Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia

Study Overview
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Brief Summary
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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 six months after their first menstrual period. 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, body mass index, and bone density. <TAB>

Detailed Description
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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 measures will be adult height, body mass index, and bone density.

Official Title
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An Open, Randomized, Long-Term Clinical Trial of Flutamide, Testolactone, and Reduced Hydrocortisone Dose vs. Conventional Treatment of Children With Congenital Adrenal Hyperplasia

Conditions
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Congenital Adrenal Hyperplasia (CAH)

Intervention / Treatment
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* Drug: Fludrocortisone
* Drug: Hydrocortisone
* Drug: Letrozole
* Drug: Flutamide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: 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 secondary central precocious puberty. Children with a bone age of 1 to 2 years may enroll in the protocol for optimization of conventional therapy, but will not be randomized to a study arm until the bone age reaches 2. EXCLUSION CRITERIA: 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).

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational 1<br>boys/flutamide, letrozole, and reduced hydrocortisone dose or conventional treatment (with hydrocortisone and fludrocortisone ) until the age of 14 | Drug: Fludrocortisone<br>* Since hydrocortisone dosage will be reduced , some patients may develop symptoms or signs of adrenal insufficiency. Patients will continue to receive an optimal fludrocortisone dose<br>Drug: Hydrocortisone<br>* reduced hydrocortisone dose can normalize the growth and adult stature of children with congenital adrenal hyperplasia<br>Drug: Letrozole<br>* Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.<br>Drug: Flutamide<br>* 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<br>|
| Experimental: Investigational 2<br>girls/flutamide, letrozole, and reduced hydrocortisone dose, the Letrozole will discontinue at 13 y.o. and continue flutamide until 2 years after menarche or when final height is reached, whichever occurs first | Drug: Hydrocortisone<br>* reduced hydrocortisone dose can normalize the growth and adult stature of children with congenital adrenal hyperplasia<br>Drug: Letrozole<br>* Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.<br>Drug: Flutamide<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adult height | The primary outcome variable is adult height which will be expressed in SD units relative to the normal population. | at 13 for boys; 14 for girls | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hormone levels (plasma, urine) | hormone levels | at study conclusion and analysis | 
| Predicted adult height (Bayley-Pinneau) | adult height | at study conclusion and analysis | 
| Weight velocity (SD units) | body mass index, and bone density | at study conclusion and analysis | 
| Growth velocity (SD units) | adult height, body mass index, and bone density | at study conclusion and analysis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital Adrenal Hyperplasia (CAH), Intervention, Children