult Women With CAH 
A phase 1 study of abiraterone acetate has been conducted in adult women with 21-hydroxylase 
deficiency (Study 212082HPL1002, hereafter referred to as Study HPL1002)(18). Six subjects were 
treated with each of two doses of abiraterone acetate suspension (100 mg or 250 mg/day) for 6 days, 
which is equivalent to about 1.5 or 4 mg/kg for a typical 60 kg woman). Androstenedione was decreased 
at nadir 4-6 h after the last dose by 90% or 96%, respectively, at 100 mg or 250 mg/d (mean decrease 
from 621 to 41 ng/dl at the higher dose, Figure 3). 24h after the final dose, the androstenedione level 
was still less than 20% of baseline (114 ng/dl) and it was only 30% of baseline (215 ng/dl) after 48h.  
 
Treatment with abiraterone acetate also decreased 17-OHP levels, but the inhibition was not as 
complete and was more transient. At nadir 4h after administration of 250 mg on day 6 of treatment, 17-
OHP had decreased from 9273 ng/dl at baseline to 1362 ng/dl (85% decrease, Figure 3) but it was back 

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to or above baseline levels by 24h after the last dose. The implications of these findings for the design 
of the present study are discussed in section 11.1.1 
 
The mean testosterone concentration also decreased 75% from baseline on Day 6 and remained 
under 50 ng/dL 2 days after the last dose. In addition, concentrations of urine testosterone metabolites, 
etiocholanolone and androsterone glucuronides, decreased as well. Abiraterone acetate was safe and 
well tolerated.  
Figure 3. Pharmacodynamics of abiraterone acetate in adult women with CAH given 250 mg daily of 
abiraterone acetate suspension. Left panel, 17-hydroxyprogesterone. Right panel, androstenedione. 
Scales are ng/dl.  Bars are means of determinations on six subjects; error bars are 1 standard error. 
Samples are numbered as follows: 1, baseline; 2, morning of day 6 at time of administration; 3-6 2h, 4h, 
6h and 8h after dose, respectively;  7, morning of day 7, 24h after last dose; 8, morning of day 8, 48 after 
last dose. The time courses with 100 mg daily were very similar (not shown). 
 
2.4. 
Previous Pediatric Use of Abiraterone Acetate 
We are aware of use of abiraterone acetate in a single pediatric patient,  a 7 year old boy with central 
precocious puberty  (19). This child was treated with 250 mg daily of abiraterone acetate and 8.5 
mg/M2/24h of hydrocortisone under single patient IND 121950, held by a co-investigator on the present 
project, Mitchell Geffner. This dose of abiraterone acetate, which is higher than that anticipated in the 
present study, was well tolerated after 1.8 years of treatment with no serious adverse effects, and 
normal blood pressure, electrolytes and liver function tests. Additionally, three children were treated in 
the present IND for one week each with a previous product, encapsulated powder prepared from 
pulverized commercial abiraterone acetate (Zytiga®) tablets. Two subjects received 1 mg/kg/day, and 
one subject received 2 mg/kg/d. No adverse events were reported. 
 

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3. 
CONCISE SUMMARY OF PROJECT 
3.1. 
Overview of Study Design 
This study consists of Phase 1 and Phase 2 portions. 
 
3.1.1. 
Phase 1 Dose-Finding  
Phase 1 is a dose-finding study which will consist of a Screening Period, a Lead-in Period of 7-9 
days with a possible 7-9 day extension, followed by a 7-day Treatment Period during which patients will 
receive abiraterone acetate dispersed tablets. Subjects will take protocol-specified doses of 
hydrocortisone and fludrocortisone during the Lead-in Period and through the Treatment Period. 
Androstenedione normalization will be determined based on morning androstenedione concentration 
on Day 8 at each dose level. If eligible, subjects have the option to enroll into the randomized Phase 2 
study. 
 
3.1.2. 
Phase 2 Double-Blind 
 The Phase 2 portion of the study is a double-blind 2:1 randomization of abiraterone acetate versus 
placebo with duration of up to 109 weeks. 
 
3.2. 
Study Drug Information 
3.2.1. 
Mechanism of action 
 
Abiraterone acetate  is a prodrug of abiraterone (17-[3-pyridyl] androsta-5,16-dien-3β-ol), an 
androgen biosynthesis inhibitor. The mechanism of action of abiraterone is selective inhibition of 
cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17). CYP17 catalyzes the conversion of 
pregnenolone and progesterone into testosterone precursors, dehydroepiandrosterone (DHEA) and 
androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. Once absorbed 
after oral administration, abiraterone acetate is rapidly converted to abiraterone, the predominant 
active metabolite detected in nonclinical and clinical studies (4;20).  
 
3.2.2. 
Formulation 
Abiraterone acetate active pharmaceutical ingredient (API)will be formulated by Sharp Clinical Services 
(Bethlehem, PA 18020) into 10 mg tablets. The 10 mg tablets will each contain: 
Abiraterone acetate 
10 mg 
Avicel PH-102 (microcrystalline cellulose) 
23.2 mg 
Lactose, MONO 316 
46 mg 
Magnesium stearate 
0.8 mg 
 
 
 Microcrystalline cellulose and lactose are the two excipients in the original Zytiga abiraterone acetate 
tablets. For Phase 2, Sharp will also prepare placebo tablets, which will contain 26.5 mg of 
microcrystalline cellulose and 52.6 mg of lactose. To maximize consistency in Phase 1, tablets should be 

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dispersed into a small amount of water or apple juice immediately before administration, and not 
swallowed whole. Note that, no food is permitted until 30 minutes after the medication is administered; 
see section 3.3.1 for details. For the most comprehensive nonclinical and clinical information regarding 
the efficacy and safety of abiraterone acetate, refer to the latest version of the United States Prescribing 
Information (USPI)  (21). For warnings regarding handling of study drug, see section 3.2.5. 
 
3.2.3. 
Physical Description of Study Drug(s) 
The test formulation of abiraterone acetate supplied for this study are tablets compounded from API. In 
Phase 2, hydrocortisone and fludrocortisone will be supplied by the sponsor (as noted on the face page, 
the Sponsor of this study is UT Southwestern Medical Center and the Sponsor-Investigator, Perrin C 
White, MD; also see section 11.4.8). 
 
3.2.4. 
Packaging and Labeling 
Abiraterone acetate will be provided in tablets containing 10 mg of abiraterone acetate. In Phase 2, 
placebo tablets will be identical in appearance to those containing active drug. Families will be instructed 
to disperse the tablets in a small volume of water or apple juice. Study drug labels will contain 
information to meet the applicable regulatory requirements. 
 
3.2.5. 
Preparation, Handling, and Storage 
The tablets must be stored at controlled temperatures ranging from 20°C to 25°C in a secure facility with 
appropriate alarms and backup storage plans in place. Storage temperatures 15°C to 30°C are allowed 
for pharmacies, hospitals, and warehouses. Records of storage conditions must be maintained and the 
sponsor notified immediately if conditions exceed the range specified.  
 
3.2.6. 
Warning Regarding the Handling of Abiraterone Acetate Tablets or Powder 
This medicine may cause harm to the unborn child if taken by women who are pregnant. It should not 
be taken by women who are breast-feeding. Women who are pregnant or who may be pregnant should 
wear gloves if they need to touch abiraterone acetate tablets.  To minimize the risk of aerosolization, 
dry tablets should not be crushed, but instead dispersed directly in liquid. Study investigators should 
notify any caregivers of this information, to ensure the appropriate precautions are taken.  
 
3.2.7. 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried and 
accounted for throughout the study. The dispensing of study drug to the subject, and the return of study 
drug from the subject, must be documented on the drug accountability form. All participants in this study 
will be minors and references to study subjects refer to the legally acceptable representatives (LAR) as 
appropriate. The subject must be instructed to return all original containers, whether empty or 
containing study drug. All study drugs will be stored and disposed of according to the sponsor's 
instructions. Site staff must not combine contents of the study drug containers. Abiraterone acetate 
must be handled in strict accordance with the protocol and the container label, and must be stored at 
the study site in a limited-access area or in a locked cabinet under appropriate environmental conditions. 

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Unused study drug and study drug returned by the subject (including empty bottles), must be available 
for verification by the sponsor's site monitor during monitoring visits. Unused study drug will be 
destroyed on site according to institutional policies. This must be documented on the drug accounting 
form. Abiraterone acetate should be dispensed under the supervision of the investigator or a qualified 
member of the investigational staff, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. Study drug may not be relabeled or reassigned for use by other subjects. The investigator 
agrees neither to dispense the study drug from, nor store it at, any site other than the study sites agreed 
upon with the sponsor. 
 
3.3. 
Dosage and Administration 
3.3.1. 
Phase 1 Dose-Finding  
In Phase 1, 8 subjects in succession will be given 2 or 4 mg/kg/d of abiraterone acetate, respectively, 
rounded to the nearest 10 mg. By comparison, adult women with CAH in a Phase 1 study were given 100 
mg or 250 mg, equivalent to 1.5 or 4 mg/kg for a typical 60 kg woman (see section 2.3.2). Abiraterone 
acetate will be taken every morning on Study Days 1 through 7 (section 4.1) on an empty stomach, at 
least 30 minutes before a low-fat breakfast (<3 grams of fat; see Appendix A for guidelines and 
suggestions to be provided to parents. Ingested fat increases absorption of abiraterone acetate; the US 
Prescribing Information calls for the patient to have abstained from eating two hours before and one 
hour after dosing, but there are no limits on the composition of the next meal. The schedule in this study 
is set in deference to the typical morning schedules of school age children. The doses used in this study 
are well below those employed for prostate cancer (the standard dose of 1000 mg/d is 13 mg/kg/d for 
a typical 75 kg man), so any increased drug absorption owing to a food effect (as well as the use of 
abiraterone acetate dispersed tablets instead of intact tablets) will be accounted for by the dose finding 
in Phase 1. Hydrocortisone 8 ± 1 mg/m2/day divided into 3 doses, and the patient’s usual dose of 
fludrocortisone (typically 0.05- 0.2 mg/day in one or two doses) taken with food will be given during the 
Lead-in Period and continued through the Treatment Period.  
 
Once 2 subjects have failed to normalize their androstenedione levels at a given dose, advancement to 
the next dose level will be considered by the Sponsor with the approval of the Data Safety and 
Monitoring Board (DSMB, see Section 11.3). The DSMB will determine whether or not to advance to the 
next dose in Phase 1 based on safety and androstenedione normalization (the lowest dose that results 
in normalization of androstenedione levels at least 7 of 8 subjects will be used for all subjects in Phase 
2). As discussed, this was already done for the 1 mg/kg/d dose level.Possible adverse effects of 
abiraterone acetate are discussed in Sections 10.1 and 11.2.  In particular, abnormal liver function tests 
(as defined in Section 11.2.2) in >1 of 8 subjects in a dose cohort, if judged by the site investigator and 
the DSMB to be related to the study drug, will preclude escalation to a higher dose. As discussed in 
Sections 10.1.1.1 and 11.2.1, the mechanism-based toxicities of hypertension, hypokalemia, edema and 
cardiac failure are not anticipated to occur in this study. To the extent they do occur, the DSMB may 
mandate a prospective decrease in fludrocortisone dose upon enrollment of additional subjects. Any 
serious adverse events in Phase 1 will be reviewed by the DSMB for relatedness to study treatment, with 
the consideration that subjects will have taken study drug for only one week. The occurrence of an SAE 
in a subject that is probably related to study treatment will preclude participation in Phase 2.  The 

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occurrence of >1 SAE in a dose cohort judged probably related to treatment will preclude escalation to 
a higher dose. The maximum tolerated dose (MTD) for the study will be declared at the dose level below 
where ≥ 2 SAEs related to study drug occur. If this occurs at the lowest dose level (1 mg/kg/d), the DSMB 
may mandate a cohort at a lower dose level (0.5 mg/kg/d). Note that this will not apply to SAEs typically 
associated with CAH including episodes of adrenal insufficiency, hypotension, or electrolyte 
abnormalities. SAEs associated with mineralocorticoid excess (hypertension, hypokalemia) may, at the 
discretion of the DSMB, prompt a protocol modification to reduce fludrocortisone doses upon starting 
abiraterone acetate (also see Section 11.2.1). 
 
3.3.2. 
Phase 2 Double-Blind 
Hydrocortisone and fludrocortisone will be given each day throughout the study. Hydrocortisone 8 ± 
1 mg/m2/day divided into 3 doses, and the patient’s usual dose of fludrocortisone (typically 0.05- 
0.2 mg/day in one or two doses) taken with food will be given during the Lead-in Period. Once the 
administration of blinded study drug begins, the hydrocortisone dose will first be titrated after 4 weeks, 
then approximately every 12-13 weeks to achieve the desired androstenedione concentration, and also 
avoid excessively high or low 17-hydroxyprogesterone or ACTH levels (discussed in detail in Section 
11.1.1).  Blinded study drug will be administered in the morning on an empty stomach (at least 30 
minutes before a low-fat breakfast or 1 hour before any breakfast).  
 
3.3.3. 
Dose Reductions 
Generally, no dose reductions of the study drug are allowed during the dose-finding and double-blind 
portions of the study (see Section 11.2 for exceptions in Phase 2).  
 
3.3.4. 
Dose Determination for Phase 2 
The following criteria will be used to set the abiraterone acetate dose for Phase 2.  
 
• For each subject in Phase 1, the serum androstenedione level on Day 8 at each dose level will be 
used for determination of normalization. If a dose of abiraterone acetate is missed, then the 
Treatment Period at that dose will be repeated and the androstenedione value on Day 8 from the 
repeated period will be used (also see section 3.3.7.1). The percentage for normalization is based on 
all subjects who received 7 consecutive doses of abiraterone acetate administered from Days 1 
through 7 at each dose level. 
• If the highest planned dose (4mg/kg/d) does not result in normalization of androstenedione levels 
on Day 8 at least 7 of 8 subjects, the DSMB (see Section 11.3) will determine whether to authorize 
testing of one or more additional dose levels (e.g., 8 mg/mg/d). This remains less on a body weight 
basis than the standard adult dosing of 1000 mg/d (13 mg/kg/d for a typical 75 kg man). 
• The lowest dose that results in normalization of androstenedione levels at least 7 of 8 subjects will 
be used for Phase 2.  See Section 14.3.1 for a discussion of sample size in Phase 1. 
• Except as discussed in Section 11.3.2, no dose escalations of abiraterone acetate are allowed during 
the Phase 2 double-blind portion of the study.  

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• PD data will be examined and exposure compared with that seen in adult women with CAH (see 
section 2.3.2) 
3.3.5. 
Dose Adjustments of Study Drug for Weight Increases During Phase 2 
Study drug will be dispensed in 10 mg tablets. Whereas study drug dose will be adjusted at every clinic 
visit (approximately every 13 weeks) as necessary, the frequency at which adjustments are actually made 
will depend on the per-kg dose selected for Phase 2; e.g., a dose of 2 mg/kg/d can be adjusted with every 
5 kg weight gain, whereas a dose of 4 mg/kg/d can be adjusted with every 2.5 kg weight gain. 
 
3.3.6. 
Treatment compliance 
The investigative site will instruct the subject as to the proper procedure for taking all study required 
medications (which may include printed instructions) and recording the dosing of study drug 
(abiraterone acetate or placebo) in the dosing diary, which will include the date, time and dose of study 
drug. The site will confirm that the study drug was taken on an empty stomach each day (at least 2 hours 
since last meal, and at least 30 minutes before a low fat breakfast, or 1 hour before a meal with 
unspecified composition). Subjects will be instructed to bring study medications (including empty vials) 
to their next visit. The site will review the dosing diary, confirm with the subject that it is correct and will 
confirm that the study drug (vials) returned is consistent with the diary. 
 
3.3.7. 
Missed Doses 
3.3.7.1. 
Phase 1 Dose-Finding 
Missed doses of abiraterone acetate will need to be reported to the investigator immediately. If a dose 
of abiraterone acetate is missed, then the Treatment Period at that dose will be repeated, and the 
androstenedione value on Day 8 from the repeated period will be used.  If a missed dose of abiraterone 
acetate occurs, the site will initiate Visit 4A.  During Visit 4A the patient/parent/legally authorized 
representative will be re-educated on study drug administration and provided instructions on when to 
recommence the abiraterone acetate (Repeat treatment period should only begin once PV4A is 
completed). Because abiraterone concentrations and pharmacodynamics effects should reach steady 
state within 6 days (18), we do not expect the prior, interrupted Treatment Period to influence the 
results, and we will not attempt to mandate a particular time interval or to monitor washout prior to 
repeating the Treatment Period.  However, to ensure safety, we will obtain the following tests prior to 
commencing the repeat Treatment Period (also see Sections 4.1.3.2 and 4.1.7): Hematology (CBC, diff, 
platelets), comprehensive metabolic profile (to include serum electrolytes, kidney function tests 
(BUN,Creatinine), liver function tests (aspartate aminotransferase (AST,) and alanine aminotransferase 
(ALT), bilirubin)).   
 
If a dose is missed in the repeated Treatment Period, the subject will be dropped from the study. The 
continuation of treatment may be granted only after a discussion with the sponsor. 
 
One dose of hydrocortisone may be missed during the first 4 days of abiraterone acetate dosing, but no 
missed doses are allowed 1 day prior to PK/PD assessment. 
 

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3.3.7.2. 
Phase 2 Double-Blind  
The importance of treatment compliance should be stressed to the subjects prior to the study start, and 
they should be counseled appropriately regarding any noted deviation from the dosing schedule. 
Subjects will be instructed to bring study medications (including empty vials) to their next visit. Dosing 
diaries will be issued and reviewed at each visit and reconciled with returned study drug (vials). Accurate 
recording of hydrocortisone dosing during double-blind Phase 2 should be stressed to the subject. 
 
Three consecutive missed doses of blinded study drug per month are allowed in the Phase 2 in the 
absence of an adverse event. Subjects who missed more than this for reasons other than adverse events 
may have study treatments discontinued due to non-compliance. The sponsor should be notified if any 
subject meets the criteria for discontinuation of study treatments due to non-compliance. The 
continuation of treatment with blinded study drug for such subjects may be granted only after a 
discussion with the sponsor. Any subjects withdrawn from study treatment should continue follow-up 
for scheduled assessments, see Section 4.5.3. 
 
