Conditions: Congenital Adrenal Hyperplasia (CAH)
Keywords: Congenital Adrenal Hyperplasia (CAH) Intervention Children
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
This study was developed to determine if a combination of four drugs (flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone) can normalize growth in children with congenital adrenal hyperplasia.

The study will take 60 children, boys and girls, and divide them into 2 groups based on the medications given. Group one will receive the new four-drug combination. Group two will receive the standard treatment for congenital adrenal hyperplasia (hydrocortisone and fludrocortisone).

The boys in group one will take the medication until the age of 14 at which time they will stop taking the four-drug combination and begin receiving the standard treatment for congenital adrenal hyperplasia. Girls in group one will take the four-drug combination until the age of 13, at which time they will stop and begin receiving the standard treatment for congenital adrenal hyperplasia plus flutamide. Flutamide will be given to the girls until two years after their first menstrual period or until adult height.

All of the children will be followed until they reach their final adult height. The effectiveness of the treatment will be determined by measuring the patient's adult height.

Detailed description:
To test the hypothesis that the regimen of flutamide (an antiandrogen), testolactone or letrozole (an inhibitor of androgen-to-estrogen conversion), and reduced hydrocortisone dose can normalize the growth and adult stature of children with congenital adrenal hyperplasia, and can avoid the complications of supraphysiologic glucocorticoid dosage, 60 children with this disorder will be randomized to receive either the above regimen or conventional treatment until they have reached age 13 years in a girl or age 14 in a boy. After these ages boys will receive the conventional treatment and girls will receive conventional treatment plus flutamide. In girls, flutamide will be continued until 6 months after menarche. All children will be followed until they have attained final adult height. The principal outcome measure will be adult height.

Arms:
arm 1: Children with congenital adrenal hyperplasia (CAH) and bone ages of 2-13 years in boys and 2-11 years in girls were randomized to receive antiandrogen (flutamide 10mg/kg/day orally), aromatase inhibitor (testolactone - 20mg/ kg/day orally OR letrozole - 1.5mg/m\^2 body surface area orally), low-dose hydrocortisone (6-8 mg/m\^2/day orally), and fludrocortisone (100-200 mcg/day, depending on lab evaluation, orally). Participants received the four-drug regimen until the age of 13 in the girls and 14 in the boys and then were switched to standard therapy. Female participants on investigational drugs were continued on flutamide until attainment of final adult height or two years post menarche. Participants who experienced early puberty received GnRH agonist therapy: depot leuprolide 7.5-15 mg/kg monthly intramuscularly or deslorelin 4 mcg/kg/day (adjusted based on weight and response) subcutaneously. arm 2: Children with congenital adrenal hyperplasia (CAH) and bone ages of 2-13 years in boys and 2-11 years in girls received standard therapy/conventional treatment (with hydrocortisone and fludrocortisone). Participants received hydrocortisone approximately 10-15 mg/m\^2/day orally, not exceeding 25mg/m\^2/day, and fludrocortisone 100-200 mcg/day orally depending on lab evaluation. Participants who experienced early puberty received GnRH agonist therapy: depot leuprolide 7.5-15 mg/kg monthly intramuscularly or deslorelin 4 mcg/kg/day (adjusted based on weight and response) subcutaneously.

Interventions: intervention 1: Fludrocortisone intervention 2: Hydrocortisone intervention 3: Letrozole intervention 4: Flutamide intervention 5: Testolactone
Intervention descriptions: intervention 1: Mineralocorticoid needed to replace aldosterone deficiency. Patients will continue to receive an optimal fludrocortisone dose intervention 2: Glucocorticoid needed to replace cortisol deficiency. Reduced hydrocortisone dose might normalize the growth and adult stature of children with congenital adrenal hyperplasia intervention 3: Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. intervention 4: Non steroidal anti-androgen that prevents the action of androgens by blocking receptor sites in target tissue. It may also produce changes in testosterone and estradiol intervention 5: Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.

Protocol document:
Prot_SAP_000.pdf: 


Abbreviated Title: Congenital Adrenal Hyperplasia
Version Date: 03/23/2023
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Précis
To test the hypothesis that the regimen of flutamide (an antiandrogen), testolactone or 
letrozole (an inhibitor of androgen-to-estrogen conversion), and reduced hydrocortisone dose can 
normalize the growth and adult stature of children with congenital adrenal hyperplasia, and can 
avoid the complications of supraphysiologic glucocorticoid dosage, 60 children with this 
disorder will be randomized to receive either the above regimen or conventional treatment until 
they have reached age 13 years in a girl or age 14 in a boy.  After these ages boys will receive 
conventional treatment and girls will receive conventional treatment plus flutamide. In girls, 
flutamide will be continued until 6 months after menarche. All children will be followed until 
they have attained final adult height. The principal outcome measures will be adult height, body 
mass index, and bone density. 


Abbreviated Title: Congenital Adrenal Hyperplasia
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Introduction
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal 
recessive disorder involving the next-to-last enzyme of cortisol biosynthesis. The deficiency in 
cortisol results in an elevation of ACTH leading to adrenal hyperplasia and hypersecretion of 
cortisol precursors.  Several of these precursors are enzymatically converted to androgens and 
estrogens, which cause rapid growth, premature epiphyseal fusion, and adult short stature.
CAH occurs in several clinically distinct variants that reflect differing severity of the 
underlying enzymatic deficiency.  The most severely affected children have an inability to 
produce enough mineralocorticoid to prevent adrenal crisis; this is termed the salt-wasting form 
of CAH.  The next most severely affected children can produce sufficient mineralocorticoid to 
avoid adrenal crisis (although they make less than the normal amount), but still produce 
excessive amounts of adrenal androgens from early fetal life.  Girls with this variant usually have 
ambiguous genitalia at birth.  Boys develop precocious pseudopuberty in early childhood.  This 
form is termed simple virilizing CAH.  The salt-wasting and simple virilizing forms of CAH are 
referred to collectively as the "classic" forms of the disorder.  
Standard medical therapy for classic CAH (21-hydroxylase deficiency) has involved daily 
administration of glucocorticoid and mineralocorticoid.  Glucocorticoid replacement suppresses 
ACTH secretion and thereby reduces adrenal stimulation and androgen production.  However, it 
does not affect the intrinsic adrenal abnormality, and thus the adrenal glands continue to secrete 
an abnormally high ratio of androgen to cortisol at any given level of adrenal activity. 
Mineralocorticoid replacement suppresses plasma renin activity and angiotensin levels, and 
corrects the tendency of these patients to lose salt.  By a mechanism still not fully understood, 
this helps to reduce adrenal androgen overproduction.  Thus, mineralocorticoid replacement 
allows a lower dose of hydrocortisone to be used than would be required if glucocorticoid alone 
were administered.  
       Despite decades of study, the growth and development of most children with CAH remain 
abnormal [1, 2] .  High levels of sex steroids induce premature epiphyseal closure; while excess 
glucocorticoid suppresses growth. The median adult height of treated boys was only at the 4th 
percentile of normal men, and the median adult height of girls, treated from before one year of age, 
was at the 25th percentile.  Maria New and her colleagues reported adult height in all subjects that 
averaged 1.7 standard deviations below the mean for the normal population, which corresponds to 
the 9th percentile [3] . These are the results at leading clinics which pioneered hydrocortisone 
treatment of CAH.  Moreover, retrospective studies indicate that the final height of treated patients 
is relatively independent of the degree of control of adrenal androgen levels, [1, 3-5] suggesting 
that both hyperandrogenism and hypercortisolism contributed to the observed adult short stature.  
A meta-analysis of data from 18 centers showed that adult heights in patients with classic CAH 
averaged 1.4 SD (10 cm) below the population mean [6] . A subsequent meta-analysis of 35 studies 
of classic CAH found the mean adult height score corrected for parental height of -1.05 standard 
deviation and mineralocorticoid use was associated with improved height outcome [7]. In addition, 
many girls encounter problems related to excess androgen despite treatment.  Thus, there is need 
for continuing research to improve the outcome of treatment.
The suboptimal outcome of treatment is related to the theoretical inadequacy of 
fludrocortisone and hydrocortisone as sole treatment.  If hydrocortisone is administered so as to 


