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

• ClinicalTrials.gov Identifier: NCT00001521
• Recruitment Status: Active, not recruiting
• First Posted: November 4, 1999
• Last Update Posted: June 24, 2022
• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )

Study Description

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 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>

Condition or disease	Intervention/treatment	Phase
Congenital Adrenal Hyperplasia (CAH)	Drug: Flutamide; Drug: Letrozole; Drug: Hydrocortisone; Drug: Fludrocortisone	Phase 2

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open, Randomized, Long-Term Clinical Trial of Flutamide, Testolactone, and Reduced Hydrocortisone Dose vs. Conventional Treatment of Children With Congenital Adrenal Hyperplasia
• Actual Study Start Date: June 8, 1995
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: December 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Investigational 1; boys/flutamide, letrozole, and reduced hydrocortisone dose or conventional treatment (with hydrocortisone and fludrocortisone ) until the age of 14	Drug: Flutamide; 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; Drug: Letrozole; Armomatase inhibitor.; Drug: Hydrocortisone; reduced hydrocortisone dose can normalize the growth and adult stature of children with congenital adrenal hyperplasia; Drug: Fludrocortisone; 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
Experimental: Investigational 2; 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: Flutamide; 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; Drug: Letrozole; Armomatase inhibitor.; Drug: Hydrocortisone; reduced hydrocortisone dose can normalize the growth and adult stature of children with congenital adrenal hyperplasia

Outcome Measures

Primary Outcome Measures :

1. Adult height [ Time Frame: at 13 for boys; 14 for girls ]
   The primary outcome variable is adult height which will be expressed in SD units relative to the normal population.

Secondary Outcome Measures :

1. hormone levels (plasma, urine) [ Time Frame: at study conclusion and analysis ]
   hormone levels
2. Predicted adult height (Bayley-Pinneau) [ Time Frame: at study conclusion and analysis ]
   adult height
3. Weight velocity (SD units) [ Time Frame: at study conclusion and analysis ]
   body mass index, and bone density
4. Growth velocity (SD units) [ Time Frame: at study conclusion and analysis ]
   adult height, body mass index, and bone density

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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).

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Deborah P Merke, M.D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Urban MD, Lee PA, Migeon CJ. Adult height and fertility in men with congenital virilizing adrenal hyperplasia. N Engl J Med. 1978 Dec 21;299(25):1392-6.

New MI, Gertner JM, Speiser PW, del Balzo P. Growth and final height in classical and nonclassical 21-hydroxylase deficiency. Acta Paediatr Jpn. 1988;30 Suppl:79-88.

Klingensmith GJ, Garcia SC, Jones HW, Migeon CJ, Blizzard RM. Glucocorticoid treatment of girls with congenital adrenal hyperplasia: effects on height, sexual maturation, and fertility. J Pediatr. 1977 Jun;90(6):996-1004.

• Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• ClinicalTrials.gov Identifier: NCT00001521
• Other Study ID Numbers: 960033; 96-CH-0033
• First Posted: November 4, 1999
• Last Update Posted: June 24, 2022
• Last Verified: September 29, 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Keywords provided by National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) ):

Congenital Adrenal Hyperplasia (CAH); Intervention; Children

Additional relevant MeSH terms:

Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction; Hyperplasia; Pathologic Processes; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Gonadal Disorders; Hydrocortisone; Fludrocortisone; Letrozole; Flutamide; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Anti-Inflammatory Agents; Androgen Antagonists