There is a possibility that subjects receiving placebo may become aware of this fact (see section 4.5.2). 
Such subjects should continue receiving the assigned treatment and return for scheduled evaluations. 
 
3.3.8. 
Missed Study Visits 
3.3.8.1. 
Phase 1 
See Section 4.1 for description of study visits. The following deviations from the timeline are permitted: 
Visit 2 may be postponed up to 2 days (i.e., scheduled 7-9 days after reducing the hydrocortisone dose).  
An exact time interval between Visits 2 and 3 is not specified, but Visit 3 should occur within 42 days (6 
weeks) of Visit 1.  Visit 4 must be 24h after Visit 3. Visit 5 may be postponed for up to 2 days, but the 
final daily dose of abiraterone acetate must be 24h before the visit (i.e., up to 9 days of abiraterone 
acetate treatment is permitted under the protocol. Visits outside mandated intervals will be logged as 
protocol deviations. In light of the centrality of PK data for Phase 1, a missed Visit 4 should be discussed 
with the sponsor to determine the best course of action. 
 
3.3.8.2. 
Phase 2 
Study visits in Phase 2 may be scheduled within a one-week interval. Visits outside mandated intervals 
will be logged as protocol deviations. 
.  
 
3.3.9. 
Rationales for Endpoints 
3.3.9.1. 
Phase 1 Dose-Finding 
This study is designed to explore the use of abiraterone acetate in pre-pubertal children with 21-
hydroxylase deficiency as a means for decreasing excess adrenal androgen secretion and daily 
requirements for glucocorticoids. Currently, abiraterone acetate is not indicated for use in pediatric 
patients, and evidence of safety of daily administration of abiraterone acetate in children is limited to a 

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single published patient (19) plus two patients treated thus far in Phase 1.  Additionally it is necessary to 
account for possibly altered PK owing to [a] the use of abiraterone acetate API in custom-formulated 
tablets, rather than using Zytiga brand tablets or FDA-approved generic tablets, [b] the use of dispersed 
rather than intact tablets, and [c] the instruction to take the study medication 30 minutes before a low 
fat breakfast, rather than one hour before a breakfast of unspecified composition (also see section 3.3.1).  
Therefore, the study is designed to assess abiraterone acetate exposure and response to treatment and 
to ensure that risks to subjects are minimized.  The disposition pathways of abiraterone are not 
anticipated to be different between children (≥2 years of age) and adults. In the proposed study, the PK 
assessments 
will 
be 
used 
to 
characterize 
drug 
exposure 
in 
children. 
In 
addition, 
pharmacokinetics/pharmacodynamics (PK/PD) relationships will be explored. 
 
The most commonly used steroid precursors or androgens for glucocorticoid titration in CAH are 17-OHP 
and androstenedione. 17-OHP is subject to greater diurnal variation and is thus more sensitive to time 
of sampling. The inhibitory effect of abiraterone acetate on 17-OHP levels is relatively transient (see 
Figure 3 in section 2.3.2) and would require titration several hours after a dose, rather than the next 
morning, which would increase the length of study visits and be burdensome for subjects. Moreover, 17-
OHP is not a direct precursor for androgens in humans whereas androstenedione is converted to 
testosterone, mostly outside the adrenal, in a single enzymatic step. Thus, androstenedione is a more 
appropriate endpoint for dose titration if the aim is to minimize inappropriate androgen secretion. 
Dihydrotestosterone will be a secondary endpoint in addition to 17-hydroxyprogesterone. This is 
necessary because 17-hydroxyprogesterone can be indirectly metabolized to dihydrotestosterone, the 
most active known androgen (via the so-called “backdoor pathway”), without using androstenedione as 
an intermediate, and biologically significant levels of dihydrotestosterone might be attained if 17-
hydroxyprogesterone levels are very elevated (22-24).  However, although dihydrotestosterone is 
normally synthesized mainly from testosterone, testosterone would itself be a redundant endpoint 
because it is synthesized only from androstenedione and not via the backdoor pathway. 
 
3.3.9.2. 
Phase 2 
3.3.9.2.1. 
Bone age advancement 
The Phase 2 primary endpoint is advancement in bone age per year advancement in chronologic age, 
which will be determined by repeated measure every 6 months for the 24-month duration of Phase 2. 
This will test the primary hypothesis that blockade of androgen synthesis in prepubertal children with 
21-hydroxylase deficiency will retard skeletal maturation. The duration of the study will not allow testing 
of a treatment effect on final adult height, which would be the ultimate aim of such treatment, so bone 
age maturation is considered the best available surrogate measure (these will be read centrally by an 
automated program, see section 4.3.5).  
 
3.3.9.2.2. 
Hydrocortisone dose 
The difference in the mean daily hydrocortisone dose between subjects who received abiraterone 
acetate compared with placebo is a secondary endpoint. This is clinically meaningful since titration of 
hydrocortisone to minimize effects of inappropriately high concentrations of androgens can be a 
challenge in growing children (3). This often requires supraphysiologic doses of hydrocortisone, which 

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can themselves adversely affect linear growth. Final adult height in CAH patients is inversely related to 
mean glucocorticoid dose (6;11). Therefore, this endpoint is an additional surrogate measure for 
potential beneficial effects of abiraterone acetate treatment on final height in these patients.  
 
3.3.9.2.3. 
Weight 
Treatment with high doses of glucocorticoids can cause excessive weight gain. Patients with CAH have 
increased fat mass. This may have unfavorable metabolic consequence including increased insulin 
resistance (25;26). Therefore, this secondary endpoint will assess whether any reduction in 
glucocorticoid dose with abiraterone acetate treatment is physiologically significant. 
 
3.3.9.2.4. 
Height 
We will measure height (i.e., linear growth rate) in our subjects, but will interpret these data cautiously. 
As noted above in section 3.3.9.2.2, high glucocorticoids can retard linear growth, and so if glucocorticoid 
doses can be reduced in subjects treated with abiraterone acetate, this might be expected to increase 
the growth rate. However, high androgen levels accelerate linear growth (at the expense of even faster 
skeletal maturation) and therefore if high androgen levels can be decreased with abiraterone acetate, 
this might actually slow linear growth. This is indeed what was observed with a four-drug regimen 
consisting of low-dose hydrocortisone, fludrocortisone, testolactone and flutamide (17). The net effect 
of abiraterone acetate treatment on linear growth rate is thus difficult to predict. 
 
3.3.9.2.5. 
Body mass index 
Body mass index will be calculated from each subject’s height and weight using the formula 
mass(kg)/height(m)2. This will be converted to age-specific Z-scores using 2000 Center for Disease 
Control data (27). 
 
3.3.10. 
Study drug dose rationale 
A dose-finding study in adults with classic 21-hydroxylase deficiency (Study HPL1002) has been 
completed (see Section 2.3.2). The primary objective of the study in adults was to determine the 
minimum dose of abiraterone acetate required to normalize serum androstenedione in premenopausal 
women on hormonal contraceptive therapy. This study represents the most appropriate human model 
for pre-pubescent children with the same disease. 
 
As noted in section 3.3.1, subjects in Phase 1 of the present study will be dosed at 2 or 4 mg/kg/d. These 
doses have been selected to be similar to the effective doses per kg for normalization of 
androstenedione in adult women with CAH, as determined in Study HPL1002 (100-250 mg/d, 
corresponding to ~1.5-4 mg/kg/d for a typical 60 kg woman; note however, that HPL1002 utilized a 
suspension--not available for the present study—which may have different bioavailability than the 
dispersed tablets to be used herein). The maximum dose is nominally ~30% of the dose per kg used in 
men with prostate cancer (1000 mg/d, or ~13 mg/kg/d for a 75 kg man).  
 

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As multiple blood samples are drawn for PK and PD in adults, a PK/PD association in adults may be 
extrapolated to children by modeling and simulation. The possibility of extrapolating the PK/PD 
relationship from adult to children will be evaluated further after data from Phase 1 become available. 
We do not anticipate a difference in the model between adults and children at the age range to be 
studied. 
 
3.3.11. 
Hydrocortisone Dose Rationale 
The suggested daily dose of hydrocortisone in children with salt-wasting 21-hydroxylase deficiency is 10-
15 mg/m2 ((3), but the average dose that is actually required to achieve adequate control is at the high 
end of this range (28). Hydrocortisone doses in excess of 15-17 mg/m2/day in adolescents have been 
associated with shorter adult height (3). Only those children who are receiving ≥10 mg/m2 of daily 
hydrocortisone are being included in the study. Normal adrenal glands in children between 2 to 9 years 
secrete the equivalent of 6 to 9 mg/m2 of hydrocortisone per day (16). Thus, the starting hydrocortisone 
dose of 8 + 1 mg/m2 approximates physiologic secretion by the adrenals. This dose is not expected to be 
associated with signs of adrenal insufficiency (3;17).  Monitoring of dosing adequacy and rules for dose 
adjustment are discussed in detail in section 11.1.1 
 
3.3.12. 
Age Rationale 
Children as young as 2 years old will also be included in this study. Children under the age of 2 will not 
be treated with abiraterone acetate because: 
 
• Due to the blood volume required for monitoring, there will be a 12 kg weight requirement as 
part of the eligibility criteria. Children younger than 2 years will be unlikely to meet the weight 
requirement. 
 
• Standard radiology practice is to use radiographs of a hemiskeleton for bone age determination 
in children younger than 2 years, whereas radiographs of the left hand and wrist are used for 
older children. There is increased radiation exposure with the hemiskeleton films, and moreover 
it will be very difficult to compare changes in films over time in each subject if some are of the 
hemiskeleton, and later ones of the left hand and wrist. 
 
• Abiraterone acetate has a well-characterized food effect (29). US Prescribing Information calls 
for the patient to have abstained from eating two hours before and one hour after dosing, with 
no limitation on the composition of the meal. This schedule is difficult for school age children; 
hence subjects in this study are allowed a low fat breakfast 30 minutes after the dose. But even 
this scheduling may be too challenging for children under 2 years old. 
 
Children after the onset of age-appropriate central puberty will not be included in this study because: 
 

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• It is not desirable to interfere with normal age-appropriate effects of puberty including bone 
mineralization, development of secondary sexual characteristics, and the pubertal growth spurt.  
 
• Children in true puberty have activation of the hypothalamus-pituitary axis, and as a result, will 
have very high gonadotropin secretion if sex steroid synthesis is blocked with abiraterone 
acetate. This may have undesirable effects such as polycystic ovaries in females. Note, however, 
that in children who have central precocious puberty triggered by CAH therapy during this study 
(see section 11.1.4), this problem will be treated with a gonadotropin releasing hormone agonist. 
  
Randomization will be stratified by age (2 to 5 years and 6  years or greater) to achieve an approximately 
equal number of subjects within each age group among the 2 treatment groups, because: 
 
• Skeletal maturation is not a truly linear process with age, and it will be desirable to compare 
treatment effects in groups with similar age composition. 
 
• The risk of inducing central precocious puberty may increase with age, and it is desirable to 
compare this risk between treatment groups. 
 
• The data do not exist to derive predicted heights for children with bone age < 6 years. 
 
3.3.13. 
Rationale for Pharmacokinetic Sampling Scheme 
The sampling scheme is intended to minimize blood draws in this pediatric population while providing 
sufficient PK and PD information. We will assess single-dose PK with samples at 0, 1, 2, 4 hours (Day 1) 
and 24 hours (Day 2), which should be adequate to determine maximum plasma concentration (Cmax) 
and elimination half-life. We will not obtain an 8 hour sample on Day 1 because such a long visit would 
be burdensome for these young subjects and their families. The sample on day 8 can be used to predict 
abiraterone steady-state accumulation. As regards pharmacodynamics, the Phase 1 study in adult 
women with CAH (HPL-1002, see Figure 3 in section 2.3.2) demonstrates that the pharmacodynamic 
peaks for suppression of 17-hydroxyprogesterone or androstenedione levels are each at 4 hours post-
dose. Because of blood volume limitations in small children, we will limit PD samples to 4 and 24 hours 
after the first dose, and the sample on Day 8.  The 4 hour sample will be near Cmax, and our main interest 
is the efficacy of steady-state inhibition of androstenedione levels, which we will determine from the 
24h and particularly the 8d samples. 
 
3.3.14. 
Other Considerations 
Contraceptive therapy is not required in this study of pre-pubescent children. However, physicians are 
expected to be vigilant about following children closely for hints of onset of puberty. Frequent physical 
examinations, as well as frequent LH (luteinizing hormone) and FSH (follicle-stimulating hormone) 
assessments will enable physicians to closely monitor the onset of puberty so that contraception will not 
be an issue.  

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3.3.15. 
Sample size 
3.3.15.1. 
Phase 1 
This is a Phase 1 study; the sample size is one of convenience (also see section 14.3.1). Phase 1 will study 
up to 8 evaluable subjects at each of two dose levels. To allow for screen failures and early withdrawals, 
a maximum of 36 subjects will be consented. Additional enrollment beyond this number will require 
review and approval by the DSMB. 
3.3.15.2. 
Phase 2 
The primary endpoint In Phase 2 is bone age advancement (change in bone age per year of chronologic 
age). In a study of flutamide and testolactone as adjunctive therapy in CAH (18), the rate of bone age 
maturation declined from 1.9 ± 0.3 to 0.7 ± 0.2 (mean  + SEM ) bone age year/chronological year in the 
children receiving the regimen with flutamide and testolactone. As there were 14 subjects per arm, this 
implies standard deviations of ~1.0. A sample size of 48 subjects (32 in the abiraterone acetate arm and 
16 in the placebo arm) will have 90% power to detect a difference in bone age advancement of 1 year 
over the 2 year period of the study with a 0.05 2-sided significance level. To allow for ~10% early 
withdrawals, 54 subjects will be randomized (36 to abiraterone acetate and 18 to placebo) and data from 
all subjects will be used for the primary (intent to treat) analysis. Up to 65 subjects will be consented to 
allow for ~15% screen failures. It is anticipated that approximately 13 subjects will be consented at each 
of 5 study sites. These will include UT Southwestern Medical Center, National Institutes of Health, 
Children’s Hospital of Los Angeles, Cohen Children’s Medical Center of New York, and University of 
Michigan. Data will be collected and stored within a common Redcap database for all study sites. 
3.3.15.3. 
Estimate of number of eligible subjects 
The lead site (UT Southwestern Medical Center/Children’s Medical Center Dallas) currently follows 41 
female and 35 male patients with CAH ages 2-9. The NIH Clinical Center follows 60 children in this age 
range. The other participating centers will likely follow similar numbers of patients. Charts on all such 
patients will be reviewed by each site investigator under a HIPAA waiver to identify those with classic 
CAH who might be potentially eligible for this study, and eliminate those with nonclassic CAH.  
 
 
4. 
STUDY PROCEDURES 
4.1. 
Phase 1, Dose Finding Study 
Phase 1 consists of  9 study visits (6 clinic visits and 3 telephone calls) over up to 86 days, but may have 
up to 13 visits (up to 8 clinic visits and up to 5 telephone calls)over 93 days  if Optional Visits and Phone 
Visits 2A and 4A are all utilized (see Sections 4.1.2.2 and 4.1.3.3) . Because the screening period may vary 
in length, study days prior to the Treatment Period are numbered negatively. See Table 1 (and figure 
below) for scheduled study activities. 
 
 

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4.1.1. 
Visit 1, Up to Day -42 
4.1.1.1. 
Consent and Screening 
All subjects must sign the informed consent/assent (see Section 9) prior to the conduct of any study 
procedures. Each parent who is participating in DNA testing must also sign a separate informed consent. 
 
The following screening procedures will be performed: 
• Vital signs, height, weight and temperature 
• Review initial inclusion/exclusion criteria 
• Physical Examination including Tanner staging 
• Medical history and demographics, and concomitant medications. 
• Blood samples for DNA confirmation of diagnosis (including at least one parent), if not already 
available 
• Complete blood count (CBC), Comprehensive Metabolic Panel (CMP), hormone levels (LH, FSH), 
serum 17-OHP, testosterone, dihydrotestosterone, androstenedione, plasma renin activity and 
ACTH. 
• Urinalysis  
• 12-lead ECG 
• Cataract examination (may be postponed to Visit 2). 
• Skeletal age assessment (radiograph of left hand and wrist). An existing radiograph completed 
within 3 months of Visit 1 may be used as long as it was clinically read as <10 years (girls) or <11 
years (boys). 
• Subject will be registered in the central database after signing consent  
 
Subjects must satisfy the initial inclusion and exclusion criteria listed in Sections 0 and 7 respectively, 
except criteria to be evaluated during screening period, prior to initiating the Lead-in Period.  
 
This clinic visit will take approximately 3 hours.  
Up to 16-21 mL of blood will be drawn (see Section 10.5 for discussion of blood volume limits). 
 
4.1.1.2. 
Phone Visit 1: Lead-in Period  
When screening laboratory test results are available and the subject has satisfied all inclusion criteria (it 
is acceptable that DNA testing be pending) and no exclusion criteria (it is acceptable that the cataract 
exam be pending), the subject will be instructed to reduce hydrocortisone dose to 8 ± 1 mg/m2/d (see 
section 3.3.11) and continue the subject’s usual fludrocortisone dose. The subject will then be instructed 
to schedule lab work to be done for Visit 2, 7-9 days after reducing the hydrocortisone dose.  
Adverse events and concomitant medications will be reviewed by study staff. 
 

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4.1.2. 
Visit 2: Clinic/Laboratory Visit 
The subject will be instructed to come to Visit 2 having not yet taken his/her morning hydrocortisone 
and fludrocortisone medication. The subject will have a blood sample obtained for androstenedione 
level between 0800 and 1000.  
This clinic visit will take approximately 40 minutes. Alternatively, this visit may be conducted by prior 
arrangements made by the Sponsor at a local Quest lab. 
Up to 2 mL of blood will be drawn. 
Adverse events and concomitant medications will be reviewed by study staff. 
 
4.1.2.1. 
Phone Visit 2 
The androstenedione level from Visit 2 will be reviewed to ensure that it is >1.5 times the upper limit of 
normal (ULN) for age, and the subject will be contacted by phone. If it is not, the subject will continue in 
the Lead-In Period for an additional 7-9 days and Optional Visit 2A will be scheduled for a repeat sample.  
 