Abbreviated Title: Congenital Adrenal Hyperplasia
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achieve perfectly physiologic levels, and thus perfectly normal ACTH levels and adrenal size 
(euplastic adrenals), the adrenals will nonetheless secrete an abnormally high ratio of androgen 
and estrogen to cortisol because the 21-hydroxylase deficiency shifts an excessive proportion of 
the steroid intermediates into the androgen and estrogen pathways.  This excess androgen and 
estrogen will, if left unchecked, accelerate growth rate and bone maturation and compromise adult 
height.  If, on the other hand, the hydrocortisone dose is increased above perfectly physiologic 
levels to control the excess androgen and estrogen production by the 21-hydroxylase-deficient 
adrenal glands, the resulting iatrogenic hypercortisolism will stunt growth rate, impair adult 
stature, decrease bone mineral density, alter intermediary metabolism, and cause hypertension.  
Thus, the existing approach to treatment produces either hypercortisolism, androgen excess, or a 
combination of these states.
Our hypothesis to improve treatment initially arose from work in the intramural program of 
NICHD to treat boys with familial male precocious puberty (FMPP).  The accelerated growth rate 
and bone maturation of these boys was controlled effectively with an antiandrogen 
(spironolactone) and an aromatase inhibitor (testolactone) [8] . We hypothesized that a similar 
approach would be effective in CAH, and would allow us to avoid the complications of 
glucocorticoid excess by reducing hydrocortisone dose to strictly physiologic levels. An 
antiandrogen other than spironolactone will be required in CAH, however, since patients with 
CAH have a defect of the aldosterone pathway that precludes the use of spironolactone because 
this drug also has aldosterone antagonist activity. Thus, we have substituted flutamide for 
spironolactone. The aromatase inhibitor is an essential component of the regimen to prevent the 
gynecomastia that would otherwise result from use of antiandrogen alone, and to prevent the 
maturational effects of estrogen upon bone, which are exerted at extremely low levels [9-11].
Flutamide (41-nitro-31 fluoromethylisobutyranilide) is a nonsteroidal antiandrogen which has 
been used in the treatment of prostate cancer and benign prostatic hypertrophy [12, 13].  It prevents 
the action of androgens by blocking the receptor sites in target tissues [14].  It may also produce 
changes in the metabolism of testosterone as well as estradiol [15, 16].  In comparison with other 
antiandrogens such as cyproterone acetate and megestrol acetate, flutamide alone has pure 
antiandrogenic activity, thus making it the most specific androgen antagonist for the treatment of 
androgen-dependent disorders [17, 18]. 
Testolactone has for many years been an approved drug to lower estrogen levels in women 
with breast cancer [19].  We have 19 years of combined experience using it in children with male-
limited precocious puberty and CAH. The rationale of combined treatment of CAH with flutamide 
and testolactone will be to block the effects of elevated androgen levels with flutamide, and to 
reduce elevated estrogen levels, which are produced by peripheral conversion from the high 
androgen levels, with testolactone.  Since these drugs act through quite different mechanisms, there 
is no reason to expect that their combinations will interfere with the efficacy of either drug or cause 
adverse effects beyond those associated with the use of these drugs individually.  In fact, 
testolactone was found, in our studies of boys with male-limited precocious puberty, to prevent 
the gynecomastia that accompanied use of antiandrogen alone [8].
Both testolactone and letrozole are aromatase inhibitors.  Testolactone was chosen as the drug of 
choice for protocol 96CH0033 years ago at a time when testolactone was being used in a variety 
of pediatric endocrine conditions.  Over the years, other more potent aromatase inhibitors have 
become available.  Letrozole is given once daily, while testolactone is given thrice daily.  Thus, 


Abbreviated Title: Congenital Adrenal Hyperplasia
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letrozole is more convenient for the patient.  Testolactone occasionally causes gastrointestinal 
discomfort.  This side effect has been observed, but less commonly, with letrozole.
Letrozole is approved by the FDA to lower estrogen levels in adult women with breast and other 
cancers.  Letrozole, like all aromatase inhibitors, has not been formally tested in children and has 
not been approved by the FDA for use in children.  However, other than testolactone, letrozole is 
the aromatase inhibitor with the most reported pediatric experience and with the most clinical 
experience by investigators at the Clinical Center.  Letrozole was used at the Clinical Center in the 
treatment of children with McCune Albright syndrome (protocol 00-D-0183).  In this protocol, 
girls with precocious puberty and McCune Albright syndrome experienced an improvement in 
their puberty without any apparent harmful side-effects[20] .  Moreover, pediatric endocrinologists 
have used letrozole to treat other endocrine conditions in children[21].  Safe and effective use of 
letrozole in children has been reported for the treatment of idiopathic short stature [22, 23]; and in 
combination with testosterone for male pubertal delay [24-26].  
Continuation of flutamide therapy during puberty has the advantage of possibly protecting the 
ovaries against the development of polycystic ovarian syndrome (PCOS).  Fertility in females with 
CAH is an ultimate and attainable goal.  Delay of the average age of menarche in girls with classic 
CAH has been reported from various clinics [2, 27].  Menstrual irregularities, anovulation, 
infertility in females with CAH is not always due to the undertreated state of hyperandrogenism. 
CAH females have been found to have increased adrenal progesterone secretion [28], as well as 
elevated estrogen of adrenal origin [27]. A PCO-syndrome type of ovarian dysfunction has been 
described in women with CAH [29]. Androgens may directly prevent the maturation of follicles 
and/or affect the hypothalamic-pituitary-gonadal axis, which then induces morphologic and 
biochemical changes characteristic of polycystic ovarian syndrome.  Ovarian dysfunction in 
females with CAH may be due to an abnormality either at the hypothalamic, pituitary or ovarian 
level, and inadequate control of excessive adrenal sex steroids (androgens, progestins, estrogens 
alone or in combination) may contribute to menstrual and reproductive disorders in CAH females.  
We hypothesize that flutamide treatment during puberty will antagonize intraovarian levels of 
androgens, normalize the age of onset of menarche and reduce the incidence of  PCOS.  The use 
of flutamide will also allow for a lower glucocorticoid dose.  
We completed a pilot study which consisted of a 6-month trial of flutamide plus testolactone, 
added to a modified conventional regimen (modified by restricting hydrocortisone dosage to a 
physiologic level), compared to conventional treatment with hydrocortisone plus fludrocortisone 
[30].  The sequence of 6-month periods was chosen randomly with a 3-month "washout" period 
between each 6-month arm.
Results from this pilot study revealed that the rate of growth, weight gain, and bone maturation 
normalized with treatment with flutamide, testolactone and low dose hydrocortisone. No 
significant adverse effects were observed.  Because a 6-month treatment period was too short to 
provide meaningful assessment of the effects of flutamide and testolactone on long-term growth 
rate, bone age advancement, and predicted adult height, a 2-year trial of flutamide plus 
testolactone, added to the modified conventional regimen of hydrocortisone and fludrocortisone 
was undertaken.  Children were randomized to receive either conventional treatment or the 
investigational regimen of flutamide, testolactone, and reduced hydrocortisone dose. An open 
design was employed because the hydrocortisone dosage adjustments required during 
conventional treatment would have made it very difficult to carry out a blind study.  Results from 


