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

NCT00001521 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: 96003396-CH-0033
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

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.

Conditions

Congenital Adrenal Hyperplasia (CAH)

Keywords

Congenital Adrenal Hyperplasia (CAH); Intervention; Children

Outcome Measures

Primary Outcomes (1)

• Adult Height Relative to General Population

  Adult height expressed in standard deviation score (SDS) units relative to the general population, with attainment of adult height defined as incremental growth \< 1.5 cm over 12 months. Adult height SDS was based on National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, National Center for Health Statistics) data at 20 years old.

  Followed to attainment of adult height, average of 11 years from date of randomization

Secondary Outcomes (20)

• Adult Height Relative to Mid-parental Height

  Followed to attainment of adult height, average of 11 years from date of randomization

• Predicted Adult Height

  At date of randomization and at pubertal onset (average of seven years from date of randomization)

• Predicted Adult Height Change

  From date of randomization to pubertal onset visit (which on average was seven years), pubertal onset to final visit (average was 4 years), and date of randomization to final visit (average of 11 years)

• Number of Years Bone Age Remained Unchanged

  From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)

• Change in Body Mass Index (BMI)

  From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)

Study Arms (2)

Investigational therapy

EXPERIMENTAL

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.

Drug: Fludrocortisone; Drug: Hydrocortisone; Drug: Letrozole; Drug: Flutamide; Drug: Testolactone

Standard therapy

EXPERIMENTAL

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.

Drug: Fludrocortisone; Drug: Hydrocortisone

Interventions

Fludrocortisone DRUG

Mineralocorticoid needed to replace aldosterone deficiency. Patients will continue to receive an optimal fludrocortisone dose

Investigational therapy; Standard therapy

Hydrocortisone DRUG

Glucocorticoid needed to replace cortisol deficiency. Reduced hydrocortisone dose might normalize the growth and adult stature of children with congenital adrenal hyperplasia

Investigational therapy; Standard therapy

Letrozole DRUG

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.

Investigational therapy

Flutamide DRUG

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

Investigational therapy

Testolactone DRUG

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.

Investigational therapy

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Subjects will be boys with bone ages 2 to 13 years and girls with bone ages 2 to 11 years with CAH due to classic 21-hydroxylase deficiency.
• Subjects must either not yet have undergone pubertal activation of the hypothalamic-pituitary-gonadal axis, or, if pubertal activation has occurred, must be receiving a GnRH 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Merke DP, Mallappa A, Parker M, Sukin C, Kulkarni SE, Keil MF, Van Ryzin C, Hill SC, Reynolds JC, Cutler GB Jr, Sinaii N. Adult Height Following Prepubertal Treatment With Antiandrogen, Aromatase Inhibitor, and Reduced Hydrocortisone in CAH. J Clin Endocrinol Metab. 2025 Jun 17;110(7):e2171-e2182. doi: 10.1210/clinem/dgae824.

  PMID: 39672600 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Adrenal Hyperplasia, Congenital

Interventions

Fludrocortisone; Hydrocortisone; Letrozole; Flutamide; Testolactone

Condition Hierarchy (Ancestors)

Adrenogenital Syndrome; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Anilides; Amides; Aniline Compounds; Amines; Androstadienes; Androstenes; Androstanes; Homosteroids

Results Point of Contact

• Title: Merke, Deborah
• Organization: Clinical Center

dmerke@nih.gov

+1 301 496 0718

Study Officials

• Deborah P Merke, M.D.

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 1999
• First Posted: November 4, 1999
• Study Start: June 8, 1995
• Primary Completion: April 1, 2024
• Study Completion: April 1, 2024
• Last Updated: June 12, 2025
• Results First Posted: June 12, 2025

Record last verified: 2024-05-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)