If the subject meets the androstenedione inclusion criterion, s/he will advance to the Treatment Period 
and Visit 3 will be scheduled.  
 
Adverse events and concomitant medications will be reviewed by study staff. 
 
4.1.2.2. 
Optional Visit 2A: Clinic/Laboratory Visit 
This visit will only occur if an extended Lead-In Period is required.  The subject will be instructed to come 
to Visit 2A having not yet taken his/her morning hydrocortisone and fludrocortisone medication. The 
subject will have a blood sample obtained for androstenedione level between 0800 and 1000.  
This clinic visit will take approximately 40 minutes. Alternatively, this visit may be conducted by prior 
arrangements made by the Sponsor at a local Quest lab. 
 
Up to 2 mL of blood will be drawn. 
Adverse events and concomitant medications will be reviewed by study staff. 
 
4.1.2.3. 
Optional Phone Visit 2A 
The androstenedione level from Visit 2A will be reviewed to ensure that it is >1.5 times the upper limit 
of normal (ULN) for age, and the subject will be contacted by phone. 
 
If the androstenedione level at Visit 2A remains <1.5 x ULN, the subject will be counted as a screen failure 
and will be replaced; all study procedures will cease, and the subject will be instructed to resume their 
usual hydrocortisone dosing. 
 
If the subject meets the androstenedione inclusion criterion, s/he will advance to the Treatment Period 
and Visit 3 will be scheduled. 

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Adverse events and concomitant medications will be reviewed by study staff. 
 
4.1.3. 
Visit 3, Day 1: Clinic Visit 
4.1.3.1. 
Treatment Period 
The subject will be instructed to come to Visit 3 fasting and having not yet taken his/her morning 
hydrocortisone and fludrocortisone medication. Baseline fasting blood samples will be drawn between 
0800 and 1000. 
The following procedures will be performed: 
• Review inclusion and exclusion criteria 
• Obtain vital signs, height, weight and temperature 
• Review adverse events and concomitant medications 
• Placement of saline-locked IV catheter to allow repeated blood draws 
• Fasting blood sample to test (Pre-dose labs):  Serum 17-OHP, androstenedione, testosterone,  
dihydrotestosterone, plasma renin activity and ACTH 
• Baseline PK sample (Pre-dose PK) 
• Dispense medications: study drug (abiraterone acetate), and provide education for at home 
dosing of study drug, hydrocortisone and fludrocortisone 
• Provide Subject Diary and instructions 
• Subject will be given first dose of study drug in clinic and wait at least 30 minutes before eating 
a low fat (only) breakfast/snack if they choose 
• PK blood samples at 60, 120 and 240 minutes after study drug dose. and repeated serum 17-OHP, 
androstenedione and dihydrotestosterone at 240 minutes after study drug dose. Each time point 
can vary plus or minus 5 minutes. 
• Following PK blood sample at 240 minutes, the morning doses of hydrocortisone and 
fludrocortisone will be given, and the IV catheter will be removed.  
 
Subjects will be furnished with Study Drug (see section 3.2). Phase 1 of this study is an open-label study. 
No randomization or blinding will occur in Phase 1. Subjects will be instructed to take a daily dose of 
abiraterone acetate on an empty stomach (at least 2 hours since last meal, and at least 30 minutes 
before a low fat breakfast, or 1 hour before a meal with unspecified composition) in the morning (see 
section 3.3.1). The first dose will be administered in the clinic as noted. 
 
This clinic visit will take approximately -5 hours.  
Up to 23 mL of blood will be drawn. 
 
4.1.3.2. 
Visit 4, Day 2: Clinic Visit 
The subject will be instructed to come to Visit 4 fasting and having not yet taken his/her morning study 
drug, hydrocortisone and fludrocortisone medication. 

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• A fasting blood sample will be drawn 24h (plus or minus 20 minutes after the Study Drug for: 
Serum 17-OHP, androstenedione, testosterone, dihydrotestosterone, and a simultaneous 
sample for PK. 
• Following blood sample, daily doses of hydrocortisone and fludrocortisone will be given. The 
subject will take the daily dose of study drug in clinic and wait at least 30 minutes before eating 
a low fat (only) breakfast/snack if they choose 
Up to 8 ml of blood will be drawn. 
Adverse events and concomitant medications will be reviewed by study staff. 
 
4.1.3.3. 
Optional Visit 4A: Clinic/Laboratory Visit 
This visit will occur if the subject misses a dose of abiraterone during the Treatment Period (see 
Section 3.3.7.1). The following procedures will be performed: 
• The subject will have a blood sample obtained between 0800 and 1000 for: CBC and 
Comprehensive Metabolic Panel.  
• Dispense new bottle of study drug (abiraterone acetate). The subject will be instructed to wait 
until Optional Phone Visit 4A to commence taking study drug.   
• Provide a new subject diary and instructions. 
• Re-educate subject/parent/legally authorized representative on study drug administration 
instructions. 
 
Up to 4 mL of blood will be drawn. 
Adverse events and concomitant medications will be reviewed by study staff. 
 
4.1.3.4. 
Optional Phone Visit 4A 
This visit will occur when the results of laboratory tests from Optional Visit 4A have been reviewed to 
ensure that no new exclusion criteria have been met. The subject will be instructed to begin taking study 
drug.  
 
4.1.4. 
Visit 5, Day 8: Clinic Visit; 24h After End of Treatment Period 
The subject will take the last daily dose of abiraterone acetate on Day 7. Visit 5 may be postponed for 
up to 2 days, but the final daily dose of abiraterone acetate must be 24h before the visit (i.e., up to 9 
days of abiraterone acetate treatment is permitted under the protocol). The subject will be instructed 
to come to Visit 5 having not yet taken his/her morning  hydrocortisone or fludrocortisone doses. A blood 
sample will be drawn between 0700 and 1000. This may require caution in timing of the final dose of 
study drug on Day 7 to ensure that the subject is present in the clinic 24 h after the dose. 
If it becomes apparent at Visit 5 that a dose of abiraterone acetate was missed, this Visit becomes Visit 
4A (see above) and Visit 5 is rescheduled. 
The following procedures will be performed: 
• Obtain vital signs, height, weight and temperature 
• Physical examination  

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• Review adverse events, and concomitant medications 
• Blood sample drawn between 0700 and 1000  (but 24h plus or minus 20 minutes after the final 
dose of study drug) to test:  Serum 17-OHP, androstenedione, testosterone, 
dihydrotestosterone, plasma renin activity, ACTH, and a simultaneous sample for PK. 
• Provide education for at home dosing of hydrocortisone and fludrocortisone.  
•  12-lead ECG. 
• Review diary 
• Drug accountability 
 
The subject will be instructed to resume his/her usual hydrocortisone dosing (as at entry into the study) 
as of the day of the screening visit.  The subject will then take his/her morning hydrocortisone and 
fludrocortisone doses.  
 
This clinic visit will take approximately 2 hours.  
Up to 12 mL of blood will be drawn. 
 
4.1.5. 
Visit 6, Day 21 (19-23 days): Clinic Visit; Monitoring of Washout 
The subject will be instructed to come to Visit 6 having not yet taken his/her morning hydrocortisone 
and fludrocortisone medication. The subject will have a blood sample obtained between 0800 and 1000 
for:  
•  CBC, Comprehensive Metabolic Panel, Serum 17-OHP, androstenedione, testosterone, LH, FSH, 
dihydrotestosterone, plasma renin activity and ACTH 
• A urinalysis will be performed.  
Adverse events and concomitant medications will be reviewed by study staff. 
 
This clinic visit will take approximately 40 minutes. Alternatively, this visit may be conducted by prior 
arrangements made by the Sponsor at a local Quest lab. 
 
Up to 16 mL of blood will be drawn. 
 
4.1.6. 
Phone Visit 6, Day 42 (40-44 days); Final Study Visit 
Interval medical history, including adverse events and concomitant medication will be reviewed with the 
subject.  Laboratory values from Visit 6 will be reviewed by the site investigator and hydrocortisone and 
fludrocortisone doses adjusted as necessary (see section 11.1). This telephone call will take 
approximately 30 minutes.  This is the final study visit. The subject will be encouraged to schedule a 
follow-up visit with his or her usual endocrinologist. 
 
4.1.7. 
Discontinuation of Treatment in Phase 1 
The Phase 1 study has only a 1 week treatment period making adverse events unlikely.  A subject's study 
treatment should be discontinued if: 

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• Entry into treatment phase in error (not fulfilling the inclusion and/or exclusion criteria) 
• Consent is withdrawn. 
• The subject misses a dose of study medication in both the original treatment period and the 
optional retreatment period (see Section3.3.7.1). 
• Non-compliance 
• Lost to follow-up 
• The investigator believes that for safety reasons (eg, adverse events) it is in the best interest of 
the subject to stop treatment. Safety concerns that may warrant discontinuation of abiraterone 
acetate include: 
– AST and/or ALT >3x of Study Day 1 levels in the absence of evidence of liver obstruction or other 
explanations for the increase in LFTs, 
– Serum bilirubin to >2x of Study Day 1 levels without any evidence of liver obstruction or 
glucuronidation capacity caused by Gilbert syndrome or some other explanation. 
– Total bilirubin ≥1.5 x ULN accompanied by any AST or ALT elevation. 
– Persistent nausea and vomiting not amenable to medical therapy and lasting more than 72 hours 
and not explainable by other causes than abiraterone acetate treatment. 
• Administration of prohibited medications (see section 7) 
• Signs of central puberty 
 
Subjects who are withdrawn early should be scheduled for an Early Termination Visit that includes all of 
the study assessments listed in section 4.1.5.  The subject should be instructed to resume the 
hydrocortisone dose used at study entry.  
4.2. 
Phase 2, Randomized Double-Blind Study 
Phase 2 consists of up to 30 study visits (including up to 15 clinic visits and up to 15 telephone calls) over 
up to 113 weeks (approximately 2 years). Because the screening period may vary in length, study days 
prior to the Treatment Period will be numbered negatively. See Table 2 (and figure below) for scheduled 
study activities. 
 
4.2.1. 
Visit 1, Up to Day -30  
4.2.1.1. 
Consent and Screening 
Phase 1 subjects entering Phase 2 must be re-consented. Genetic (DNA) testing to confirm diagnosis will 
not be repeated for subjects who participated in Phase 1.  All subjects must sign the informed 

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consent/assent (see Section 9) prior to the conduct of any study procedures. Each parent who is 
participating in DNA testing must also sign a separate informed consent. 
 
The following screening procedures will be performed: 
• Review inclusion and exclusion criteria 
• Obtain vital signs, height, weight and temperature 
• Physical Examination 
• Medical history and demographics, including adverse events, history and concomitant 
medications 
• Blood samples for DNA confirmation of diagnosis (including parents), if not already available 
• Hematology (CBC, diff, platelets), serum electrolytes, kidney function tests (BUN, creatinine), 
liver function tests (AST, ALT, bilirubin), hormone levels (LH, FSH), serum 17-OHP, testosterone, 
dihydrotestosterone, androstenedione and plasma renin activity and ACTH. 
• Urinalysis 12-lead ECG 
• Cataract examination  
• Skeletal age assessment (radiograph of left hand and wrist) 
• Pelvic Ultrasound for girls 
• Testicular Ultrasound for boys 
• Subject will be registered in the central database after signing consent  
 
Subjects must satisfy the inclusion and none of the exclusion criteria listed in Sections 0 and 7 
respectively, prior to initiating the Treatment Phase.  
 
This clinic visit will take approximately 3 hours.  
Volume of blood draw:  9-12 mL (pending necessity of DNA confirmation of diagnosis).  
 
4.2.1.2. 
Phone Visit 1; Lead-in Period  
When screening laboratory test results are available and the subject has satisfied all inclusion criteria 
and no exclusion criteria, the subject will be instructed to reduce hydrocortisone dose to 8 ± 1 mg/m2/d 
(see section 3.3.11) and continue his/her usual fludrocortisone dose. If the subject is taking an increased 
dose of hydrocortisone for the stress of an intercurrent illness (see Section 11.1.2) the dose reduction 
will be postponed until the illness has resolved and the subject has been afebrile for at least 24 hours. 
The subject will then be instructed to schedule lab work to be done for Visit 2. 
 
Adverse events and concomitant medications will be reviewed by study staff. 
 

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4.2.2. 
 
 
 Visit 2: Clinic/laboratory Visit 
The subject will be instructed to come to Visit 2 having not yet taken his/her morning hydrocortisone 
and fludrocortisone medication. The patient will have a blood sample obtained for androstenedione 
level between 0800 and 1000.  
This clinic visit will take approximately 40 minutes.  
Up to 1 mL of blood will be drawn. 
 
4.2.2.1. 
 
Phone Visit 2 
The androstenedione level from Visit 2 will be reviewed to ensure that it is >1.5 times the upper limit of 
normal (ULN) for age, and the subject will be contacted by phone. If it is not, the subject will continue in 
the Lead-In Period and Optional Visit 2A will be scheduled for a repeat sample.  
 
If the subject meets the androstenedione inclusion criterion, s/he will advance to the Treatment Period 
and Visit 3 will be scheduled.  
 
Adverse events and concomitant medications will be reviewed by study staff. 
 
4.2.2.2. 
 
Optional Visit 2A: Clinic/laboratory Visit 
The subject will be instructed to come to Visit 2A having not yet taken his/her morning hydrocortisone 
and fludrocortisone medication. The patient will have a blood sample obtained for androstenedione 
level between 0800 and 1000.  
This clinic visit will take approximately 40 minutes.  
Up to 1 mL of blood will be drawn. 
 
4.2.2.3. 
 
Optional Phone Visit 2A 
The androstenedione level from Visit 2A will be reviewed to ensure that it is >1.5 times the upper limit 
of normal (ULN) for age, and the subject will be contacted by phone. 
If the androstenedione level at Visit 2A remains <1.5 x ULN, the subject will be counted as a screen failure 
and will be replaced; all study procedures will cease, and the subject will be instructed to resume their 
usual hydrocortisone dosing. 
 
If the subject meets the androstenedione inclusion criterion, s/he will advance to the Treatment Period 
and Visit 3 will be scheduled. 
 
Adverse events and concomitant medications will be reviewed by study staff. 

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4.2.3. 
Visit 3, Day 0: Clinic Visit 
4.2.3.1. 
Randomization 
A 2-stage stratified randomization procedure will be applied with stratification factors of age group (2 to 
5 year vs. 6 to 9 year) and study site. Within each stratum, subjects are then assigned to 1 of 2 treatment 
groups at a 2:1 allocation ratio (active drug to placebo) based on the randomization schedule. The 
randomization schedule will be balanced using randomly permuted blocks. All subjects must commence 
treatment within 3 calendar days of randomization. 
The treatment to which a subject is assigned will be determined by consecutive envelopes provided to 
the research pharmacist at each study site by the sponsor-investigator’s statistician. All other study 
personnel will be blinded to the subjects’ treatment assignments. 
4.2.3.2. 
Treatment Period 
The subject will be instructed to come to Visit 3 fasting and having not yet taken his/her morning 
hydrocortisone and fludrocortisone medication. A baseline fasting blood sample will be drawn between 
0800 and 1000.The following procedures will be performed: 
• 
Review adverse events, exclusion criteria, interval medical history and concomitant medications 
• 
Obtain vital signs, height, weight and temperature 
• 
Fasting blood sample to test:  hematology CBC, diff, platelets), serum electrolytes, kidney 
function tests (BUN, Creatinine), liver function tests (AST, ALT and bilirubin), lipid panel, insulin, hormone 
levels (LH, FSH), Serum 17-OHP, androstenedione, testosterone, dihydrotestosterone, plasma renin 
activity and ACTH, and baseline PK sample 
• 
Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing. To ensure standardization, hydrocortisone 
and fludrocortisone will be provided to study pharmacies from a single source.  
• 
Provide Subject Diary and instructions 
• 
Subject will be given first dose of study drug in clinic and wait at least 30 minutes before eating 
a low fat (only) breakfast/snack if they choose 
• 
PK blood sample 120 minutes after study drug dose 
• 
Following PK blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will 
be given  
Subjects will be furnished with Study Drug as well as hydrocortisone and fludrocortisone as part of the 
study. The drugs will be dispensed by the local study pharmacist and dosed as determined in Phase 1. 
Subjects will be instructed to take the Study Drug on an empty stomach (at least 2h since last meal) in 
the morning (see section 3.3.1). The first dose will be administered in the clinic as noted.  
 
This clinic visit will take approximately 2.5-3 hours. Up to 13 mL of blood will be drawn (11 ml at first 
blood draw, 2 ml at second). 

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4.2.4. 
Phone Visit 3, Week 2 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 3 (the previous clinic visit) will be reviewed by the site investigator and hydrocortisone and 
fludrocortisone doses adjusted as necessary (see section 11.1). This telephone call will take 
approximately 30 minutes. 
 
4.2.5. 
Visit 4, Week 4: Clinic Visit 
The subject will be instructed to come to Visit 4 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone or fludrocortisone medication. A baseline fasting blood sample will be drawn 
between 0800 and 1000. 
The following procedures will be performed: 
• Physical examination 
• Obtain vital signs, height, weight and temperature 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests 
(BUN,Creatinine), liver function tests (AST, ALT, bilirubin), hormone levels (LH, FSH), lipid panel, 
insulin, serum 17-OHP, androstenedione, testosterone, dihydrotestosterone and plasma renin 
activity and ACTH. 
• Trough PK sample 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  
• Adjust study medication as needed depending on weight gain of subject.   
• Provide Subject Diary and instructions 
• Subject will be given dose of study drug in clinic and wait at least 30 minutes before eating a 
low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione and dihydrotestosterone 120 
minutes after study drug dose 
• Following PK blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will 
be given  
 
Subjects will be furnished with Study Drug (see section 3.2) as well as hydrocortisone and fludrocortisone 
as part of the study. The drugs will be dispensed by the local study pharmacist and dosed as determined 
in Phase 1 (see section 3.3.2). Subjects will be instructed to take the Study Drug on an empty stomach in 
the morning (see section 3.3.1). The first dose will be administered in the clinic as noted.  
 