Abbreviated Title: Congenital Adrenal Hyperplasia
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this 2-year study show that there is continued normalization of the rate of growth, weight gain, and 
bone age maturation, without any significant adverse side effects [31]. Based upon these findings, 
we have decided to conduct a long-term trial to test the hypothesis that this new regimen can 
normalize the growth and development of children with CAH.
Evaluation of the Project in Relation to Criteria for NICHD Clinical Protocols
 
(1) The protocol addresses fundamental aspects of human physiology or pathophysiology.
The protocol addresses four fundamental issues related to the pathophysiology of congenital 
adrenal hyperplasia and its impact on growth and development. First, it tests the hypothesis that 
some of the undesired outcomes of conventionally treated patients, such as obesity, are due to 
glucocorticoid excess, and that these undesired outcomes can be avoided by reduction of the 
glucocorticoid dose to physiologic levels [32, 33]. To our knowledge the current trial is the only 
long-term randomized study of CAH that involves the restriction of hydrocortisone dose to a 
strictly physiologic level. Second, the protocol examines the hypothesis that estrogen contributes 
to the impaired adult height in CAH by using an inhibitor of estrogen synthesis. This hypothesis 
is in accord with the observation of delayed epiphyseal fusion and tall stature in individuals with 
a defect in the estrogen receptor [11] or in  the estrogen biosynthetic enzyme aromatase [34]. To 
our knowledge, the current study is the only long-term randomized trial of an aromatase inhibitor 
in any of the LHRH-independent forms of precocious puberty.  Lastly, the protocol addresses the 
hypotheses that early exposure to androgens influences the developing brain and ovaries and has 
an effect on cognition and reproductive function in females.
(2) The protocol outcome has a reasonable potential to impact significantly on the public health.
Congenital adrenal hyperplasia occurs in only 1 in 15,000 individuals. Thus, even the complete 
elimination of the disorder would have at best a minimal impact on the public health. No study of 
a new treatment regimen for congenital adrenal hyperplasia can be expected to meet the above 
criterion because the disorder is so rare.
  Ancillary studies of the population of children with CAH followed in this protocol have the 
potential to impact significantly on public health.  Extending our studies to the pubertal period in 
girls with CAH may provide insight into the long-term consequences of early ovarian exposure to 
androgens.  PCO affects 7% of women of reproductive age and is a significant public health issue.  
The effects of extraovarian sources of androgens (i.e. adrenal) on the development of PCO is not 
well understood. Moreover, the protocol includes behavioral and cognitive testing which may 
provide insight into how hormones affect behavior and the developmental consequences of early 
exposure to androgens.  Learning disabilities are a significant public health issue and are much 
more common in boys than girls.  Studies of children with CAH may provide insight into hormonal 
influences in the development of learning disabilities.
(3) The protocol represents research in the diagnosis or treatment of orphan or rare diseases that is 
relatively unlikely to be performed outside the Clinical Center.
Congenital adrenal hyperplasia is indeed an orphan or rare disease. During a recent literature 
review, we failed to find a single study, even a short-term study, in which two or more therapies 




Abbreviated Title: Congenital Adrenal Hyperplasia
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conventional treatment (because of the two additional drugs), the cost of monitoring will be less. 
This is due to the reduced need to monitor androgen levels when they are being blocked by an 
antiandrogen. Since the cost of monitoring multiple steroid levels at 3-6 month intervals 
throughout childhood can be quite high, the increased drug cost may be offset by reduced 
monitoring cost. Our prediction is that the cost-benefit ratio for the investigational approach will 
be favorable if the long-term benefits that we hypothesize are in fact achieved.
Study objectives and endpoints
 
Success in normalizing adult height is a sensitive measure of control of excess sex steroid 
action and avoidance of excess glucocorticoid action during childhood. 
Primary objective

To demonstrate the superior efficacy of the combination regimen of an antiandrogen, 
aromatase inhibitor and reduced hydrocortisone dose compared with standard 
glucocorticoid replacement therapy in achieving taller adult stature in classic congenital 
adrenal hyperplasia. 
Secondary Objectives 

To assess the safety and tolerability of antiandrogen, aromatase inhibitor and reduced 
hydrocortisone dose combination therapy. 

To assess the effect of antiandrogen, aromatase inhibitor and reduced hydrocortisone dose 
combination therapy on height gain, growth velocity and bone maturation prior to puberty.

To assess the effect of antiandrogen, aromatase inhibitor and reduced hydrocortisone dose 
combination therapy on height gain and bone maturation during puberty

To assess the effect of antiandrogen, aromatase inhibitor and reduced hydrocortisone dose 
combination therapy on development of TART in males and establishment of menstrual 
regularity in females

To assess the effect of antiandrogen, aromatase inhibitor and reduced hydrocortisone dose 
combination therapy on fasting glucose, body mass index, and bone mineral density 

To assess hormonal control based on percent of visits within the normal (or optimal) range 
for 17OHP, androstenedione, PRA and ACTH

To assess sex differences in outcomes.
A.  Primary Endpoint
The operational definition of attainment of adult height was defined as the study visit at which the 
incremental growth declined <1.5 cm (0.6 inch) over 12 months. 
The primary outcome variable is adult height which will be expressed in SD units relative to the 
normal population.