This clinic visit will take approximately 2.5-3 hours.  
Up to 16 mL of blood will be drawn (14 ml at first blood draw, 2 ml at second). 
 

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4.2.6. 
Phone Visit 4, Week 6-7 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 4 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.7. 
Visit 5, Week 12: Clinic Visit 
The subject will be instructed to come to Visit 5 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone and fludrocortisone medication. The 2-hour blood sample will be omitted. The 
subject will take the morning hydrocortisone, fludrocortisone and Study Drug doses after the blood 
sample is drawn between 0800 and 1000. 
The following procedures will be performed: 
• Physical examination 
• Obtain vital signs, height, weight and temperature 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, diff, platelets), serum electrolytes, kidney function tests (BUN, Creatinine), 
liver function tests (AST, ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), serum 17-
OHP, androstenedione, testosterone, dihydrotestosterone and plasma renin activity and ACTH. 
• Trough PK sample 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  
• Adjust medication depending on weight gain of subject as needed (see Section3.3.5) 
• Provide Subject Diary and instructions 
• Study Drug and daily dose of hydrocortisone and fludrocortisone will be given after blood sample 
is drawn. 
 
This clinic visit will take approximately 1.5 hours.  
Up to 12 mL of blood will be drawn. 
 
4.2.8. 
Phone Visit 5, Week 13-14 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 5 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.9. 
Visit 6, Week 26: Clinic Visit 
The subject will be instructed to come to Visit 6 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone or fludrocortisone medication. A baseline fasting blood sample will be drawn 
between 0800 and 1000. 
The following procedures will be performed: 
• Physical examination 

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• Obtain vital signs, height, weight and temperature 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests (BUN, 
Creatinine), liver function tests (AST, ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), 
serum 17-OHP, androstenedione, testosterone, dihydrotestosterone and plasma renin activity 
and ACTH. 
• Trough PK sample 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  
• Adjust medication depending on weight gain of subject as needed (see Section3.3.5) 
• Provide Subject Diary and instructions 
• Subject will be given first dose of study drug in clinic and wait at least 30 minutes before eating 
a low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione, and dihydrotestosterone 120 
minutes after study drug dose 
• Urinalysis  
• Following PK blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will 
be given  
• Skeletal age assessment (radiograph of left hand and wrist) 
 
Subjects will be furnished with Study Drug (see section 3.2) as well as hydrocortisone and fludrocortisone 
as part of the study. The drugs will be dispensed by the local study pharmacist and dosed as determined 
in Phase 1 (see section 3.3.2). Subjects will be instructed to take the Study Drug on an empty stomach in 
the morning (see section 3.3.1). The first dose will be administered in the clinic as noted.  
 
This clinic visit will take approximately 2.5-3 hours.  
Up to 16 mL of blood will be drawn (14 ml at first blood draw, 2 ml at second). 
 
4.2.10. 
Phone Visit 6, Week 27-28 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 6 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.11. 
Visit 7, Week38: Clinic Visit 
The subject will be instructed to come to Visit 7 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone and fludrocortisone medication. The 2 hour blood sample will be omitted. The 
subject will take the morning hydrocortisone, fludrocortisone and Study Drug doses after the blood 
sample is drawn between 0800 and 1000. 
The following procedures will be performed: 
• Physical exam by provider 

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• Obtain vital signs, height and weight 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests (BUN, 
Creatinine), liver function tests  (AST, ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), 
serum 17-OHP, androstenedione, testosterone and dihydrotestosterone, and plasma renin 
activity and ACTH   
• PK blood sample prior to abiraterone acetate 
• Adjust study medication depending on weight gain of subject (see Section3.3.5) 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  
• Provide Subject Diary and instructions 
• Subject will be given dose of study drug in clinic and wait at least 30 minutes before eating a 
low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione and dihydrotestosterone 120 
minutes after study drug dose 
 
 This clinic visit will take approximately 1.5 hours.  
Up to 12 mL of blood will be drawn. 
 
4.2.12. 
Phone Visit 7, Week 39-40 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 7 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.13. 
Visit 8, Week 52: Clinic Visit 
The subject will be instructed to come to Visit 8 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone or fludrocortisone medication. A baseline fasting blood sample will be drawn 
between 0800 and 1000. 
 
The following procedures will be performed: 
• Physical examination 
• Obtain vital signs, height, weight and temperature 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests (BUN, 
Creatinine), liver function tests (AST, ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), 
serum 17-OHP, androstenedione, testosterone, dihydrotestosterone and plasma renin activity 
and ACTH. 
• Trough PK sample 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  

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• Adjust medication depending on weight gain of subject as needed (see Section3.3.5) 
• Provide Subject Diary and instructions 
• Subject will be given dose of study drug in clinic and wait at least 30 minutes before eating a 
low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione and dihydrotestosterone 120 
minutes after study drug dose 
• Urinalysis  
• Following blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will be 
given  
• Cataract examination  
• Skeletal age assessment (radiograph of left hand and wrist) 
• Pelvic Ultrasound for girls 
• Testicular Ultrasound for boys 
 
Subjects will be furnished with Study Drug (see section 3.2) as well as hydrocortisone and fludrocortisone 
as part of the study. The drugs will be dispensed by the local study pharmacist and dosed as determined 
in Phase 1 (see section 3.3.2). Subjects will be instructed to take the Study Drug on an empty stomach in 
the morning (see section 3.3.1). The first dose will be administered in the clinic as noted.  
 
This clinic visit will take approximately 2.5-3 hours.  
Up to 16 mL of blood will be drawn (14 ml at first blood draw, 2 ml at second). 
 
4.2.14. 
Phone Visit 8, Week 53-54 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 8 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.15. 
Visit 9, Week 64: Clinic Visit 
The subject will be instructed to come to Visit 9 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone and fludrocortisone medication.   
A baseline fasting blood sample will be drawn between 0800 and 1000. 
 
The following procedures will be performed: 
• Physical exam by provider 
• Obtain vital signs, height and weight 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests (BUN, 
creatinine), liver function tests (AST, ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), 

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serum 17-OHP, androstenedione, testosterone, dihydrotestosterone, and plasma renin activity 
and ACTH 
• Trough PK sample 
• Adjust study medication depending on weight gain of subject (see Section3.3.5) 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  
• Provide Subject Diary and instructions 
• Subject will be given dose of study drug in clinic and wait at least 30 minutes before eating a 
low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione and dihydrotestosterone 120 
minutes after study drug dose 
 
Following PK blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will be 
given.  
This clinic visit will take approximately 2.5 hours.  
Up to 16mL of blood will be drawn (14 ml at first blood draw, 2 ml at second). 
 
4.2.16. 
Phone Visit 9, Week 65-66 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 9 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.17. 
Visit 10, Week 78: Clinic Visit 
The subject will be instructed to come to Visit 10 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone or fludrocortisone medication. A baseline fasting blood sample will be drawn 
between 0800 and 1000. 
The following procedures will be performed: 
• Physical examination 
• Obtain vital signs, height, weight and temperature 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests (BUN, 
Creatinine), liver function tests (AST, ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), 
serum 17-OHP, androstenedione, testosterone, dihydrotestosterone, and plasma renin activity 
and ACTH. 
• Trough PK sample 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  
• Adjust medication depending on weight gain of subject as needed (see Section3.3.5) 
• Provide Subject Diary and instructions 

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• Subject will be given dose of study drug in clinic and wait at least 30 minutes before eating a 
low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione and dihydrotestosterone 120 
minutes after study drug dose 
• Urinalysis  
• Following PK blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will 
be given  
• Skeletal age assessment (radiograph of left hand and wrist) 
 
Subjects will be furnished with Study Drug (see section 3.2) as well as hydrocortisone and fludrocortisone 
as part of the study. The drugs will be dispensed by the local study pharmacist and dosed as determined 
in Phase 1 (see section 3.3.2). Subjects will be instructed to take the Study Drug on an empty stomach in 
the morning (see section 3.3.1). The first dose will be administered in the clinic as noted.  
 
This clinic visit will take approximately 2.5-3 hours.  
Up to 16 mL of blood will be drawn (14 ml at first blood draw, 2 ml at second). 
 
4.2.18. 
Phone Visit 10, Week 77-78 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 10 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.19. 
Visit 11, Week 90: Clinic Visit 
The subject will be instructed to come to Visit 11 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone and fludrocortisone medication. A baseline fasting blood sample will be drawn 
between 0800 and 1000. 
The following procedures will be performed: 
• Physical exam by provider 
• Obtain vital signs, height and weight 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests (BUN, 
creatinine), liver function tests (AST,ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), 
serum 17-OHP, androstenedione, testosterone, dihydrotestosterone, and plasma renin activity 
and ACTH 
• Trough PK sample 
• Adjust study medication depending on weight gain of subject (see Section3.3.5) 
• Dispense medications: study drug (abiraterone acetate or placebo), hydrocortisone and 
fludrocortisone and provide education for at home dosing  
• Provide Subject Diary and instructions 

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• Subject will be given dose of study drug in clinic and wait at least 30 minutes before eating a 
low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione and dihydrotestosterone 120 
minutes after study drug dose 
• Following PK blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will 
be given  
 
This clinic visit will take approximately 2.5-3 hours.  
Up to 16 mL of blood will be drawn (14 ml at first blood draw, 2 ml at second). 
 
4.2.20. 
Phone Visit 11, Week 91-92 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 11 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.21. 
Visit 12, Week 104 Clinic Visit; End of Treatment Period 
The subject will be instructed to come to Visit 12 fasting and having not yet taken his/her morning Study 
Drug, hydrocortisone or fludrocortisone medication. A baseline fasting blood sample will be drawn 
between 0800 and 1000. 
The following procedures will be performed: 
• Obtain vital signs, height, weight and temperature 
• Physical Examination 
• Review adverse events exclusion criteria, interval medical history and concomitant medications 
• Hematology (CBC, differential, platelets), serum electrolytes, kidney function tests (BUN, 
creatinine), liver function tests (AST, ALT, bilirubin), lipid panel, insulin, hormone levels (LH, FSH), 
serum 17-OHP, androstenedione, testosterone, dihydrotestosterone, and plasma renin activity 
and ACTH. 
• Trough PK sample 
• Dispense medications:  Final hydrocortisone and fludrocortisone and provide education for at 
home dosing  
• Provide Subject Diary and instructions 
• Subject will be given final dose of study drug in clinic and wait at least 30 minutes before eating 
a low fat (only) breakfast/snack if they choose 
• PK blood sample and repeated serum 17-OHP, androstenedione and dihydrotestosterone 120 
minutes after study drug dose 
• Urinalysis  
• Following PK blood sample at 120 minutes, daily dose of hydrocortisone and fludrocortisone will 
be given  
• 12-Lead ECG will be performed immediately before the 120 minute PK blood sample. 
• Skeletal age assessment (radiograph of left hand and wrist) 

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• Testicular ultrasound for boys 
• Pelvic ultrasound for girls 
• Cataract examination 
 
The subject will be instructed to increase the hydrocortisone dose to the dose (per square meter of body 
surface area) that the subject was taking at Phase 2 study enrollment. The subject’s current 
fludrocortisone dose will be continued. Subject will be transitioned back to standard of care and given 
new prescriptions with instructions for post study follow up care. 
 
This clinic visit will take approximately 4 hours.  
Up to 16 mL of blood will be drawn (14 ml at first blood draw, 2 ml at second). 
 
4.2.22. 
Phone Visit 12, Week 105 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 12 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.23. 
Visit 13, Week 106: Clinic/laboratory Visit; Monitoring of Washout 
The subject will be instructed to come to Visit 13 having not yet taken his/her morning hydrocortisone 
and fludrocortisone medication. The patient will have a blood sample obtained for serum 17-OHP, 
androstenedione, dihydrotestosterone, and plasma renin and ACTH levels between 0800 and 1000.  
This clinic visit will take approximately 40 min.  
Up to 5 mL of blood will be drawn. 
 
4.2.24. 
Phone Visit 13, Week 107 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 13 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
4.2.25. 
Visit 14, Week 108: Clinic/Laboratory Visit; Monitoring of Washout 
The subject will be instructed to come to Visit 14 having not yet taken his/her morning hydrocortisone 
and fludrocortisone medication. The patient will have a blood sample obtained for serum 17-OHP, 
androstenedione, ACTH, plasma renin activity, and dihydrotestosterone level between 0800 and 1000.  
This clinic visit will take approximately 40 minutes.  
Up to 5 mL of blood will be drawn. 
 

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4.2.26. 
Phone Visit 14, Week 109; Final Study Visit 
Interval medical history, including adverse events, will be reviewed with the subject. Laboratory values 
from Visit 14 will be reviewed by the site investigator and hydrocortisone and fludrocortisone doses 
adjusted as necessary (see section 11.1). This telephone call will take approximately 30 minutes. 
 
This is the final study visit. 
 

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TABLE 1: Phase 1 Multi-Center Study to Assess the Efficacy and Safety of Abiraterone Acetate as Adjunctive Therapy in  
 
1. Subjects will have an optional Visit 2A only if lab results from Visit 2 indicate that androstenedione level is not at least 1.5 times greater than the upp
Visit 2A indicate that androstendione levels are still less than 1.5 times ULN the subject will be withdrawn from the study.  Optional visit 3A and phone v
 of abiraterone during the Treatment Period (see Section 3.3.7.1). 
2. Clinic Visits 3-4 may be up to +2 days. Phone Visits (PV) are required between Clinic Visits and at the End of Study. PV should be completed when lab 
Dose adjustment /confirmation for hydrocortisone and fludrocortisone should be completed at time of PV (See protocol section 11.1). 
3. Results of previous testing may be used. 
4. See Protocol Section 11.2.2 for management of abnormal liver function tests. 
5. Blood samples  to be drawn between 0800-1000 AM in a fasting state. Morning hydrocortisone and fludrocortisone dosing should be withheld until a
PHASE 1 
Screening
Visit Number 
1
PV1
2
PV2
2A 5
PV2A
3
4
4A
PV 4A
V5
6 5
PV6
Time (days)
up to -30
up to -20
up to -10
1
2
8
21
42
Visit Type2
CLINIC
PHONE LAB Only PHONE Optional 
LAB 
Only
Optional 
PHONE
CLINIC  
Fasting5
CLINIC   
Fasting5
Optional 
Clinic/lab 
visit 
Optional
 Clinic 
EOT 
Monitor 
of 
Washout
PHONE 
Final 
visit
Informed Consent and Assent (ICF and IAF) 
X
Review of Inclusion/Exclusion criteria 
X
X
X
X
Medical history and demographics 
X
X
Review adverse effects
X
X
X
X
X
X
Con Meds
X
X
X
X
X
X
Tanner staging
X
Physical examination
X
X
Height and weight 
X
X
X
Vital signs 
X
X
X
Cataract exam
X
12-lead ECG
X
X
Blood samples for DNA confirmation of diagnosis
X
Complete blood count
X
X
X
Comprehensive metabolic panel
X
X
X
LH, FSH
X
X
ACTH
X
X
X
X
Serum 17-hydroxyprogesterone (17-OHP)   
X
X
X
X
X
Serum androstenedione   
X
X
X
X
X
X
X
Dihydrotestosterone
X
X
X
X
X
Testosterone
X
X
X
X
X
Plasma renin activity  
X
X
X
X
PK Blood Sampling
X
X
X
Urinalysis 
X
X
Skeletal age assessment
X
Dispense subject diary and instructions
X
X
Dispense Study Drugs6
X
X
Review Labs (Dose Adjustment of hydrocortisone)7
X
X
X
X
Review Labs (Final off study Dose Adjustment)7
X
Blood volumes, ml
16-21
2
2
23
8
4
12
16
Lead -In
Treatment
Follow Up

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6. Study Drugs include: Abiraterone acetate or placebo, hydrocortisone, and fludrocortisone. 
7. See Protocol Section 11.1.1 for dose adjustment parameters. 
 
 

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TABLE 2: Phase 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 
 
 
 
PHASE 2
SCREENING
Visit Number 
1
2A1,6
2 6
3
4
5
6
7
8
9
10
11
12
13
14 6
EOS
Time in Weeks (Screening through 
randomization in Days)
up to -30
up to -20
up to -10
0
4
12
26
38
52
64
78
90
104
106
108
109
Visit Type2 (PV=PHONE VISIT)
CLINIC
PV
LAB Only
PV
LAB Only
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC  
Fasting6
PV
CLINIC EOT 
Fasting6
PV
LAB Only
PV
LAB Only
PV
Informed Consent and Assent (ICF and IAF) 
X
Review of Inclusion/Exclusion criteria 
X
X
Medical history and demographics 
X
Review adverse effects and medical history
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization/IWRS
X
Physical examination/Tanner Stage4
X
X
X
X
X
X
X
X
X
X
Height and weight 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
Blood samples for DNA confirmation of 
diagnosis3
X
Hematology (CBC, diff, platelets)
X
X
X
X
X
X
X
X
X
X
X
Serum electrolytes  
X
X
X
X
X
X
X
X
X
X
X
Kidney function tests (BUN,Creatinine)
X
X
X
X
X
X
X
X
X
X
X
Liver function tests  (AST,ALT, bilitrubin)5
X
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
X
X
X
X
Insulin
X
X
X
X
X
X
X
X
X
X
LH, FSH
X
X
X
X
X
X
X
X
X
X
X
ACTH
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 17-hydroxyprogesterone (17-OHP)   
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum androstenedione   
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Testosterone 
X
X
X
X
X
X
X
X
X
X
X
Dihydrotestosterone
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma renin activity  
X
X
X
X
X
X
X
X
X
X
X
X
X
PK /PD Blood Sampling  7
X
X
X
X
X
X
X
X
X
X
Urinalysis (dipstick)
X
X
X
X
X
Skeletal age assessment
X
X
X
X
X
Dispense Study Drug, hydrocortisone and 
fludrocortisone 
X
X
X
X
X
X
X
X
X
X
Review Labs and adjust dose of 
hydrocortisone and fludrocortisone)8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Labs (Final off study Dose 
Adjustment) 8
X
Cataract Examination
X
X
X
Testicular Ultrasound for boys4
X
X
X
Pelvic Ultrasound for girls4
X
X
X
Blood volumes, ml
12
1
1
13
16
12
16
12
16
16
16
16
16
5
5
2. Clinic Visits 3-14 may be up to +2 days. Phone Visits (PV) are required between Clinic Visits and at the End of Study . PV should be completed when lab results from previous Clinic Visit are available. Dose adjustment /confirmation for hydrocortisone and fludrocortisone should be 
LEAD-IN
TREATMENT
WASH OUT
FOLLOW UP
1. Subjects will have an optional Visit 2A only if lab results from Visit 2 indicate that androstenedione level is not at least 1.5 times greater than the upper limit of normal (ULN). If lab results from visit 2A indicate that androstendione levels are still less than 1.5 times ULN the subject will be 
3. Results of previous testing may be used.
4. If signs of central precocious puberty present during the study, a gonadotropin releasing hormone agonist may be used for treatment (See Protocol  Section 11.1.4).
5.See Protocol Section 11.2.2 for management of abnormal liver function tests.
6. Blood  samples  to be drawn between 0800-1000 AM in a fasting state. Morning hydrocortisone and fludrocortisone dosing should be withheld until after blood samples are collected. 
8. See Protocol Section 11.1 for dose adjustment parameters.
7. PK/PD blood sampling requires 2 samples 120 minutes apart

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4.3. 
Evaluations 
4.3.1. 
Vital Signs 
Oral, otic or temporal temperature (same method should be used throughout the study (degrees 
Celsius)), pulse, respiratory rate, and blood pressure (same method should be used throughout the 
study) will be measured as outlined in the Time and Events Schedules (Tables 1 and 2) and Sections 4.1 
and 4.2. Blood pressure and heart rate measurements will be assessed while subject is sitting with a 
completely automated device, if available. When vital signs and blood draws are both required, the vital 
sign measurements will be obtained prior to the scheduled blood draw visit. 
4.3.2. 
Height and weight 
Subject height will be measured with a properly calibrated stadiometer. Heights will be measured three 
times in immediate succession (with subjects instructed to bend and stretch between measurements) 
and the average used. Weight will be measured in kilograms and with the subject lightly clothed and 
without shoes. 
4.3.3. 
Physical Examination 
Physical examinations, including general appearance, head, eyes, ears, nose and throat (HEENT), chest, 
cardiac, abdomen, extremities and neurologic and lymph node examinations, and Tanner staging and 
testicular volume will be conducted at the times specified in the Time and Events Schedules (Tables 1 
and 2) and Sections 4.1 and 4.2. Any clinically significant abnormality in physical findings noted during 
the study should be reported as an adverse event. Any clinically significant abnormalities persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a clinically 
stable endpoint. 
4.3.4. 
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will be 
collected. The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the CRF. The 
following tests will be performed by the reference laboratory (Quest): 
•  Complete Blood Count(includes Differential and Platelets)  
White blood cell (WBC) 
Red blood cell (RBC) 
Hemoglobin 
-Hematocrit 
MCV 
Platelet count 
MCH 
MCHC 
RDW 
MPV and Differential (Absolute and Percent -
Neutrophils, 
Lymphocytes, 
Monocytes,
Eosinophils, and Basophils) 
*If abnormal cells are noted on a manual review of the peripheral blood smear or if the automated 
differential information meets specific criteria, a full manual differential will be performed. 

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•  Comprehensive Metabolic panel 
Sodium 
Calcium 
Potassium 
Albumin 
Alkaline Phosphatase 
Albumin/Globulin Ratio (calculated) 
Chloride 
TProtein, total 
Blood urea nitrogen (BUN) 
BUN/Creatinine Ratio (calculated) 
Creatinine with GFR Estimated 
Carbon Dioxide 
Glucose 
Globulin (calculated) 
- 
Total Protein, 
ALT 
AST 
Bilirubin, total 
 
• Urinalysis, Complete 
Appearance 
pH 
Occult blood 
Color 
Specific gravity 
Protein 
Ketones 
Glucose 
Reducing substances 
Leukocyte esterase 
WBC 
Squamous Epithelial cells 
Renal epithelial cells 
Yeast 
Bacteria 
Calcium oxalate crystals 
Uric acid crystals 
Granular cast 
Comments 
 
Bilirubin 
Nitrite 
RBC 
Transitional epithelial cells 
Amorphous sediment 
Microscopic observation 
Crystals 
Triple phosphate crystals 
Hyaline casts 
Casts 
Bilirubin ictotest 
 

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• Other tests: 
Serum Androstenedione 
Dihydrotestosterone 
Serum 17-hydroxyprogesterone (17-OHP) 
Plasma renin activity 
LH 
FSH 
-Banking of frozen serum for subsequent   
 determination of abiraterone levels. All 
banked samples will be destroyed at study 
conclusion. 
ACTH, plasma 
Testosterone, total 
CAH (21- Hydroxylase Deficiency) Common 
Mutations 
 
 
4.3.5. 
Skeletal (bone) age 
The skeletal age will be assessed by radiograph of the left hand and wrist before initiation of study 
treatment, and will be done according to the Time and Events Schedule during the study. An existing 
radiograph obtained within 3 months may be used if clinical read as <9 years (girls) or <10 years (boys). 
All images must be submitted as anonymized DICOM files either on CD or by secure file transfer. Images 
will be read by BoneXpert, an automated computer-based bone age analysis program that has been 
validated on children with precocious puberty and CAH (30;31). Any radiographs that cannot be read by 
BoneXpert will be evaluated by a blinded group of three readers, with the median value being used.  
 
Note that these automated and blinded readings are for purposes of study outcome. The care 
team is free to read them independently and communicate them to the family. 
4.3.6. 
ECG Evaluations 
ECGs (12-lead) will be recorded until 4 regular consecutive complexes are available. Computer-
generated interpretations of ECGs should be reviewed for data integrity and reasonableness by the 
investigator. Further evaluation of ECG abnormalities will be at the clinical judgment of the investigator 
but should generally include referral to a pediatric cardiologist. 
NOTE: When blood sampling or vital sign measurement is scheduled for the same visit as ECG recording, 
the procedures should be performed in the following order: ECG(s), vital signs, blood sampling.  
4.4.7  Cataract Examinations  
Cataract examination using slit lamp will be done by a qualified ophthalmologist or optometrist and will 
be conducted at the times specified in the Time and Events Schedule. It is not necessary that this be a 
dilated exam. 
4.4. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the CRF and laboratory requisition 
form. Refer to the Time and Events Schedule for the timing and frequency of all sample collections. 
Instructions are as follows: 

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4.4.1. 
PK sampling will be collected at: 
• Visit 3: Pre-abiraterone dosing 
• Visit 3: 60 minutes post dosing 
• Visit 3: 120 minute post dosing 
• Visit 3: 240 minute post dosing 
• Visit 4: Pre-abiraterone dosing 
• Visit 5: Pre-abiraterone dosing 
4.4.2. 
Collect:  1mL of blood in the plain red top tube. Immediately after collection, invert the tube 
8-10 times. Label the tube with Patient number, visit number, date of collection and time of 
collection. Be sure to record the sample in the PK log found in the regulatory binder. 
4.4.3. 
Processing: Allow sample to clot at room temperature (~45-60 minutes). Centrifuge blood 
sample at room temperature or in a refrigerated centrifuge set at 4°C to separate the serum 
(e.g., <1300 rcf for 10-15 minutes.).  
4.4.4. 
Divide serum between the two cryovials supplied with kit. Be sure the cryovials are labeled 
with the patient number, visit number, date of collection and time of collection. Place one 
of the vials in the “A” (primary) storage cryobox and the other cryovial into the “B” (backup) 
storage cryobox. 
4.4.5. 
Store Samples in a -80°C freezer until shipment. 
4.5. 
End of Study  
4.5.1. 
Completion 
A subject will be considered to have completed the Phase 1 portion of the study after Phone Visit 6. A 
subject enrolled in the Phase 2 double-blind portion of the study is considered to have completed the 
Phase 2 study after Phone Visit 14 (108-109 weeks). 
4.5.2. 
Unblinding 
Under normal circumstances, the blind should not be broken until all subjects have completed the week 
109 study procedures and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the subject 
(e.g., accidental overdose) or if medical necessity is determined by the investigator. In such cases, the 
investigator may in an emergency determine the identity of the treatment by contacting the study 
pharmacist. In the event the blind is broken, the principal investigator and DSMB must be informed as 
soon as possible. The date, time, and reason for the unblinding must be documented in the appropriate 
section of the case report form (CRF), and in the source document. The documentation indicating the 
code break must be retained with the subject's source documents in a secure manner. 
Subjects who have had their treatment assignment unblinded should continue receiving the assigned 
treatment and return for scheduled evaluations. 
It is recognized that the clinical team caring for each patient may be able to infer treatment group 
assignment based on clinical data available to them including hydrocortisone dose, serum 17-
hydroxyprogesterone and androstenedione levels, and the relationship between these levels and levels 
of ACTH.  The clinical team will be encouraged to not share such suppositions with the subject, but 

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subjects where this has occurred should continue receiving the assigned treatment and return for 
scheduled evaluations. 
4.5.3. 
Discontinuation of Treatment 
If a subject's study treatment must be discontinued before the end of the treatment regimen, this will 
not result in automatic withdrawal of the subject from the study. 
A subject's study treatment should be discontinued if: 
• The investigator believes that for safety reasons (eg, adverse events) it is in the best interest of the 
subject to stop treatment. Safety concerns that may warrant discontinuation of abiraterone acetate 
include (also see Section 11.2.2): 
– AST and/or ALT >3x of Study Day 1 levels in the absence of evidence of liver obstruction or other 
explanations for the increase in LFTs, 
– Serum bilirubin to >2x ULN of Study Day 1 levels without any evidence of liver obstruction or 
glucuronidation capacity caused by Gilbert syndrome or some other explanation. 
– Total bilirubin ≥1.5 x ULN accompanied by any AST or ALT elevation 
– Persistent nausea and vomiting not amenable to medical therapy and lasting more than 72 hours 
and not explainable by other causes than abiraterone acetate treatment. 
– Development of cataracts during the study 
• Administration of prohibited medications (see section 7) 
• Dosing noncompliance 
• Onset of central puberty during Phase 1. 
 If a subject discontinues study treatment before the end of the double-blind phase, end-of-treatment 
assessments (see Sections 4.2.23, 4.2.24, 4.2.25 and 4.2.26) will be obtained. If study treatment is 
discontinued owing to abnormal liver function, the subject should be monitored until the laboratory 
abnormalities resolve (see Section 11.2.2). To permit a complete intention-to-treat analysis, follow-up 
scheduled radiographic  bone age assessments should be continued. 
4.5.4. 
Withdrawal from the Study 
• A subject will be withdrawn from the study for any of the following reasons: Non-compliance 
• Lost to follow-up 
• Withdrawal of consent to continue collection of data 
• Randomized in error (not fulfilling the inclusion and/or exclusion criteria) 
 
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel to 
contact the subject and determine the reason for withdrawal. The measures taken to follow up must be 
documented. 

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When a subject withdraws before completing the study an End of Termination Visit should be completed 
and the reason for withdrawal is to be documented in the CRF and in the source document. Study drug 
assigned to the withdrawn subject may not be assigned to another subject. Subjects in Phase 1 who 
withdraw due to non-compliance may be replaced (see Section 3.3.7). Subjects in Phase 2 who withdraw 
due to non-compliance will not be replaced. 
4.5.5. 
Transition of Care 
At the completion of study treatment, or upon early withdrawal, each subject will be instructed to 
increase the hydrocortisone dose to the dose (per square meter of body surface area) that the subject 
was taking at study enrollment. The subject’s current fludrocortisone dose will be continued. The subject 
will be transitioned back to standard of care and given new prescriptions with instructions for post study 
follow up care. 
 
4.6. 
Subjects’ Financial Responsibility 
Subjects will receive all evaluations gratis during the course of the study and (in Phase 2 only) standard 
of care medications including hydrocortisone and fludrocortisone. If a subject develops precocious 
central puberty requiring treatment with a gonadotropin-releasing hormone agonist during the study 
(see section 11.1.4), this will be billed to the patient’s insurance. All other medical and dental care is the 
responsibility of the subject.  
 
5. 
SUB-STUDY PROCEDURES 
Participation in the following substudies is mandatory. 
5.1. 
Pharmacokinetics Evaluations 
Phase 1 Dose-Finding: Blood samples will be collected for the determination of abiraterone plasma 
concentrations predose and 1, 2 and 4 hours postdose on Study Day 1 (Visit 3), predose on Study Day 2 
(Visit 4; this is 24 hours postdose from Visit 3), and 24 hours post dose on Study Day 8 (Visit 5).  Phase 2 
Double-Blind: Blood samples will be collected for the determination of abiraterone plasma 
concentrations predose and 2 hours postdose on Study Week 4 (Visit 4) and Weeks 52 (Visit 14) and 104 
(Visit 22). 
5.1.1. 
Analytical Procedures 
The concentrations of abiraterone in plasma will be determined using a validated liquid 
chromatography-mass spectrometry/mass spectrometry method by the laboratory of Dr Richard Auchus 
at the University of Michigan. If required, some plasma samples may be analyzed to document the 
presence of circulating metabolites using a qualified research method (32). Samples will be stored at -80 
C at each study site prior to shipment to the University of Michigan. 
5.1.2. 
Pharmacokinetic Parameters 
Pharmacokinetic analysis will be restricted to determination of peak and trough drug levels. 

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5.1.3. 
    Pharmacodynamic Evaluations 
Blood samples for determination of androstenedione, dihydrotestosterone and 17-OHP will be collected 
simultaneously with every sample for abiraterone determination. The exact dates and times of blood 
sample collection will be recorded. Further information regarding handling and shipment of blood 
samples will be provided in the laboratory manual. 
5.1.4. 
    Pharmacokinetic/Pharmacodynamic Evaluations 
The relationship between abiraterone plasma and serum hormone concentrations at all administered 
doses will be explored using different PK/PD models. Data will be analyzed using non-linear mixed effect 
models. 
5.2. 
DNA Testing 
Blood samples for genotyping will be collected from all subjects who have not already had genetic testing 
documented.  Subjects will be genotyped at Quest Laboratories for CYP21A2 to confirm the diagnosis of 
classic 21-hydroxylase deficiency. One or both parents will also be genotyped (when permitted by local 
regulations) to allow setting of phase on the subject’s mutations (i.e., determine which mutations are 
associated with each parental allele); this is necessary because many mutant alleles carry more than one 
mutation. If no parent is available, the subject will be genotyped and the results reviewed by the Principal 
Investigator. Subjects with an equivocal clinical history for classic disease (e.g., a male with no history of 
electrolyte abnormalities and a previously documented maximum 17-OHP level <10,000 ng/dl) and 
uninterpretable genotypes owing to absent parental data will not be allowed to enter the study. Samples 
will be discarded once the study is complete. 
 
6. 
CRITERIA FOR INCLUSION OF SUBJECTS: 
Each subject must satisfy all of the following criteria to advance to the Treatment Phase of the study. 
 
1. Pre-pubescent girls (age 2 years [12 kg minimum] to 8 years inclusive (i.e.,prior to the 9th birthday); 
skeletal age <11 years (Phase 1) or <10 years (Phase 2) or boys (age 2 years [12 kg] to 9 years inclusive; 
skeletal age <12 years (Phase 1) or <11 years(Phase 2)). The broader bone age criterion in Phase 1 is to 
assist with recruitment. 
 
2. Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B (see section 2.1.2) 
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. 

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5. Both parents must sign the informed consent form unless one parent is deceased, unknown, 
incompetent, or not reasonably available or when only one parent has legal responsibility for the care 
and custody of the child. 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  
 
7. 
CRITERIA FOR EXCLUSION OF SUBJECTS: 
To advance to the Treatment Phase of the study a subject must not meet any of the following 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 are discussed in Section 11.2.2. 
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, 

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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 (see section 11.1.4). 
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. 
 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a 
subject's status changes (including laboratory results) during screening, but prior to the first dose of 
study drug such that they now meet an exclusion criterion, they should be excluded from participation 
in the study. 
 
8. 
SOURCES OF RESEARCH MATERIAL 
Existing medical records will be used for screening purposes, including: 
 
8.1. 
History 
• Age  
• Neonatal course, including evidence of salt-wasting such as weight loss, hypotension, 
hyponatremia and hyperkalemia 
• Hospitalizations, particularly for vomiting, dehydration, hypotension, and other signs of adrenal 
crisis 
• Surgeries, including (in females) feminizing genitoplasty 
• Growth records for both height and weight 
• Past and present doses of hydrocortisone, fludrocortisone and sodium chloride 
• Past or present use of medications to affect puberty or synthesis of sex steroids, including 
gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor blockers 
• Past or present use of growth hormone 
 
8.2. 
Physical examination 
• Vital signs, particularly blood pressure 
• Height and weight 

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• Presence of clitoromegaly or labial fusion in girls 
• Tanner stage: Signs of puberty including presence of adult body odor, axillary or pubic hair, penile 
or testicular enlargement (boys) or breast development (either sex). 
 
8.3. 
Laboratory data 
• Comprehensive Metabolic panel, CBC, urinalysis 
• Steroid levels including 17-hydroxyprogesterone, androstenedione, testosterone, and 
dihydrotestosterone 
• FSH and LH 
• Plasma renin activity or direct renin levels and ACTH 
• Pharmacokinetics for abiraterone acetate 
• Bone age data from skeletal radiographs 
• Genotyping, if available 
 
New clinical data will be obtained in this study. Please refer to section 4.3 for a list of these data. 
 
9. 
RECRUITMENT METHODS AND CONSENTING PROCESS 
Subjects may be patients of the investigators, of the investigators’ colleagues within each participating 
institution, patients referred by other physicians, or self-referred.  Records at each site will be screened 
by local study personnel under a HIPAA Waiver to identify potentially eligible subjects. Consistent with 
local IRB requirements, each potentially eligible patient family will be informed of the study by their 
physician at a regularly scheduled visit and asked for permission to have study personnel meet with them 
after the visit to explain the study. Other recruitment materials including posters, brochures, web pages 
and letters to physicians may be used but must be approved by both the sponsor and by the reviewing 
IRB. 
 