Abbreviated Title: Congenital Adrenal Hyperplasia
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B Secondary Endpoints
Secondary outcome variables will be examined between the two study arms at baseline, pubertal 
onset and adult height (final visit). To examine sex differences, the secondary outcomes variables 
will be examined by-sex between the two study arms.
‘Pubertal Onset’ is defined as the visit when patients entered puberty (Tanner 2 breast in females, 
testicle size > 3mL) or completed therapy with the aromatase inhibitor and or LHRHa.
i.Adult height achieved will also be expressed standard deviation (SD) units and in cm as the 
difference in height achieved in relation to their target height (i.e., mid-parental height, 
calculated based on their parental heights) 
ii.
Height achieved (SD units) from baseline to pubertal onset 
iii.
Height achieved (SD units) from pubertal onset to adult height
iv.
Predicted adult height (using Bayley-Pinneau method) at pubertal onset 
v.
Predicted adult height (using Bayley-Pinneau method) change from baseline to pubertal 
onset 
vi.
Predicted adult height (using Bayley-Pinneau method) change from pubertal onset to final 
height
vii.Growth velocity (in SD units) from baseline to pubertal onset 
viii.Growth velocity (in SD units) from pubertal onset to adult height
ix.
Percent of visits with ACTH in normal range from baseline to pubertal onset 
x.Percent of visits with ACTH in normal range from pubertal onset to adult height
xi.Percent of visits with androstenedione in normal range from baseline to pubertal onset
xii.Percent of visits with androstenedione in normal range from pubertal onset to adult height
xiii.Percent of visits with 17-hydroxyprogesterone in the optimal range (<1,200 ng/dL) or high 
(>1,200 ng/dL) from baseline to pubertal onset
xiv.Percent of visits with 17-hydroxyprogesterone in the in the optimal range (<1,200 ng/dL) or 
high (>1,200 ng/dL) from pubertal onset to adult height
xv.Percent of patients with onset of central precocious puberty (CPP)
xvi.Rate of bone maturation as change in bone age from baseline to pubertal onset / change in 
chronological age from baseline to pubertal onset; change in bone age from pubertal onset 
to adult height / change in chronological age from pubertal onset to adult height; change in 
bone age from baseline to adult height / change in chronological age from baseline to adult 
height. Bone age assessment will be performed manually using Greulich and Pyle atlas 
method and by automated software (BoneXpert) in a subset of patients visit who have 
availability of digital bone age images.
xvii.Number of years bone age remain unchanged from baseline to pubertal onset 
xviii.Dose of hydrocortisone at baseline, pubertal onset and adult height, baseline to pubertal and 
pubertal to adult height
xix.Cumulative glucocorticoid exposure over time
C. Exploratory Endpoints
i.Insulin resistance based on HOMA-IR at the final visit
ii.
BMI (as SD units) change from baseline to ‘pubertal onset’ visit
iii.
BMI (as SD units) change from ‘pubertal onset’ to adult height
iv.
BMI (as SD units) at adult height


Abbreviated Title: Congenital Adrenal Hyperplasia
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v.
BMD (Z-score) at adult height
vi.
Age at menarche
vii.Percent of patients (females only) with normal menstrual cyclicity at adult height
D. Safety Endpoints
i.
Adverse events (AEs) – particularly GI related adverse events, abnormal liver function tests.
ii.
Percent of patients (males only) with development of Testicular adrenal rest tumors (TART) 
at pubertal onset and adult height
Study Design and Methods
Patient Selection
Subjects will be boys with bone ages 2 to 13 years and girls with bone ages 2 to 11 years with 
classic 21-hydroxylase.  Subjects must either not yet have undergone pubertal activation of the 
hypothalamic-pituitary-gonadal axis, or, if pubertal activation has occurred, must be receiving an 
LHRH agonist to suppress their secondary central precocious puberty.  This requirement is to 
ensure that growth during the study will not be compromised by secondary central precocious 
puberty. Children with a bone age of 1 to 2 years may enroll in the protocol for optimization of 
conventional therapy as described below, but will not be randomized to a study arm until the bone 
age reaches 2. Monitoring of such children will be identical to older children randomized to the 
conventional arm.
Exclusion criteria include children who have concurrent illnesses requiring glucocorticoid 
treatment (such as severe asthma), or requiring drugs that markedly alter hydrocortisone 
metabolism (such as anticonvulsants), and children who cannot be brought into reasonable control 
with conventional treatment (an unusual occurrence).
Protocol
Before entry into the study, adequacy of the patient's CAH management will be documented.  
Treatment will be modified as needed to achieve optimal control, according to state-of-the-art 
concepts of CAH management, as outlined below.  
Secondary central precocious puberty will be defined by meeting one or more of the following 
criteria:
1) Peak Leuprolide-stimulated LH/FSH ratio consistent with central puberty.
3) Baseline LH-ICMA of greater than 0.3 [35].
4) Clinical evidence of central precocious puberty (breast development in girls and testicular 
enlargement in boys).
Patients who are in secondary central precocious puberty will be offered treatment with a 
commercially available LHRH agonist, Lupron Depot(administered via monthly intramuscular 
injection, TAP) or an investigational LHRH agonist, Deslorelin (administered via daily 
subcutaneous injection). Since 1979, Deslorelin has been used at the NIH for the treatment of 


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central precocious puberty and has been shown to be safe and effective [35].  Other commercially 
available products include Histrelin (Roberts) and Lupron Injection, both administered via daily 
subcutaneous injection. We have chosen to continue to use Deslorelin because it is readily 
available through the NIH Pharmacy (there was a recent shortage of Histrelin), it is less expensive 
than the commercially available subcutaneous products, and we have extensive personal 
experience in its use.   
Choice of medication will be based on patient and family preferences.  Families will be 
counseled on the advantages and disadvantages of these two therapies.  Both medications are 
known to effectively suppress the hypothalamic-pituitary-gonadal axis.  Known side effects 
include rash, and local injection site reactions (milder with Deslorelin).  Lupron has the advantage 
of monthly administration and the disadvantage of an increase risk of local injection site abscess 
formation  (Deslorelin may cause redness at the injection site but has not been reported to result in 
abscess formation). Lupron also may require more dose adjustments in the beginning of therapy. 
Anaphylactoid reactions are an extremely rare risk for both medications.  Children will return to 
the NIH day hospital 3 months after starting LHRH analog therapy for evaluation of hypothalamic-
pituitary-gonadal suppression.  Those patients who are currently being treated with Deslorelin 
(previously under protocol 79-CH-112) will be continued on Deslorelin or switched to Lupron, 
depending on patient preference.
Once degree of CAH control has been judged optimal, children will be randomized to receive 
either the regimen of flutamide, testolactone or letrozole, and reduced hydrocortisone dose or 
conventional treatment (with hydrocortisone and fludrocortisone) until the age of 13 in the girls 
and 14 in the boys. At that time the regimen of flutamide, testolactone, and reduced hydrocortisone 
dose will be discontinued in boys so that the subjects can progress through puberty. At age 13 
years, girls who are receiving flutamide and testolactone or letrozole therapy will discontinue the 
aromatase inhibitor therapy (to allow normal progression of puberty) and continue flutamide (to 
continue androgen blockade).  Flutamide therapy will continue until 2 years after menarche or 
when final height is reached, whichever occurs first. 
Children who are also receiving concurrent LHRH analog to suppress central puberty will also 
discontinue this agent at age 13 in the girls or age 14 in the boys. The operational definition of age 
13 or 14 will be the NIH study visit that is closest to their thirteenth or fourteenth birthday. The 
operational definition of attainment of final height, as in our other long-term trials, will be the 
study visit at which the incremental growth over the previous 12 months declines to less than 1.5 
cm (0.6 inch).
During flutamide and aromatase inhibitor treatment hydrocortisone dose will be decreased in 
4 equal weekly steps to approximately 8 mg/m2/day.  During this month close contact will be 
maintained with the family by telephone and/or outpatient visits (for local patients), or referring 
physician visits (for distant patients), to check for symptoms or signs of adrenal insufficiency.  If 
the hydrocortisone dosage of approximately 8 m2/day produces symptoms or signs of adrenal 
insufficiency in any subject, the dosage will be adjusted on an individual basis to a dosage that 
will not cause symptoms or signs of adrenal insufficiency.
 Patients will initially be placed on Testolactone 20 mg/kg/day of testolactone.  The dose will 
then be increased at weekly intervals to 30 and then 40 mg/kg/day, which will be the maximum 
dose for the study (approximately equivalent to the usual maximal adult dose of 2 grams per day). 