All subjects in this study are children (minors) who can be enrolled only after obtaining consent of a 
legally acceptable representative.  Each legally acceptable representative must give written consent 
according to local requirements after the nature of the study has been fully explained. The consent form 
and assent form must be signed before performance of any study-related activity. The consent and 
assent forms that are used must be approved by both the sponsor and by the reviewing IRB and be in a 
language that the subject can read and understand. The informed consent and assent should be in 
accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and sponsor policy.  
 
Before enrollment in the study, the investigator or an authorized member of the investigational staff 
must explain to potential subjects or their legally acceptable representatives the aims, methods, 
reasonably anticipated benefits, and potential hazards of the study, and any discomfort participation in 
the study may entail. A certified interpreter must be used for any language in which the person obtaining 

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consent and the legally acceptable representative are not mutually fluent. Subjects will be informed that 
their participation is voluntary and that they may withdraw consent to participate at any time. They will 
be informed that choosing not to participate will not affect the care the subject will receive. Subjects will 
be told of alternative treatments available if they decline to take part and that such refusal will not 
prejudice future treatment.  
 
Finally, they will be told that the investigator will maintain a subject identification register for the 
purposes of long-term follow up if needed and that their records may be accessed by health authorities 
and authorized sponsor staff without violating the confidentiality of the subject, to the extent permitted 
by the applicable law(s) or regulations. By signing the ICF (and, if required by the local IRB, a HIPAA 
consent) the subject or legally acceptable representative is authorizing such access, and agrees to allow 
his or her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, if needed.  
 
The subject’s legal guardian or parent representative will be given sufficient time to read the ICF and the 
opportunity to ask questions. After this explanation and before entry into the study, consent should be 
appropriately recorded by means of either the subject's or his or her legally acceptable representative's 
personally dated signature. After having obtained the consent, a copy of the ICF must be given to the 
subject/legal guardian or parent. 
 
If the subject or legally acceptable representative is unable to read or write, an impartial witness should 
be present for the entire informed consent process (which includes reading and explaining all written 
information) and should personally date and sign the ICF after the oral consent of the subject or legally 
acceptable representative is obtained. 
 
Assent must be obtained from children (minors) capable of understanding the nature of the study, 
typically subjects 10 years of age and older, depending on the institutional policies. Written assent 
should be obtained from subjects meeting the local minimum age requirement for assent who are able 
to write. 

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10. 
POTENTIAL RISKS 
10.1. 
Study drug (abiraterone acetate) (33-35).  
The efficacy and safety of abiraterone acetate (1,000 mg daily tablet dose) and prednisone therapy in 
adult humans has been studied in men with metastatic, castration-resistant prostate cancer (mCRPC) as 
detailed below. However, it should be noted that toxicities associated with mineralocorticoid excess (ie, 
hypertension, fluid retention/edema, cardiac failure and hypokalemia) are not expected in patients with 
classic 21-hydroxylase deficiency because of such patients cannot synthesize deoxycorticosterone, 
which is a 21-hydroxylated steroid, or any other mineralocorticoid. 
10.1.1. 
Warnings and precautions 
10.1.1.1. 
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid 
Excess 
Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of 
increased mineralocorticoid levels resulting from CYP17 inhibition.  In the two randomized clinical trials 
grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and 
grade 3 to 4 edema in 1% of patients treated with abiraterone acetate. Co-administration of a 
corticosteroid suppresses ACTH drive, resulting in a reduction in the incidence and severity of these 
adverse reactions. Use caution when treating patients whose underlying medical conditions might be 
compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart 
failure, recent myocardial infarction or ventricular arrhythmia. These mechanism-based toxicities are 
not expected to occur in patients with 21-hydroxylase deficiency, who cannot synthesize 
mineralocorticoids. Also see section 11.2.1. 
 
10.1.1.2. 
Adrenocortical Insufficiency  
Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking 
abiraterone acetate and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in 
patients receiving abiraterone acetate in combination with prednisone, following interruption of daily 
steroids and/or with concurrent infection or stress.  All subjects in the present study have congenital 
adrenal hyperplasia and thus already have adrenal insufficiency.  Adjustments to hydrocortisone dosing 
during this trial are discussed in sections 11.1.1 and 11.1.2. 
 
10.1.1.3. 
Hepatotoxicity  
In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported 
in 4% of patients who received abiraterone acetate, typically during the first 3 months after starting 
treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test 
elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme 
increases occurred in 1% of patients taking abiraterone acetate. No deaths clearly related to abiraterone 
acetate were reported due to hepatotoxicity events. We will measure serum transaminases (ALT and 
AST) and bilirubin levels prior to starting treatment with abiraterone acetate and periodically thereafter 
(see section 4 and Tables of Assessments). Subjects with baseline hepatic impairment will be excluded 
from the study (see section 7).  We will promptly measure serum total bilirubin, AST, and ALT if clinical 

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symptoms or signs suggestive of hepatotoxicity develop (see section 11.2.2 for discussion of 
management of abnormal liver function tests).  
10.1.2. 
Adverse reactions  
10.1.2.1. 
Clinical Trial Experience  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed 
in the clinical trials of a drug cannot 
be directly compared to rates in the 
clinical trials of another drug and may 
not reflect the rates observed in 
clinical practice. Two randomized 
placebo-controlled 
multicenter 
clinical trials enrolled patients who 
had metastatic castration-resistant 
prostate cancer who were using a 
gonadotropin-releasing 
hormone 
(GnRH) agonist or were previously 
treated with orchiectomy. In both 
Study 1 and Study 2 abiraterone 
acetate was administered at a dose of 
1,000 mg daily in combination with 
prednisone 5 mg twice daily in the 
active treatment arms. Placebo plus 
prednisone 5 mg twice daily was 
given to control patients. The most 
common adverse drug reactions 
{>10%) 
reported 
in 
the 
two 
randomized 
clinical 
trials 
that 
occurred more commonly (>2%) in 
the abiraterone acetate arm were 
fatigue, joint swelling or discomfort, 
edema, hot flush, diarrhea, vomiting, 
cough, 
hypertension, 
dyspnea, 
urinary tract infection and contusion. 
The 
most 
common 
laboratory 
abnormalities (>20%) reported in the 
two randomized clinical trials that 
occurred more commonly (>2%) in 
the abiraterone acetate arm were 
anemia, 
elevated 
alkaline 
phosphatase, 
hypertriglyceridemia, 
lymphopenia, hypercholesterolemia, 
hyperglycemia, 
elevated 
AST, 

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hypophosphatemia, elevated ALT and hypokalemia.  
Study 1: Metastatic CRPC Following 
Chemotherapy. Study 1 enrolled 1195 
patients with metastatic CRPC who 
had 
received 
prior 
docetaxel 
chemotherapy. Patients were not 
eligible if AST and/or ALT >2.5 X ULN in 
the absence of liver metastases. 
Patients with liver metastases were 
excluded if AST and/or ALT >5X ULN. 
Table 1 shows adverse reactions on the 
abiraterone acetate arm in Study 1 
that occurred with a >2% absolute 
increase in frequency compared to 
placebo or were events of special 
interest. The median duration of 
treatment with abiraterone acetate 
was 8 months. Table 2 shows 
laboratory abnormalities of interest 
from Study 1. Grade 3-4 low serum 
phosphorus (7%) and low potassium 
(5%) occurred at a greater than or 
equal to 5% rate in the abiraterone 
acetate arm.  
Study 2: Metastatic CRPC Prior to 
Chemotherapy. Study 2 enrolled 1088 
patients with metastatic CRPC who 
had not received prior cytotoxic 
chemotherapy. 
Patients 
were 
ineligible if AST and/or ALT >2.5X ULN 
and patients were excluded if they had 
liver metastases. Table 3 shows 
adverse reactions on the abiraterone 
acetate arm in Study 2 that occurred 
with a >2% absolute increase in 
frequency compared to placebo. The 
median duration of treatment with 
abiraterone acetate was 13.8 months. 
Table 
4 
shows 
laboratory 
abnormalities that occurred in greater 
than 15% of patients, and more 
frequently (>5%) in the abiraterone 
acetate arm compared to placebo in 

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Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) 
occurred at a greater than 5% rate in the abiraterone acetate arm.  
Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred 
more commonly in patients treated with abiraterone compared to patients on the placebo arm (2.1% 
versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking abiraterone and led to 5 
treatment discontinuations and 2 deaths. Grade 3·4 cardiac failure occurred in 0.2% of patients taking 
placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo 
group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated 
with arrhythmia and one patient with sudden death in the abiraterone acetate arms and no deaths in 
the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the abiraterone acetate 
arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death 
in 3 patients in the placebo arms and 2 deaths in the abiraterone acetate arms.  As noted in sections 
10.1.1.1 and 11.2.1, mechanism-based cardiovascular toxicity is not expected in the present study. 
10.1.3. 
Post Marketing Experience  
The following additional adverse reactions have been identified during post approval use of abiraterone 
acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and 
Connective Tissue Disorders: myopathy, including rhabdomyolysis. These adverse effects are 
presumably mediated by severe hypokalemia which, as discussed in section 11.2.1, should not be 
encountered in the present study. 
 
10.2. 
Drug Interactions 
10.2.1. 
Drugs that Inhibit or Induce CYP3A4 Enzymes 
Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. In a dedicated drug interaction trial, 
co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. 
Strong CYP3A4 inducers represent an exclusion criterion and should be not used during this study. In a 
dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no 
clinically meaningful effect on the pharmacokinetics of abiraterone. 
 

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10.2.2. 
Effects of Abiraterone on Drug Metabolizing Enzymes 
ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-
drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- 
and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 
1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with 
substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments 
cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate 
drug. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 
substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg 
abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a 
CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone. 
 
10.3. 
Increased Abiraterone exposure with food 
Abiraterone acetate must be taken on an empty stomach. Abiraterone Cmax and AUC0-∞ (exposure) were 
increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was ad 
ministered with a meal compared to a fasted state. The United States Prescribing Information states that 
no food should be consumed for at least two hours before the dose of abiraterone acetate is taken and 
for at least one hour after the dose of abiraterone acetate is taken. However, as discussed in sections 
3.3.1 and 3.3.9.1, we will permit a low-fat breakfast (see Appendix A) 30 minutes after the dose in 
deference to the morning schedules of school-age children 
 
10.4. 
Androgen blockade 
This study will be conducted solely in prepubertal children who normally have low levels of sex 
steroids. Thus adverse effects of blockade of sex steroid synthesis encountered in adults (e.g., decreased 
bone mineral density, low libido) are not expected in this study.  
Children with inadequately treated CAH have high blood levels of androgens, which can condition 
the hypothalamic-pituitary-gonadal axis such that high levels of gonadotropins will be secreted when 
androgen levels are finally brought under control. This can cause central precocious puberty, which may 
then require treatment with a gonadotropin releasing hormone agonist. This was observed in a trial of a 
four drug regimen consisting of low dose hydrocortisone, fludrocortisone, testolactone (an aromatase 
inhibitor to prevent estrogen-induced epiphyseal fusion), and flutamide (an androgen receptor blocker 
to prevent virilization (17). Four children in the experimental treatment arm and two children in the 
control arm were receiving deslorelin therapy (P = 0.6) after two years of treatment. No serious adverse 
effects were observed. 
 
10.5. 
Study procedures 
The risks of venipuncture are pain, bleeding and bruising. Patients with CAH ordinarily require 
blood samples at each visit to monitor their treatment but will require more frequent sampling in this 
study. Blood volumes will be limited to 2.5 ml/kg body weight for a single blood draw and 5 ml/kg within 
30 days. These are half the generally accepted safe volumes for children (36).  

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Patients with CAH ordinarily have X-rays taken yearly of the left hand and wrist to assess skeletal 
maturation (“bone age”).  They will have this assessment every 6 months as part of the study and will 
thus receive 2-3 more X-ray exposures over the course of the study than is the standard of care. The 
effective dose of a pediatric hand X-ray is remarkably small, 0.0001 mSv, corresponding to 30 minutes 
of the natural background radiation (37).  This is a negligible radiation exposure. 
 
10.6. 
Risks of standard of care 
The standard of care for CAH is discussed in section 2.1.3. The risks of venipuncture are discussed in 
section 10.5. The risks of inadequate dosing of hydrocortisone include hyponatremia, hypoglycemia and 
hypotension. The risks of excessive dosing of hydrocortisone include excessive weight gain and retarded 
linear growth. All subjects will continue to receive hydrocortisone, but subjects in the active drug arm 
may require lower doses of hydrocortisone, thus reducing the risks of overdosing. The risks of 
hydrocortisone underdosing might be increased in the active drug arm, but doses will be similar to those 
used to treat other forms of adrenal insufficiency and so the increased risk is low and subjects will be 
carefully monitored for adequacy of hydrocortisone dosing (section 11.1.1). 
 
Almost all patients in this study will receive fludrocortisone as part of their standard of care. The risks of 
underdosing fludrocortisone include hyponatremia, hyperkalemia and hypotension. The risks of 
overdosing include hypertension. Fludrocortisone doses should not differ between the two study arms, 
and so there should be no difference in these risks between the study arms. Monitoring of 
fludrocortisone therapy is discussed in section 11.1.3. 
 
11. 
SUBJECT SAFETY AND DATA MONITORING 
11.1. 
Ensuring Adequate Conventional Therapy 
11.1.1. 
Hydrocortisone 
In Phase 2, to ensure standardization, hydrocortisone will be provided to study pharmacies from a single 
source for dispensing to subjects (see Section 4).  As discussed in Section 2.1.3, the goals of glucocorticoid 
therapy in CAH are to avoid both glucocorticoid insufficiency and androgen excess. The standard of care 
for monitoring hydrocortisone dosing is to utilize 17-hydroxyprogesterone and androstenedione levels 
as measures of activation of the hypothalamic-pituitary-adrenal (HPA) axis; glucocorticoid deficiency 
activates the HPA axis whereas glucocorticoid excess suppresses it. Abiraterone acetate treatment 
inhibits synthesis of these compounds (indeed, that is the desired therapeutic effect) and renders their 
levels inaccurate as a measure of HPA axis activation in subjects who are receiving the active drug. 
Therefore, a more complex monitoring scheme is necessary, with analytes (all to be drawn between 
0800-1000) listed in order of consideration. Values over the specified limits will prompt a ~20% increase 
in hydrocortisone dose with a repeat level to be obtained to be obtained ~4 weeks later.  
• Androstenedione. This androgen is routinely monitored in children with CAH. Its synthesis is 
efficiently inhibited in adult women with CAH (Figure 3). The goal is to maintain it at less than the 
upper limit of normal (ULN) for prepubertal children, which is ~50 ng/dl.  
• Dihydrotestosterone. This potent androgen is not routinely monitored in CAH patients. We will 
do so in this study because it can be synthesized from 17-hydroxyprogesterone via the so-callled 

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“backdoor pathway” (22-24) without going through androstenedione as an intermediate. 
Because the effect of abiraterone acetate on 17-hydroxyprogesterone levels is less complete and 
more transient than its effect on androstenedione, it is possible that dihydrotestosterone levels 
might be significantly elevated even if androstenedione levels are normal. Therefore, a 
dihydrotestosterone level >ULN for prepubertal children (3 ng/dl) will prompt an uptitration of 
the hydrocortisone dose.  
• 17-hydroxyprogesterone. Although monitoring androstenedione and dihydrotestosterone will 
ensure that subjects are not exposed to excessive androgen levels, these steroids are not very 
ACTH-responsive and cannot be used to detect marked HPA axis activation, which might indicate 
potentially dangerous underdosing (or noncompliance) with hydrocortisone. It is unlikely that 
abiraterone acetate treatment will have a major effect on 17-hydroxyprogesterone levels in the 
morning, 24 h after the last dose (see Figure 3), and so this steroid can be used to monitor the 
HPA axis. The standard-of-care upper limit of the target range for this compound is ~1000 ng/dl 
(3), but that limit is selected to avoid excessive androgen secretion. In children with CAH, a level 
of ~5000 ng/dl corresponds to an ACTH level of ~400 pg/ml (data not shown), which is the lower 
end of the range observed in children with untreated but symptomatic Addison’s disease (38). It 
seems prudent to uptitrate the hydrocortisone dose when this level of 17-hydroxyprogesterone 
is exceeded.  
• HPA axis activation will also be assessed directly by periodically measuring ACTH (corticotropin) 
levels. As discussed in the previous point, the aim will be to maintain morning ACTH levels within 
the reference range or up to 400 pg/ml (approximately 6-7 times the upper limit of the reference 
range).  In the absence of an obvious physiologic stressor such as a recent intercurrent illness, a 
value greater than this  will prompt uptitration in total daily hydrocortisone dose, followed by a 
repeat ACTH level 2-4 weeks later. Conversely, a value below the reference range (<10 pg/ml) 
will prompt approximately a 20% decrease in total daily hydrocortisone dose, followed by a 
repeat ACTH level 2-4 weeks later. Because 17-hydroxyprogesterone and ACTH levels are 
correlated, this might seem redundant, but on the one hand we cannot be certain that 
abiraterone acetate will not suppress 17-hydroxyprogesterone levels to some extent, and on the 
other hand ACTH levels may take considerably longer to be returned from the laboratory.  
• In interpreting the laboratory testing as described above, the clinician should be aware of the 
subject’s physical condition and, even if laboratory tests do not reach thresholds for dose 
adjustment, increase the hydrocortisone dose for signs and symptoms of adrenal insufficiency 
such as unexplained fatigue, anorexia, weight loss, or orthostatic hypotension. Conversely, the 
hydrocortisone dose should be decreased for signs of Cushing syndrome such as poor linear 
growth or excessive weight gain. 
11.1.2. 
Hydrocortisone Dosing During Illness 
• Hydrocortisone doses should be temporarily tripled for febrile illness or other significant physical 
stress per standard of care and returned to normal dosing when the illness has resolved clinically 
and the subject is afebrile.  
• Intramuscular or intravenous hydrocortisone sodium succinate should be administered according 
to the study physician’s clinical judgment for illnesses causing repeated emesis and/or 
dehydration and/or hypotension, and for surgical procedures requiring general anesthesia. 
Typical doses are 100 mg/m2 bolus followed by 25 mg/m2 every 6 hours for 24 hours.  

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• Any study visits should be postponed until the subject has returned to normal hydrocortisone 
dosing for at least 24 hours. 
 
11.1.3. 
Fludrocortisone 
In Phase 2, to ensure standardization, fludrocortisone will be provided to study pharmacies from a single 
source for dispensing to subjects (see Section 4). Fludrocortisone dosing will be monitored according to 
the standard of care with blood pressure, electrolytes, and plasma renin levels. Blood pressure 
consistently above the reference range for age and/or suppressed plasma renin should prompt 
consideration of a reduction in fludrocortisone dose of 0.025-0.05 mg/d.  Conversely, high serum 
potassium or low sodium levels, or elevated plasma renin, should prompt consideration of an increase 
in fludrocortisone dose. The adequacy of any dose adjustment should be confirmed with repeat 
monitoring labs 2-4 weeks after the adjustment (or sooner at the discretion of the treating physician). 
 
11.1.4. 
Precocious Puberty 
Subjects may be treated with a gonadotropin-releasing hormone agonist (e.g., leuprolide, histrelin) at 
the discretion of the study physician if there are signs of central precocious puberty (before age 8 years 
in girls, or at any time in the study in boys) including: 
• Physical signs including breast development in girls and testicular enlargement in boys. Pubic or 
axillary hair might be signs of adrenal androgen secretion and will not be themselves considered 
to be signs of central precocious puberty. 
• Uterine enlargement and ovarian follicular development on pelvic sonogram, or testicular 
enlargement on testicular sonogram. 
• Pubertal response on leuprolide stimulation test (any value for luteinizing hormone [LH] >4.0). 
Whereas treatment with a gonadotropin releasing hormone agonist is an exclusion criterion, it is not 
required to withdraw subjects from the study for such treatment started after enrollment. 
 
11.2. 
Study Drug Dose Modifications and Management of Toxicity 
Dose interruptions can be considered if an adverse event can be attributed to a concurrent illness (i.e., 
not related or doubtfully related to study drug) or to an alternative explanation. Abiraterone acetate or 
placebo without a dose modification can be resumed after resolution of the adverse event or if the 
subject condition has returned to baseline. 
 
11.2.1. 
Hypokalemia and hypertension. 
Although hypokalemia and hypertension are mechanism based adverse effects of abiraterone acetate 
treatment in patients with intact adrenal glands, they are mediated by increased secretion of 
deoxycorticosterone, which is not synthesized in patients with 21-hydroxylase deficiency.  If these 
problems occur in subjects in this study, they are most likely a consequence of excessive administration 
of fludrocortisone and can be readily addressed by decreasing the dose of this agent. 
 

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11.2.2. 
Management of Abnormal Liver Function Tests 
Categories of abnormal LFTs are defined as follows: 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 x ULN 
Total bilirubin ≥2 x ULN (in the absence of Gilbert syndrome) 
Total bilirubin ≥1.5 x ULN accompanied by any AST or ALT abnormality (>ULN). 
Any AST or ALT elevation associated with nausea, vomiting, anorexia, abdominal pain, or fatigue.  
 
The first incidence of AST or ALT ≥3 x ULN, total bilirubin ≥2 x ULN (in the absence of Gilbert syndrome), 
or total bilirubin ≥1.5 x ULN accompanied by any AST or ALT elevation below the ranges described in the 
other categories, or any AST or ALT elevation with associated clinical symptoms, requires that the subject 
discontinue study treatment immediately and that at least once weekly follow-up continue 
(measurement of liver enzymes) until resolution of abnormal LFTs. The sponsor should be notified 
immediately. No rechallenges with study medication will be permitted. 
 
In the case of an AST or ALT <3 x ULN, total bilirubin <2 x ULN (in the absence of Gilbert syndrome), or 
total bilirubin <1.5 x ULN accompanied by any AST or ALT elevation below the ranges described in the 
other categories, dosing is allowed to continue provided that the subject has LFTs monitored weekly for 
3 weeks. Upon worsening of LFT severity (>10% increase in any laboratory test), the study drug will be 
discontinued immediately and the site will notify the sponsor. If LFTS are stable or improving after 3 
weeks, testing will continue at least monthly for 3 months or until resolution of abnormal LFTs (16). 
11.3. 
 Data Safety and Monitoring Board (DSMB) 
The DSMB will consist of three pediatric endocrinologists not otherwise involved with the study and the 
statistician. The principal investigator will attend all meetings and conference calls but will not vote and 
may be asked to absent himself for confidential discussions by the DSMB. 
11.3.1. 
Phase 1 Dose-Escalation 
The DSMB will convene prior to enrollment of the first subject, and after completion of each of the three 
dose cohorts, but in any case no less frequently than every 6 months. The DSMB may convene at 
additional times for data review or any safety-related issues. Any DSMB member or site principal 
investigator has the right to request a DSMB meeting, which will be convened within 3 working days 
after the request has been made to the study principal investigator. The DSMB will review all safety data 
and available PK and PD information. This information will be curated by the sponsor/investigator’s 
statistician at UT Southwestern Medical Center. 
Decisions regarding changes in the timing of PK sampling, and exploration of alternative doses will be 
made by the DSMB. Adverse event profile (type, intensity, time of onset, and duration) and PK or PD 
data will be considered by the DSMB during the decision-making process. 
All decisions made by the DSMB will be documented in a DSMB decision document and distributed to 
investigators before administration of abiraterone acetate to any additional subject. The study site’s IRB 

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will be notified before implementation of any DSMB decision, as required. Completed decision 
documents will be retained in the study master file and in the study center’s files. 
11.3.2. 
Phase 2 Double-Blind  
The DSMB will monitor data on an ongoing basis to ensure the continuing safety of the subjects enrolled 
in this study and to meet efficacy objectives. The committee will meet periodically (at least every 6 
months) to review interim data. After the review, the DSMB will make recommendations regarding the 
continuation of the study. 
Potential events that would prompt consideration of modifying or terminating the study include, but are 
not limited to: 
• AST, ALT >3x or bilirubin >2x baseline levels in 4 or more subjects.  
• Any serious adverse event (see section 11.4) thought to be probably related to study drug. 
• Lack of androstenedione normalization in at least 60% of the first 5 subjects on active drug after 
3 months. This information will be provided to the DSMB by the study statistician. This would 
suggest that the abiraterone acetate dose is inadequate and may need to be increased. If 1 or 2 
mg/kg/d was originally selected as the dose for Phase 2, the next highest dose will be selected. 
We will not attempt to expand the size of the study. If, however, 4 mg/kg/d was originally 
selected for Phase 2 and this dose proves inadequate, the DSMB may mandate reopening Phase 
1 to test 8 subjects for a week at 8 mg/kg/d. This dose is still less than the FDA approved dose for 
abiraterone acetate in adult men with prostate cancer.  
11.4. 
Adverse Event Reporting 
11.4.1. 
Definitions 
11.4.1.1. 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not related to the medicinal 
product. 
 
11.4.1.2. 
 
Adverse Drug Reaction (ADR) 
A noxious and unintended response to any dose of the drug (or biological) product for which there is a 
reasonable possibility that the product cause the response.  ‘‘Reasonable possibility’’ means there is 
evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 
 

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11.4.1.3. 
Medicinal Product 
The specific drug under study and any other medicinal product. 
11.4.1.4. 
Product Quality Complaint (PQC) 
Any discrete concern that questions the identity, quality, durability, reliability, safety, efficacy or 
intended performance of a drug product. 
 
A complaint may allege an injury or malfunction associated with the use of the drug product. It may also 
involve the design, literature, packaging, advertising, availability, physical appearance or promotion of 
the drug product. 
 
11.4.1.5. 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Institution/Principal Investigator it results in any of the following outcomes:  
• Death,  
• a life-threatening adverse event,  
o Life-threatening adverse event or life-threatening suspected adverse reaction.  
 An adverse event or suspected adverse reaction is considered ‘‘life-threatening’’ 
if, in the view of either the Institution/Principal Investigator, its occurrence places 
the patient or subject at immediate risk of death. It does not include an adverse 
event or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
• inpatient hospitalization or prolongation of existing hospitalization,  
• a persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or  
• a congenital anomaly/birth defect.  
• is a suspected transmission of infectious agents by a medicinal product 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
11.4.1.6. 
Special Reporting Situations  
When a report contains a product, an identifiable patient, and identifiable reporter, the following events 
represent Special Reporting Situations: 
• overdose of a medicinal product  
• pregnancy exposure (maternal and paternal) 

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• exposure to a medicinal product from breastfeeding  
• suspected abuse/misuse of a medicinal product 
• inadvertent or accidental exposure to a medicinal product  
• any failure of expected pharmacological action (i.e., lack of effect) of a medicinal product 
• unexpected therapeutic or clinical benefit from use of a medicinal product 
• medication error involving a product (with or without patient exposure to the medicinal product, 
e.g., name confusion) 
• suspected transmission of any infectious agent via a medicinal product. 
 
11.4.2. 
Management of Adverse Events, Serious Adverse Events and Special Reporting Situations 
For each subject, AEs, SAEs, and Special Reporting Situations should be recorded after informed consent is 
obtained until the subject has completed participation in the study as follows: 
 
A Serious Adverse event or Special Reporting Situations must be reported to Sponsor if it occurs during a 
subject’s participation in the Study (whether receiving Study Product or not) and within 30 days of receiving 
the last dose of Study Product. 
 
Any serious adverse event or Special Reporting Situations that is ongoing when a subject completes his/her 
participation in the Study must be followed until any of the following occurs: 
• the event resolves or stabilizes; 
• the event returns to baseline condition or value (if a baseline value is available); 
• the event can be attributed to agents(s) other than the Study Product, or to factors unrelated to 
Study conduct. 
 
11.4.3. 
Recording of Adverse Events, Serious Adverse Events and Special Reporting Situations 
Recording should be done in a concise manner using standard, acceptable medical terms. 
 
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a laboratory value or 
vital sign) but should reflect the reason for the procedure or the diagnosis based on the abnormal 
measurement. 
 
Preexisting conditions that worsen in severity or frequency during the Study should also be recorded (a 
preexisting condition that does not worsen is not an adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to the procedure or surgery 
is considered an adverse event. Any event requiring in-patient hospitalization that occurs during the course of 
a subject’s participation in a trial must be reported as an SAE. Hospitalizations that do not meet the criteria 
for SAE reporting are: 
• Reasons described in the Protocol, e.g. drug administration, Protocol-required testing 
• Surgery or procedure planned prior to entry into the Study. 
 

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If, in the Principal Investigator’s judgment, a clinical significant worsening from baseline is observed in any 
laboratory or other test parameter (e.g. electrocardiogram (ECG), angiogram), physical exam finding, or vital 
sign, a corresponding clinical adverse event should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded as the adverse 
event, whenever possible.  However, a complete description of the signs, symptoms and investigations which 
led to the diagnosis should be provided. For example, if clinically significant elevations of liver function tests 
are known to be secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be recorded. 
If the cause is not known, the abnormal test or finding should be recorded as an adverse event, using 
appropriate medical terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation). 
 
11.4.4. 
Maintenance of Safety Information 
Safety information will be maintained in a clinical database/repository in a retrievable format. At a minimum, 
at the end of the treatment phase (=”last patient off treatment”) as well as the end of the follow-up phase 
(=”last patient out”) of the Study, the Institution/Principal Investigator shall provide all adverse events, both 
serious and non-serious, in report format. However, in certain circumstances more frequent review of the 
safety data may be necessary, e/g/ to fulfill a regulatory request,. 
 
11.4.5. 
FDA Reporting Requirements 
The Sponsor/Investigator (UT Southwestern) is responsible for reporting serious adverse events to the 
FDA in accordance with applicable IND Safety Requirements (21 CFR 312.32). 
 
The following  safety information SAEs, Adverse Events of Special Interest, Pregnancies, Special Reporting 
Situations, and PQCs should be reported within 24 hours of becoming aware of the event(s).  
 
All non-serious AEs should be reported according to the timeframe outlined in the Research Funding 
Agreement section entitled Reporting of Data. 
 
11.4.6. 
Transmission Methods: 
The following methods are acceptable for transmission of safety information to Sponsor: 
• Facsimile (fax), receipt of which is evidences in a successful fax transmission report to 1-214-648-
9772 
• Reporting may be done electronically via an acceptable encrypted email format.  
• Telephone (for business continuity purposes, if fax or authorized electronic system is nonfunctional). 
 
 
11.4.7. 
Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), Pregnancies, 
and Special Reporting Situations 
 
11.4.7.1. 
Serious Adverse Events (SAE), Adverse Events of Special Interest, 
Pregnancies, and Special Reporting Situations 
 

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All available clinical information relevant to the evaluation of an SAE, Adverse Events of Special Interest, and 
Special Reporting Situations including pregnancy reports (with or without an AE) including paternal exposure 
are required. 
 
• The Institution and/ or Principal Investigator is responsible for ensuring that these cases from 
clinical studies are complete and if not are promptly followed-up. This includes ensuring the 
reports are fully investigated and thoroughly documented by the Principal Investigator and that 
follow-up information is summarized e.g. hospital records, coroner’s reports, autopsy results and 
recorded on the appropriate forms. 
• A study case is not considered complete until all clinical details needed to interpret the case are 
received and the event has resolved, or otherwise explained, or the patient is lost to follow-up. 
Reporting of follow-up information should follow the same timeline as initial reports. 
• Copies of any and all relevant correspondences with regulatory authorities and ethics committees 
regarding any and all serious adverse events, irrespective of association with the Study Drug in the 
course of the Study, by facsimile within 24 hours of such report or correspondence being sent to 
applicable health authorities. 
 
11.4.7.2. 
Product Quality Complaints 
Any PQC, with or without an AE, (including reports of suspicion of counterfeiting, diversion, or tampering, and 
suspected transmission of pathogens) will be transmitted to Sponsor, within 24 hours of becoming aware of 
the event(s). 
 
11.4.8. 
Contacting Sponsor Regarding Safety 
The Sponsor of this study is University of Texas Southwestern Medical Center, Dallas, TX. The Sponsor-
Investigator (Principal Investigator) is Perrin C White, MD, Professor of Pediatrics at this institution. The 
names (and corresponding telephone numbers) of the individuals who should be contacted regarding 
safety issues or questions regarding the study are listed on the Contact Information page(s), which will 
be provided as a separate document. 
 
12. 
PROCEDURES TO MAINTAIN CONFIDENTIALITY 
 
12.1. 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be limited to 
those data that are necessary to fulfill the objectives of the study. These data will be collected and 
processed with adequate precautions to ensure confidentiality and compliance with applicable data 
privacy protection laws and regulations. Electronic data will be stored on secure servers that require 
password protection and maintain audit records of access, and/or on laptops with password-protected 
encrypted hard drives. All data sent between institutions via e-mail, file transfer protocols or physical 
media must be encrypted and password protected. Sponsor personnel whose responsibilities require 
access to personal data agree to keep the identity of study subjects confidential. Hardcopy 

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documentation must be stored in locked file cabinets or locked offices secured with either key or badge 
access.  
 
The informed consent and HIPAA permission obtained from the subject’s legally acceptable 
representative includes explicit consent for the processing of personal data and for the investigator to 
allow direct access to his or her original medical records for study-related monitoring, audit, IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries. 
 
The subject’s legally acceptable representative has the right to request through the investigator access 
to the subject’s personal data and the right to request rectification of any data that are not correct or 
complete. Reasonable steps will be taken to respond to such a request, taking into consideration the 
nature of the request, the conditions of the study, and the applicable laws and regulations. 
 
12.2. 
Disclosure to Outside Entities 
All data, whether electronic or hardcopy, will be referenced to a unique patient identifier, with subjects’ 
identifying information kept in separate secure files. The following entities will be granted access to 
some or all data and specimens from this study: 
 
•  Quest Laboratories as the central reference laboratory for this project. 
• The UT Southwestern Institutional Review Board (IRB), as the IRB for the sponsor.  
• Local IRBs 
• Central data management and study monitoring 
• Data safety and monitoring board 
• Representatives of the Food and Drug Administration (FDA).   
• Representatives of other governmental and regulatory agencies.   
• Treating endocrinologists 
 
13. 
POTENTIAL BENEFITS 
Benefits to all subjects will include careful medical monitoring of their disease and free study-related 
medical care for the duration of the study including physical exams, laboratory tests, and medication. 
 
Benefits to subjects randomized to active Study Drug (abiraterone acetate) may include maintenance on 
a lower dose of hydrocortisone which may minimize excessive weight gain and linear growth delay 
associated with glucocorticoid excess. Additionally, the hypothesized retardation of skeletal maturation 
may improve final adult height; patients with classic CAH average ~7 cm shorter than expected for their 
parental heights.  
 