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Patients placed on letrozole will receive a dose comparable to the dose used to suppress estrogens 
in adult women (1.5 mg per square meter of body surface area).  This is the same dose of letrozole 
used for the treatment of girls with McCune Albright Syndrome.  
Flutamide will also be administered in increasing doses.  Patients will initially be placed on 5 
mg/kg/day of flutamide.  The dose will then be increased at weekly intervals to 7.5 and then 10 
mg/kg/day, which will be the maximum dose for the study.  This is approximately the same dose 
used to treat men with prostate cancer (750 mg/day, or about 10 mg/kg/day).
Subjects will be evaluated as outpatients, day-hospital patients, or inpatients on the pediatric 
endocrine ward at 6-month intervals until final adult height is attained. The following evaluations 
will be made:
   
   
(1) Ten standing height measurements by stadiometer.
   
(2) Ten sitting height measurements.
   
(3) Weight.
   
(4) Bone age.
   
(5) Two 24-hour urine collections for cortisol.
   
(6) A leuprolide stimulation test, to assess pubertal status of the hypothalamic-pituitary-
gonadal axis will be performed at the first visit and all subsequent visits after the child has reached 
a bone age of 10 in boys or 9 in girls, or if there is clinical suspicion of hypothalamic-pituitary-
gonadal activation (i.e. testicular enlargement in boys, breast tissue in girls).  Children who are 
started on an LHRH analog for central precocious puberty and those who switch LHRH analog 
medication type will have leuprolide stimulation test performed 3 months after beginning 
treatment to confirm efficacy of this treatment. Additional leuprolide stimulation testing while 
receiving an LHRH analog will only be done if clinically indicated.  This testing will resume once 
the patient is taken off LHRH analog therapy. Measurement of gonadotropins by third-generation 
immunochemiluminometric assays (ICMA) will be done. Blood withdrawal: 12 mL.     
   
(7) Measurement of plasma 17-hydroxyprogesterone, DHEA-S, androstenedione, estradiol, 
testosterone, cortisol, and ACTH, estradiol starting as near 0800 h as feasible. The morning 
hydrocortisone dose will be held until after these samples have been obtained.  Blood withdrawal: 
18 mL.
   
(8) Blood to be frozen for possible future hormone measurements: 17 mL. 
(9)
Upright and supine plasma renin activity. Blood withdrawal: 14 mL.
   
(10) Routine CBC, thyroid panel and SMAC.  Blood withdrawal: 8 mL.
   
(11) One-hour cortrosyn (ACTH) test to assess levels of steroid intermediates in response to 
ACTH stimulation. Cortisol, 17-hydroxyprogesterone, androstenedione, and DHEA will be 
measured at time 0 and 60 minutes after ACTH bolus infusion.  Blood withdrawal: 24 mL.  This 
test will be performed at the beginning and end of the study, and, if indicated, at some other visits.
(12) Fasting glucose, insulin and leptin levels.  Blood withdrawal: 5 mL.
(13) Lipid profile.  Blood withdrawal: 2.5 mL.
(14) Plasma and urinary catecholamines and metanephrines Blood withdrawal: 20 mL.
(15) Bone densitometry (DEXA): to be performed at start of treatment, annually thereafter 
(e.g., every other NIH visit), and at attainment of final adult height, to measure bone density of the 
forearm, femoral neck, and spine (AP and lateral).
(16) MRI abdomen: to be performed after 2-3 years on the protocol and after the patient’s 
6th birthday.
(17) Boys will have a testicular ultrasound and girls will have a pelvic ultrasound done 


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each visit. 
(18) Photographs will be taken with the patient wearing a bathing suit or underwear.  This 
will be done at the beginning of the study and then yearly thereafter.
(19) If clinically indicated, an adrenal ultrasound and/or an additional MRI of the 
abdomen and adrenals may be done at follow-up visits.
(20) An apparent cortisol metabolic clearance rate determination will be performed in all 
patients.  In patients in the flutamide-testolactone treatment group, this test will be performed 
twice, once off flutamide and testolactone and once on flutamide and testolactone.
Determining the apparent cortisol metabolic clearance rate in our CAH patients will enable us to 
determine if a patient's dose of hydrocortisone is related to their metabolic clearance of cortisol 
and if flutamide and/or testolactone interfere with the metabolic clearance of hydrocortisone. 
Cortisol metabolic clearance rate will be determined by infusing hydrocortisone overnight, starting 
at 6:00 p.m. and ending the hydrocortisone infusion at 2:00 a.m., at an infusion rate of 0.6 
mg/m2/hour.  Oral hydrocortisone will be withheld on the day of testing.  This testing will be done 
at the randomization visit for all new patients.  Patients already on flutamide and testolactone will 
have one of their visits extended by 3 days in order to perform this testing on and off flutamide 
and testolactone.
(21) Psychological assessment will be performed at baseline and completion of the study. The 
following standard tests will be performed: Wechsler Intelligence Scale to determine IQ, 
California Verbal Learning Test to evaluate verbal-memory skills, Woodcock Johnson 
Achievement Tests to identify learning disabilities, Bender-Gestalt Test to evaluate visual-motor 
skills and Continuous Performance Test to evaluate attention.  Additional testing may be 
performed if clinically indicated.  If desired, a report will be provided to the parents for potential 
use by the child’s school.  Patients will be invited to participate in an NIMH study involving 
magnetic resonance imaging of the brain to examine the effects of androgen exposure on brain 
morphology.  The proposed psychological assessment will augment this data. We plan to collect 
data prior to the onset of puberty and after puberty.  
Many children with CAH enrolled in 96CH003 are in special education classes or have 
documented language or perceptual delays by parental report.  Learning disabilities are 6 times 
more likely to occur in males than females.  The role of androgens in this phenomenon is unknown. 
Sex differences in patterns of brain maturation in children have been found [36].   This sexual 
dimorphism is of interest in light of the differences in prevalence, age of onset, and 
symptomatology noted in nearly every neuropsychiatric disorder of childhood onset.  Sexually 
distinct patterns of normal brain development may be due to the X or Y chromosomes, effects of 
hormones, or environmental factors.  Several studies on CAH children have suggested that CAH 
females are similar to males in both their behavior and/or cognition.  For example, a study of CAH 
control females with equivalent general intelligence found CAH patients to have inferior verbal 
vs. visual and arithmetic scores typical of male vs. female differences [37].  CAH females have 
been shown to have improved spatial skills, typical of males [38].  Studies of gender-related 
behavior have shown that CAH females have more masculine type orientation than their unaffected 
sisters [39] and have more masculinized play preferences [40].  These type of data have been 
interpreted as a consequence of early in utero androgen exposure since testosterone is known to 
promote development of the right hemisphere and delays maturation of the left hemisphere.  We 
hypothesize that in CAH females, the organization of the brain is more like males than females, 
while CAH boys are more like unaffected males.