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14. 
BIOSTATISTICS  
14.1. 
General Considerations 
All continuous endpoints will be summarized using descriptive statistics, which will include the number 
of subjects (n), mean, standard deviation, median, and interquartile range. All categorical endpoints will 
be summarized using frequencies and percentages. The baseline measurement will be the last value on 
or before the date of first study treatment. 
An interim analysis of safety and efficacy will be performed after 24 subjects have completed 104 weeks 
of treatment. An interim Clinical Study Report will be written on the basis of this data cutoff. 
When all subjects have completed the 109 weeks of Phase 2, a final Clinical Study Report will be written. 
14.2. 
Subject Information 
Evaluable subjects at Phase 1 are defined as subjects who have completed all study procedures. 
The intent-to-treat (ITT) population includes all subjects randomized into the Phase 2 portion of the 
study. 
All subjects who receive at least 1 dose of study drug will be analyzed for safety. 
14.3. 
Sample Size Determination 
14.3.1. 
Phase 1 Dose-Finding 
This is a Phase 1 dose finding study; the sample size is one of convenience. We want to identify a dose 
that will reliably (0.95 probability) result in normalization of androstenedione levels. With a sample size 
of 8, the margin of error is 0.16, hence the lower limit of the 95% confidence interval is 0.79. Thus a goal 
of at least 7/8 subjects (>0.87) to have normalized androstenedione levels is appropriate. Also see 
section 3.3.15.1.  
14.3.2. 
Phase 2 Double-Blind 
The primary endpoint In Phase 2 is bone age advancement (change in bone age per year of chronologic 
age) (see Section 14.5.1). In a study of flutamide and testolactone as adjunctive therapy in CAH (17), the 
rate of bone age maturation declined from 1.9 ± 0.3 to 0.7 ± 0.2 (mean + SEM) bone age yr/chronological 
yr in the children receiving the regimen with flutamide and testolactone. As there were 14 subjects per 
arm, this implies standard deviations of ~1.0. A sample size of 48 subjects (32 in the abiraterone acetate 
arm and 16 in the placebo arm) will have 90% power to detect a difference in bone age advancement of 
1 year over the 2-year period of the study with a 0.05 2-sided significance level. To allow for ~10% 
attrition, 54 subjects will be randomized (36 to abiraterone acetate and 18 to placebo) and data from all 
subjects will be used for the primary analysis based on the intent to treat approach. 
14.4. 
Pharmacokinetic and Pharmacodynamic Analyses (Phase 1) 
 

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14.4.1. 
Pharmacokinetic analysis 
For each dose level in Phase 1, peak and trough plasma concentrations of abiraterone will be plotted. 
Plasma concentration data at each time point will be summarized with mean and standard deviation for 
each dose.  
14.4.2. 
Pharmacodynamic Analyses 
The counts and percentages of subjects with serum androstenedione normalization on Day 8 at each 
dose level will be summarized and the associated exact 2-sided 95% binomial confidence intervals for 
the percentages will be provided. Mean and mean change from baseline in serum androstenedione and 
17-OHP concentrations will be summarized with mean, standard deviation, median, and interquartile 
range. All Phase 1 PD analysis will be performed on evaluable subjects. 
14.5. 
Outcome Analyses 
For Phase 2 double-blind, a mixed linear model (e.g., PROC MIXED in SAS) will be used to fit a linear 
model for repeated measures and to examine time and treatment effects on: 
• bone maturation 
• hydrocortisone dose 
• height  
• BMI percentile 
• blood pressure 
• hormonal data (see below).   
To take age effect on the mean differences into account, an analysis of covariance (ANCOVA) model will 
be also applied to the primary and secondary efficacy endpoints by including a stratification factor of 
age group (2 to 5 years vs. 6 to 9 years) and other appropriate covariates to evaluate the differences in 
mean and mean change from baseline between the 2 treatment groups. All efficacy analysis will be 
performed on the ITT population by including all subjects randomized into the Phase 2 double-blind 
portion of the study. 
14.5.1. 
Bone age 
Bone age in years will be obtained as output from an automated program (BoneXpert, see section 4.3.5) 
or, for films that cannot be read by the program due to image quality, the median of 3 investigators’ 
independent readings will be used. The outcome will be expressed as the change in bone age from 
baseline at each time point, with (as noted above) a repeated measures analysis as the primary outcome.   
14.5.2. 
Hydrocortisone dosing  
Hydrocortisone dose at each time point will be expressed in mg per m2 of body surface area, which will 
be calculated by the Mosteller formula (39) as BSA (m2) = SQR RT ( [Height(cm) x Weight(kg) ]/ 
3600). 
 

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14.5.3. 
Physical Examination 
Descriptive statistics of height, height Z-score for age, weight, body mass index (BMI), BMI percentile for 
age (27), and pubertal (Tanner) stage (at Visit 1), and changes from baseline, will be summarized at each 
scheduled time point. 
14.5.4. 
Vital Signs 
Descriptive statistics of heart rate and blood pressure (systolic and diastolic) sitting values and changes 
from baseline will be summarized at each scheduled time point. Blood pressure Z scores for age will be 
calculated. The percentage of subjects with blood pressure values beyond age-adjusted limits (i.e., Z 
scores >2.0) will be summarized at each scheduled time point. 
14.5.5. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly abnormal 
results (specified in the Statistical Analysis Plan) will be used in the summary of laboratory data. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and at each scheduled 
time point. Changes from baseline results will be presented in pre- versus posttreatment cross-
tabulations (with classes for below, within, and above normal ranges). Preplanned comparisons between 
treatment groups will include: 
• 17-hydroxyprogesterone 
• Androstenedione 
• ACTH 
 
14.5.6. 
DNA Analyses 
Congenital adrenal hyperplasia subtypes as determined by genotype, will be included as covariates in 
the statistical analysis. Subjects will be divided into 3 groups. Group A will consist of those who carry null 
mutations on both alleles (see Figure). Group A1 will include patients who carry at least one intron 2G 
mutation who are expected to have a slightly milder phenotype. Group B patients, who carry the 
Ile172Asn mutation as the most severe mutation on at least one allele, generally have a simple virilizing 
phenotype. Group C patients, who carry Pro30Leu or Val281Leu as the most severe mutation on at least 
one allele, generally have a nonclassic phenotype and will not be included. 
14.6. 
Safety Analyses 
All subjects who receive at least 1 dose of study drug (ie, abiraterone acetate or placebo) will be analyzed 
for safety. Safety data during Phase 1 will be summarized overall. Safety data collected during Phase 2 
will be summarized by treatment groups. Safety variables will be summarized descriptively for vital signs, 
adverse events, clinical laboratory parameters, and ECG. Serious adverse events, adverse events, and 
discontinuations from study treatment due to adverse event will be provided in listings.  
Adverse events, including laboratory adverse events, will be categorized as mild, moderate, severe (see 
next Section). Adverse events will be summarized by system organ class and preferred term. Deaths and 
other serious adverse events will be provided in a listing. Treatment-emergent adverse events resulting 
in study drug discontinuation, dose modification, dosing interruption or delay will also be listed and 

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tabulated by preferred term. Other safety endpoints, including vital signs, clinical laboratory parameters, 
and ECG, will be summarized descriptively. Shift tables for select laboratory parameters will be 
presented. 
14.6.1. 
Adverse Events 
The verbatim terms used in the source and CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA), version 19.0. All treatment-emergent 
adverse events reported up to 30 days after the last dose of study drug in each phase of the study will 
be included in the analysis. For each adverse event, the percentage of subjects who experience at least 
1 occurrence of the given event will be summarized by treatment group. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those subjects 
who die, who discontinue treatment due to an adverse event, or who experience a severe or a serious 
adverse event 
Severity grading is as follows: 
Mild:   asymptomatic   or   mild symptoms;  clinical  or  diagnostic observations 
only; intervention not indicated.  
 Moderate;   minimal,   local   or noninvasive intervention indicated;    
Severe: hospitalization  or  prolongation  of hospitalization indicated; 
Disabling or life-threatening;  
Death 
 
14.6.2. 
Cardiac Function Tests 
Electrocardiogram parameters will be summarized by treatment groups using descriptive statistics. The 
percentage of subjects with clinically significant ECG changes will be summarized as appropriate.  
 
15. 
ADMINISTRATIVE REQUIREMENTS 
15.1. 
Protocol Amendments 
All protocol amendments will be issued by the sponsor/Principal Investigator with prior notice to UT 
Southwestern IRB. Protocol amendments must not be implemented without prior IRB approval except 
when necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IRB.. During the course of the study, in situations where a departure from the 
protocol is unavoidable, the investigator or other physician in attendance will contact the appropriate 
sponsor representative (see Contact Information page(s) provided separately). Whenever possible, this 
contact should be made before implementing any departure from the protocol. In all cases, contact with 
the sponsor must be made as soon as possible to discuss the situation and agree on an appropriate 
course of action. The data recorded in the CRF and source documents will reflect any departure from the 
protocol, and the source documents will describe this departure and the circumstances requiring it. The 
local IRB must be notified of any protocol deviation. 

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15.2. 
Regulatory Documentation 
15.2.1. 
Required Pre-study Documentation 
The following documents must be provided to the sponsor before shipment of study drug to the 
investigational site: 
• Protocol and amendment(s), if any, signed and dated by the principal investigator 
• A copy of the dated and signed, written IRB approval of the protocol, amendments, informed 
consent form, any recruiting materials, and if applicable, subject compensation programs. This 
approval must clearly identify the specific protocol by title and number and must be signed by 
the chairman or authorized designee. 
• Name and address of the IRB, including a current list of the IRB members and their function, with 
a statement that it is organized and operates according to GCP and the applicable laws and 
regulations. If accompanied by a letter of explanation, or equivalent, from the IRB, a general 
statement may be substituted for this list. If an investigator or a member of the investigational 
staff is a member of the IRB, documentation must be obtained to state that this person did not 
participate in the deliberations or in the vote/opinion of the study. 
Regulatory authority approval or notification, and 
• Signed and dated statement of investigator and sub-investigators (eg, Form FDA 1572)  
• Documentation of investigator qualifications (eg, curriculum vitae) 
• Completed investigator financial disclosure form from the principal investigator 
• Signed and dated clinical trial agreement, which includes the financial agreement 
 
The following documents must be provided to the sponsor before enrollment of the first subject: 
• Completed investigator financial disclosure forms from all clinical sub-investigators 
• Documentation of sub-investigator qualifications (eg, curriculum vitae) 
  
15.3. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the sponsor 
site contact for completeness. 
 
The subject identification and enrollment log will be treated as confidential and will be filed by the 
investigator in the study file. All reports and communications relating to the study will identify subjects 
by assigned number. 
 
The investigator must also complete a subject screening log, which reports on all subjects who were seen 
to determine eligibility for inclusion in the study. 
 

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15.4. 
Source Documentation 
At a minimum, source documentation must be available for the following to confirm data collected in 
the CRF: subject identification, eligibility, and study identification; study discussion and date of informed 
consent; dates of visits; results of safety and efficacy parameters as required by the protocol; record of 
all 
adverse 
events 
and 
follow-up 
of 
adverse 
events; 
concomitant 
medication; 
drug 
receipt/dispensing/return records; study drug administration information; and date of study completion 
and reason for early discontinuation of study drug or withdrawal from the study, if applicable. In 
addition, the author of an entry in the source documents should be identifiable. 
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care. Specific details 
required as source data for the study will be reviewed with the investigator before the study and will be 
described in the monitoring guidelines. 
 
15.5. 
Data Reporting 
Data for each patient will be recorded on the eCRF. An eCRF must be completed for every patient 
enrolled in the study.  Data will be entered directly from the source documentation into the eCRF within 
2 business days of visit. The eCRF data will be entered by study-site personnel and then reviewed and 
electronically signed by the Investigator listed on Form FDA 1572, within a reasonable time period after 
data collection. All study-site personnel must use an electronic signature access method to enter, review, 
or correct study data. Electronic signature procedures shall comply with the Code of Federal Regulations 
(CFR) Title 21 Part II and the ICH Guidelines for GCP (Topic E6, April 2000) Section 5.5.3. Passwords and 
electronic signatures will be strictly confidential. 
 
For all clinical trials, the data should be recorded on the source documents first and not entered directly 
into the computer. The eCRF will not be regarded as source data for any data points. The investigator 
must verify that all data entries in the CRFs are accurate and correct. All CRF entries, corrections, and 
alterations must be made by the investigator or other authorized study-site personnel.  
 
15.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
associated personnel before the study, and periodic monitoring visits by the Sponsor. Written 
instructions will be provided for collection, preparation, and shipment of samples.  
 
Guidelines for CRF completion will be provided and reviewed with study personnel before the start of 
the study. The sponsor will review CRFs for accuracy and completeness during monitoring visits and after 
transmission to the sponsor; any discrepancies will be resolved with the investigator or designee, as 
appropriate. After upload of the data into the clinical study database they will be verified for accuracy 
and consistency with the data sources. 
 

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15.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs and all 
source documents that support the data collected from each subject, as well as all study documents as 
specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical Trial, and all study 
documents as specified by the applicable regulatory requirement(s). The investigator/institution will 
take measures to prevent accidental or premature destruction of these documents. 
 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
 
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility 
of keeping the study records, custody must be transferred to a person who will accept the responsibility. 
The sponsor must be notified in writing of the name and address of the new custodian. Under no 
circumstance shall the investigator relocate or dispose of any study documents before having obtained 
written approval from the sponsor. 
 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports. 
 
15.8. 
Monitoring 
The sponsor will perform monitoring visits as frequently as necessary. The monitor will record dates of 
the visits in a study site visit log that will be kept at the site. The first post-initiation visit will be made as 
soon as possible after enrollment has begun. At these visits, the monitor will compare the data entered 
into the CRFs with the hospital or clinic records (source documents). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the CRF are 
known to the sponsor and investigational staff and are accessible for verification by the sponsor site 
contact. If electronic records are maintained at the investigational site, the method of verification must 
be discussed with the investigational staff.  
 
Direct access to source documentation (medical records) must be allowed for the purpose of verifying 
that the data recorded in the CRF are consistent with the original source data. Findings from this review 
of CRFs and source documents will be discussed with the investigational staff. The sponsor expects that, 
during monitoring visits, the relevant investigational staff will be available, the source documentation 
will be accessible, and a suitable environment will be provided for review of study-related documents. 
The monitor will meet with the investigator on a regular basis during the study to provide feedback on 
the study conduct. 

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15.9. 
Study Completion/Termination 
15.9.1. 
Study Completion 
The study is considered completed with the last study assessment for the last subject participating in the 
study. The final data from the investigational site will be sent to the sponsor (or designee) after 
completion of the final subject assessment at that site, in the time frame specified in the Clinical Trial 
Agreement. 
 
15.9.2. 
Study Termination 
The sponsor reserves the right to close the investigational site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Investigational sites will be closed upon study completion. 
An investigational site is considered closed when all required documents and study supplies have been 
collected and a site closure visit has been performed. 
 
The investigator may initiate site closure at any time, provided there is reasonable cause and sufficient 
notice is given in advance of the intended termination. 
 
Reasons for the early closure of an investigational site by the sponsor or investigator may include but 
are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB or local health 
authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the investigator 
 
 
15.10. 
On-Site Audits 
The sponsor’s representatives may visit the site at any time during or after completion of the study to 
conduct an audit of the study in compliance with regulatory guidelines and company policy. These audits 
will require access to all study records, including source documents, for inspection and comparison with 
the CRFs. Subject privacy must, however, be respected. The investigator and staff are responsible for 
being present and available for consultation during routinely scheduled site audit visits conducted by the 
sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part of a 
national GCP compliance program or to review the results of this study in support of a regulatory 
submission. The investigator should immediately notify the sponsor if they have been contacted by a 
regulatory agency concerning an upcoming inspection. 
 
15.11. 
Use of Information and Publication 
Any data generated as a result of this study are considered confidential and remain the sole property of 
the sponsor. The investigator agrees to maintain this information in confidence and use this information 
only to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent. The investigator is obligated to provide the sponsor with all data obtained in the study. 

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The results of the study will be reported in a Clinical Study Report generated by the sponsor and will 
contain CRF data from all investigational sites that participated in the study, and direct transmission of 
clinical laboratory data from a central laboratory into the sponsor's data base. Results of exploratory 
analyses performed after the Clinical Study Report has been issued will be reported in a separate report 
and will not require a revision of the Clinical Study Report. Study subject identifiers will not be used in 
publication of exploratory results.  
 
Authorship of publications resulting from this study will be based on the guidelines on authorship, such 
as those described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
which state that the named authors must have made a significant contribution to the design of the study 
or analysis and interpretation of the data, provided critical review of the paper, and given final approval 
of the final version. 
 
The sponsor will register and/or disclose the existence of and the results of clinical studies as required 
by law, including registration on the ClinicalTrials.gov website.  
 
 

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Reference List 
 
 
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 (19)  Serrano-Gonzalez M, Ryabets-Lienhard A, ., Auchus RJ, Geffner M. Steroidogenesis Inhibitors to 
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 (24)  Attard G, Reid AH, Auchus RJ, Hughes BA, Cassidy AM, Thompson E, et al. Clinical and biochemical 
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 (36)  Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World Health 
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Appendix A-Low Fat Guidelines 
 
A low fat breakfast should contain fewer than 3 grams of fat. When you eat less fat, you eat 
fewer calories. Your child may need to eat more calories from carbohydrates or proteins. 
 
Choosing Low-fat Foods 
 
Breads, Cereals, Rice, and Pasta 
• Choose whole-grain breads 
• Avoid foods such as donuts, sweet rolls, muffins, biscuits, cornbread, and 
pancakes. 
• Hot and cold cereals are usually low in fat 
• Avoid granola and adding butter to hot cereals 
• Avoid anything fried. 
 
Vegetables and Fruit 
• Fruits and vegetables are low in fat; they add flavor and variety to your diet 
• They contain fiber, vitamins, and minerals 
• Avoid adding margarine, butter, full-fat dressings, or sour cream. 
• Try using herbs, low-fat yogurt, and low-fat dressings for flavor 
 
Meats 
• Baking, broiling, roasting or grilling will minimize fat added to protein sources 
• Use either a nonstick pan or nonstick cooking spray 
• Trim all visible fat and remove skin before cooking 
• Select lean cuts of meat which have the word “loin” or “round” in the name 
 
Milk, Yogurt and Cheese 
• Use skim/fat free milk 
• Use string cheese as a low-fat, high calcium food source 
• Use fat free cottage cheese 
• Plain non-fat yogurt can replace sour cream in many recipes 
 
 
Label Lingo 
 

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You may see words on the label that can help you choose lower fat foods. Always read the 
Nutrition Facts to see exactly how much fat is in the food. 
 
Fat free 
½ gram of fat or less per serving 
Low saturated fat 
1 gram of fat or less per serving 
Low fat 
3 grams of fat or less per serving 
Light or lite 
1/3 fewer calories or has 50% less fat than 
comparable products per serving 
 
 
 
 
Breakfast Selections 
 
1. Oatmeal with berries and 2 oz sliced turkey or ham 
o Season oatmeal with cinnamon, nutmeg, or pumpkin spice 
2. Vegetable Omelet and whole wheat bread 
o Egg whites with fresh or frozen vegetables (spinach, peppers, onions, mushrooms, 
tomatoes) 
o Serve with 1 slice whole wheat toast 
3. Egg whites and fruit 
o Ensure to separate the egg and discard yolk portion 
o Serve with any fruit 
4. Cereal and skim milk 
o Choose cereals with no more than 2 grams of fat per serving; ensure to measure out 
1 serving size 
5. Light or Fat-free yogurt and cereal/oats 
o See recommendations for cereal above 
o Yogurt should have no more than 2 grams fat per serving 
6. Whole wheat English Muffin and fruit 
o Option to add jelly to English muffin 
o Eat with 1 serving of fruit – banana, apple, berries, etc