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(22) At the time of menarche, girls will be asked to keep a calendar documenting their 
menstrual history. 
Due to the known hepatotoxicity of flutamide in some patients (see Risks below), patients who 
randomize to the flutamide and aromatase inhibitor arm will have liver function tests drawn by 
their local physician every 2 weeks for the first 3 months, then once a month for the next 9 months, 
then every 3 months for the duration of the study. Parents will also be carefully instructed about 
the signs and symptoms of liver toxicity and the procedure to follow if such symptoms occur (see 
consent). We have not, however, observed flutamide-associated liver toxicity in any child 
receiving flutamide during our initial 6-month pilot study or the ongoing current study.
If a patient develops premature pubertal activation of the hypothalamic-pituitary-gonadal axis 
during the study, he or she will receive treatment with an LHRH analog. Since we cannot predict 
with certainty who may develop secondary central precocious puberty during the study, all patients 
and their families will receive an explanation of the use of LHRH analogs and available treatment 
regimens.  If a child develops premature pubertal activation of the hypothalamic-pituitary-gonadal 
axis, the NIH will supply a commercially available LHRH agonist, Lupron (monthly intramuscular 
injection) or an investigational LHRH agonist, Deslorelin (daily subcutaneous injection) Choice 
of medication will be based on family preference and demonstrated efficacy in each patient.
Because the degree of control of CAH often varies over time for unexplained reasons, 
adjustments in total hydrocortisone dose will be permitted during the conventional treatment arm 
throughout the study, as would be the case in clinical practice.  These dose adjustments will be 
guided by both clinical and biochemical criteria as outlined in the following discussion of the 
principles that are currently used in managing these patients.
Hydrocortisone Dose Adjustment During Conventional Treatment
We will attempt to optimize the child's management during a baseline period.  While 
administering hydrocortisone (preferably in a dose of 10-15 mg/m2/day, and not exceeding 25 
mg/m2/day), the mineralocorticoid dose will be adjusted to maintain a normal plasma renin activity 
in children with 21-hydroxylase deficiency.  With plasma renin activity in the normal range, 
hydrocortisone dose will generally be increased if:
(1) the growth rate is 2 standard deviation (SD) units or more above the median normal value 
for age;
(2) the rate of bone age advancement exceeds 2 years per chronologic year; or
(3) plasma 17-hydroxyprogesterone (17-OHP) levels are excessively elevated in association 
with growth rate and rate of bone maturation that are above the median normal values.
Because spot measurements of plasma 17-OHP correlate rather poorly with growth rate and 
bone maturation, plasma 17-OHP  will be used as an aid to judgement rather than as a treatment 
goal in itself.  At the present time, 0800-0900 plasma 17-OHP levels of 500 to 1300 ng/dL are 
considered appropriate, levels of 1300 to 3000 ng/dL prompt consideration of a hydrocortisone 
dose increase (assuming that plasma renin activity is normal), levels of 3000 to 6000 ng/dL prompt 
strong consideration, and levels >6000 ng/dL will ordinarily lead to a dosage increase.
Hydrocortisone dose will generally be decreased if:


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(1) the growth rate is 2 SD units or more below the median normal value for age, if the bone 
age is prepubertal, or the growth rate seems inappropriately suppressed relative to age and bone 
age, if the bone age is in the pubertal age range;
(2) the body mass index exceeds 2 SD units above the median value for age, or if signs of 
Cushing's syndrome are appearing;
(3) there is no detectable bone maturation over a period of more than 6 months; or
(4) plasma 17-OHP appears excessively suppressed in association with a subnormal growth 
rate or rate of bone maturation.  Plasma 17-OHP levels below 500 ng/dL will ordinarily raise 
consideration of a dosage decrease; levels below
200 ng/dL will raise strong consideration.
We have chosen a thrice-daily hydrocortisone dose schedule for this study. There are no 
controlled studies that compare a twice-daily and thrice-daily approach; however the thrice-daily 
hydrocortisone dose schedule is the most commonly used conventional regimen. 
Hydrocortisone Dose Adjustment During Investigational Treatment
Congenital adrenal hyperplasia occurs in several clinically distinct variants that reflect differing 
severity of the underlying enzymatic deficiency, even among the classic forms.  For example, the 
salt-wasting and simple-virilizing forms of 21-hydroxylase deficiency have different clinical 
courses: salt-wasters experience many more episodes of adrenal crisis and may require more 
glucocorticoid for adequate control.  Even within the salt-waster and simple-virilizer subgroups of 
CAH, clinical heterogeneity is seen.  This may be due to varying genotypes or other unknown 
factors.
A hydrocortisone dose of 8 mg/m2/day was chosen in our initial pilot study based on estimates of 
normal production rate; however, children may vary in their glucocorticoid daily requirements.  
Our hypothesis that the regimen of flutamide, an aromatase inhibitor and a reduced hydrocortisone 
dose can normalize the growth of children with, CAH while  avoiding the complications of 
supraphysiologic glucocorticoid, does not require identical glucocorticoid doses in all children on 
the new regimen.  Regimens will be more closely tailored to the individual differences in 
glucocorticoid requirement.  The hydrocortisone dose will be allowed to vary in the flutamide-
aromatase inhibitor treatment arm.
With plasma renin activity in the normal range, hydrocortisone dose will generally be increased if 
2 or more of the following occur:
1)
the rate of bone age advancement exceeds 2 years per chronologic year and there is no 
evidence of central precocious puberty as the cause;
2)
plasma 17-hydroxyprogesterone levels exceed 10,000 ng/dL;
3)
plasma androstenedione levels exceed 400 ng/dL;
4)
testosterone levels exceed 100 ng/dL in girls or prepubertal boys;


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5)
signs of virilization (clitoral growth, voice deepening, acne) on physical examination;
6)
presence of adrenal rest tissue on testicular ultrasound in boys (see below);
7)
evidence of  macronodular disease on adrenal ultrasound or MRI (see below).
With plasma renin activity in the normal range, hydrocortisone dose may be decreased if 2 or more 
of the following occur:
1)
plasma 17-hydroxyprogesterone levels are below 500 ng/dL;
 
2)
plasma androstenedione levels are below 50 ng/dL;
3)
the rate of bone age advancement is less than 1 year per chronologic year;
4)
weight percentile is greater than or equal to height percentile.
Treatment of Testicular Adrenal Rest Tissue or Macronodular Disease.
Testicular ultrasound is a sensitive method for detecting testicular adrenal rest tissue; however, 
testicular ultrasounds are not routinely done on CAH patients and the incidence of adrenal rest 
tissue with this sensitive method is unknown. Typically, testicular adrenal rests are thought to be 
evidence of poor control, but this may only be the case if significant growth occurs.  If a small 
amount of adrenal rest tissue is present, and there is no growth over time, a change in treatment 
may not be necessary.  Our studies of male patients with CAH support this approach [41].  If 
interval growth occurs between visits (i.e. over 6 months), glucocorticoid dose will be increased 
20%, or to a minimum of 12 mg/m2/day in the flutamide-aromatase inhibitor group.  If interval 
growth occurs on a hydrocortisone dose of at least 12 mg/m2/day in the flutamide-aromatase 
inhibitor treatment group, or 18 mg/m2/day in the conventional treatment group, then a 10-day 
course of dexamethasone (15 mcg/kg/day given qhs) will be instituted.  Flutamide and aromatase 
inhibitor therapy will be continued.
If the rare occurrence of  adrenal macronodular disease develops, a 10 day course of 
dexamethasone (15 mcg/kg/day given qhs) will be instituted. Subsequently, glucocorticoid dose 
will be increased to a minimum of 12 mg/m2/day in the flutamide-aromatase inhibitor treatment 
group, and flutamide and aromatase inhibitor therapy will be continued.  Glucocorticoid dose will 
be increased to a minimum of 15 mg/m2/day in the conventional treatment arm.  
The boy with significant testicular adrenal rest tissue and the patient who is developing 
macronodular enlargement represent special cases in which it may not be appropriate to restrict 
hydrocortisone dosage to the physiologic range. Fortunately, this is a small proportion of patients 
with CAH.  We recognize that the final analysis of the data will need to take account of these 
subgroups.
Monitoring and Criteria for Withdrawal of Subjects from Study
Patients will be monitored every 3 months, with visits alternating between their local physician 
and NIH (every 6 month visit to NIH). At the visit to the local physician, a single blood sample 




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with the subject or continued analysis of identifiable data) will require that consent be obtained 
from the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained.
If reconsent is not feasible, we request waiver of informed consent to continue to use data and/or 
specimens for those individuals who become lost to follow up or who have been taken off study 
prior to reaching the age of majority.
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d):
(1) The research involves no more than minimal risk to the subjects.
a.
Analysis of samples and data from this study involves no additional risks to 
subjects.
(2) The research could not practicably be carried out without the waiver or alteration.
a.
Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again. A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research. 
(3) As the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using such 
information or biospecimens in an identifiable format. 
a.
Though the purpose of future studies cannot yet be known, they often involve 
the correlation of clinical outcomes and clinical interventions with laboratory 
studies.  Such information would be unavailable if access to medical record 
numbers was unavailable. 
(4) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects.
a.
Retention of these samples or data does not affect the welfare of subjects. 
(5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation.
a.
We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of 
majority.
Research Use, Storage and Disposition of Human Subjects’ Samples and Data
Samples will be stored according to NICHD and NIH policy.  Samples may be used in the future, 
with identifiers, for studies not described here, based on the subject’s consent.  Blood samples may 
be shared with collaborators, without personal identifiers. 
All of the stored study research specimens are labeled by a numeric, alpha-numeric identification 
code that only the study team can link to the subject.  Specimens are stored in locked lab freezers 
and in the NICHD biorepository, which is accessed via a locked door.  All stored research 
specimens are logged into a specimen tracking database.  Variables included in the database are 
ID, specimen type, aliquot, date of collection, and location.  All usage and/or disbursement of the 
specimens is documented and tracked in the database. Only investigators or their designees will 
have access to the specimens and/or data.  
Subject confidentiality will be maintained to the greatest extent possible.  Research results will be 


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labeled using a unique code.  Publications will not include subject names nor will they contain 
personal identifying information.  
Any loss or unanticipated destruction of specimens (e.g. due to freezer malfunction) or data (e.g. 
misplacing a print-out of data with identifiers) that would affect the scientific integrity of the study 
will be reported to the IRB as an unanticipated problem by the PI.  
This protocol will be kept open as long as there is a possibility of future research use of the 
specimens and/or data.  When there is no longer a need, the specimens will be destroyed or, after 
IRB approval, transferred to another repository.  Data will be archived by the investigator in 
compliance with requirements for retention of research records, or after IRB approval, destroyed 
or transferred to another repository.
Analysis of Study (please also see attached SAP Appendix A)
 

The primary outcome (adult height expressed in SD units) will be compared between 
groups at the conclusion of the study using the unpaired two-tailed Student’s t-test, or 
nonparametric Wilcoxon rank sum test, as appropriate

Secondary outcome measures during the study include hormone levels (percent of visits 
in ranged defined above) and treatment doses, BMI (as SD  units), final BMD (Z-score), 
growth velocity (in SD units), rate of bone maturation, and predicted adult height 
(Bayley-Pinneau method, automated software in a subset of patients) at baseline, 
pubertal onset, and final visit. These outcomes will be compared between the study 
arms by multivariable mixed models for repeated measures. These models will allow 
for within-subject comparisons between timepoints, as well as account for their 
correlations across time, adjust for potential confounders, and specify the appropriate 
outcome distribution (e.g., normal, binomial, or Poisson distribution for type of data). 
They are a robust method for accommodating missing data, especially in measures that 
are repeated and collected longitudinally. Post-hoc comparisons will identify the 
driving factors and group effect influencing any observed differences, and will be 
corrected for multiple comparisons as applicable.
We have chosen a group size of 30, giving this study the same statistical power as the study of 
Deslorelin-induced pubertal delay (83-CH-199). With an expected standard deviation of 6 cm for 
the final height measurements (approximately that of the normal population), the group size 
required to give a 80% power to detect a 5-cm difference (about 2 inches) at a p<0.05 is 24.  The 
group size needed to detect a 6-cm difference is 17.  This is regarded by the pediatric endocrine 
community as a reasonable power for a growth study - for example, the Genentech Collaborative 
Study of Turner Syndrome had a group size of 17. Thus, the study is designed to detect at least a 
5 cm difference in final height, a clinically meaningful difference, and allows for a 25% drop out 
rate over the course of the study. This is regarded by the pediatric endocrine community as a 
reasonable power for a growth study - for example, the Genentech Collaborative Study of Turner 
Syndrome had a group size of 17. Thus, the study is designed to detect at least a 5 cm difference 
in final height, a clinically meaningful difference, and allows for a 25% drop out rate over the 


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course of the study.
Please find attached study analysis plan.
Human Subject Protections
Subject Selection
Exclusion criteria include children who have concurrent illnesses requiring glucocorticoid 
treatment (such as severe asthma), or requiring drugs that markedly alter hydrocortisone 
metabolism (such as anticonvulsants), and children who cannot be brought into reasonable control 
with conventional treatment (an unusual occurrence).
The incidence of classical CAH appears to be nearly the same in all ethnic groups, and lower 
in African Americans (ref: Therrell BL, Jr., Berenbaum SA, Manter-Kapanke V, et al. Results of 
screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal 
hyperplasia. Pediatrics 1998; 101(4 Pt 1): 583-90.  Based upon our previous studies, the 
anticipated gender and ethnic distribution of this study will reflect the gender and ethnic 
distribution of the United States population.
The study includes a vulnerable population (children) because treatments designed to address 
the growth abnormalities in CAH can only be evaluated in subjects who are growing. However, 
the procedures involved in this study are essentially the same as would be required in children 
receiving conventional treatment for CAH outside of a study. Additionally, the expertise provided 
by the study team, may reduce the psychological stress of evaluation compared to some other 
settings. Moreover, the expertise of the physician team may mitigate some of the physical 
consequences of the disorder (such as iatrogenic Cushing syndrome), even for those subjects who 
are in the conventional treatment arm. 
Evaluation of Benefits and Risks/Discomforts
Data from this study will be evaluated annually by the NICHD Data Safety Monitoring 
Committee.
The potential benefits include a 50% chance of receiving state-of-the-art monitoring and drug 
adjustment, if one is randomized to conventional treatment, and a 50% chance of receiving the 
hypothesized benefits of the new investigational regimen, if one is randomized to that arm and if 
the hypothesized benefits are in fact realized. The psychological assessment has the benefit of 
identifying an unknown learning disability.
The risks and discomforts of participation in this study include: 
(1) pain associated with having an intravenous needle inserted into a hand or arm vein, and the 
possibility of a bruise;
(2) the inconvenience of urine collections;
(3) blood withdrawal: 120 mL per 6 months for the conventional arm.  If the  leuprolide 


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stimulation test and ACTH test are omitted, blood withdrawal is 84 mL. For those receiving 
flutamide, additional blood withdrawal will be necessary for liver function tests: 12 mL in the first 
6 months, 6 mL for the subsequent 6 months and 2 mL thereafter. These amounts are  within the 
National Institutes of Health guidelines of 7 mL per kg body weight per 6 weeks.  If a child meets 
this blood limit, certain tests will be omitted.
(4) inconvenience and discomfort of being upright for 2 hours for an upright renin test.
(5)
Aromatase inhibitor.  Over twenty years of testolactone use, and our own experience with 
protocols 82-CH-165 and 85-CH-16, have revealed only minor dose-related gastrointestinal side 
effects and no serious toxicity.  This side effect has been observed, but less commonly, with 
letrozole.
Other than testolactone, letrozole is the aromatase inhibitor with the most reported pediatric 
experience and with the most clinical experience by investigators at the Clinical Center.  No 
harmful side-effects have been reported. 
(6) Flutamide.  Aside from infrequent nausea, diarrhea, and dizziness, the most common side-
effect when flutamide was used in prostate cancer has been gynecomastia and breast tenderness 
(34% of patients). We have found, however, that combined treatment with aromatase inhibitor 
prevents development of gynecomastia, as was the case during combined spironolactone plus 
testolactone treatment [8].  Infrequent adverse events reported in the literature include 
thromboembolic complications [15] and neutropenia [42].  Should the latter develop, the drug will 
be discontinued immediately.  
The most serious adverse effect of flutamide is hepatotoxicity. This risk was not detected in 
animal or pre-marketing clinical studies. It became apparent through the spontaneous reporting of 
15 deaths believed to be due to flutamide-related hepatotoxicity from among the nearly 700,000 
flutamide prescriptions for prostate cancer between 1989 and 1991 [43]. The  median duration of 
flutamide treatment among the fatal cases was 2 months, with the longest duration being 7 months. 
In each fatal case flutamide administration was continued despite evidence of deteriorating liver 
function. In other cases in which flutamide was discontinued after liver toxicity was recognized, 
the abnormality of liver function was reversible.
In a study of 1,091 consecutive patients with prostate cancer treated with flutamide, 4 (or 
1 in 273) developed significant liver dysfunction during the first month of treatment, which 
resolved completely with discontinuation of the drug. Thus, liver toxicity due to flutamide usually 
develops early in the course of treatment. This is the rationale for the schedule of hepatic 
monitoring in the flutamide-treated patients in this study: every 2 weeks for the initial 3 months of 
treatment, every month for the next 9 months, and every 3  months thereafter. In addition to the 
monitoring, each parent will be instructed in the signs and symptoms of liver toxicity and what to 
do if they should occur (see consent) .
If an elevation in liver function tests occurs, the following monitoring will be done.  If the liver 
enzyme values are greater than 3 times the upper limit of normal, flutamide will be discontinued 
immediately.  If the liver enzyme values are elevated but less than a 3-fold increase, liver function 
tests will be repeated immediately but the drug will not be discontinued.  If the elevation is 
confirmed by repeat testing, the child will have weekly liver function tests for 3 weeks. If the 


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values are increasing by more than 10%, flutamide will be discontinued. If values are remaining 
the same (or within 10%), flutamide will be continued and the previous regimen of liver function 
test monitoring will be resumed with a minimum of monthly evaluations for the first three months. 
The above monitoring program was developed after consulting both the Food and Drug 
Administration and an internationally recognized expert on drug-induced hepatic injury. With 
these precautions, it is believed that the risk of serious hepatic injury, such as occurred in adults 
before this risk of the drug was recognized [43], can be eliminated. During the 8 years that we 
have used flutamide, involving approximately 30 children, no hepatotoxicity has been observed.
The use of flutamide during pregnancy may result in ambiguous genitalia in a male fetus.  Other 
potential teratogenic effects are unknown.  Ovulation and pregnancy either prior to menarche or 
in the first 6 months following menarche in girls with classic CAH is extremely unlikely.  All 
female subjects have undergone genital surgery for correction of ambiguous genitalia and many 
require a second surgery in adolescence before sexual intercourse will be possible.  These 
structural abnormalities further reduce the unlikely possibility of pregnancy.  Patients and their 
parents will be counseled together and separately as to the importance of not becoming pregnant 
while on flutamide.  We will perform a pregnancy test each visit for pubertal girls on flutamide.
(6) Since hydrocortisone dosage will be reduced below that usually employed, some patients may 
develop symptoms or signs of adrenal insufficiency. We consider that this is unlikely to be a 
serious risk because; (1) patients will continue to receive an optimal fludrocortisone dose, (2) CAH 
patients remain capable of producing some endogenous hydrocortisone, and (3) the restricted 
dosage of approximately 8 mg/m2/day is equivalent to the most recent estimates of normal 
production rate and, in concert with the first 2 factors, should prevent any subjects from 
experiencing adrenal crisis.  If, however, symptoms or signs of adrenal insufficiency do occur at 
this dosage, the hydrocortisone dose will be increased on an individual basis to a dose that does 
not cause such signs or symptoms.
(7) Efficacy of the new treatment approach.  Since the new approach to be tested in this study has 
only been employed previously in short-term studies, there is the theoretical possibility that its 
long-term effectiveness could be less than that of conventional therapy.  In this event participants 
randomized to the investigational regimen would miss the full benefit of conventional treatment. 
(8) Leuprolide stimulation test.  This is a standard test of pubertal onset.  It has no known risk.
(9) ACTH test.  This is a standard test of adrenal function.  It has no known risk.
(10) Bone density of the forearm, femur, and lumbar spine will be determined annually by DEXA. 
(Bone age x-rays of the wrist will also be performed every six months).   The maximal tissue dose 
is 90 mrem to skin of lower back.  The total effective dose is less than 1 mrem.  Effective dose is 
the uniform whole-body dose, which is used to relate the dose received by each organ to a single 
value.  The effective dose is well within the RSC guidelines for children of 500 mrem.
(11) Magnetic Resonance Imaging (MRI). This procedure is without known risk and involves no 
radiation exposure.  Approximately 1% of subjects are too claustrophobic to be studied.  During 
the MRI scan, the patient hears rhythmic tapping sounds due to switching on and off of the gradient 
coils.  Subjects are warned of this prior to scanning and most do not find it objectional.  Ear plugs 
are provided.  Metal objects are exclusionary criteria and patients will be carefully screened for 
these exclusionary criteria.  There are no known adverse effects of magnetic resonance imaging 


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but guidelines for use have been established by the FDA.  For purposes of this protocol the NIHs 
MRI units operate well within those guidelines and their use has been previously approved in an 
IRB protocol for child age volunteers (CC#87-CC-91).
(12) There are possible discomforts associated with talking about topics such as behavior 
problems, or mental health problems.
Recruitment, Consent, and Assent Processes
Subjects will be recruited through announcements mailed to pediatricians and family practitioners 
(see sample at end of this section).
Consent will be obtained by one of the members of the research team. Consent will be documented 
in writing and witnessed on the consent document (see below). A copy of the consent document 
will be provided to the parent for reference about the study details. Parents will be encouraged to 
ask any questions that they may have, before or after the consent process.
Children will generally be present and have the opportunity to ask questions during explanation of 
the study and the consent process with the parents. Whenever it is appropriate for the childs age 
and level of understanding, the child will be given a chance to read (or have read to them) and sign 
the study assent document.  The assent will be obtained by one of the members of the research 
team.


Abbreviated Title: Congenital Adrenal Hyperplasia
Version Date: 03/23/2023
Page 24 of 26
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