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

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

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.

Study Overview

• Status: Completed
• Conditions: Congenital Adrenal Hyperplasia (CAH)
• Intervention / Treatment: Drug: Flutamide; Drug: Letrozole; Drug: Fludrocortisone; Drug: Hydrocortisone; Drug: Testolactone

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

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

Description

• INCLUSION CRITERIA:

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.

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Investigational therapy; 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: 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; Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.; Drug: Fludrocortisone; Mineralocorticoid needed to replace aldosterone deficiency. Patients will continue to receive an optimal fludrocortisone dose; Drug: Hydrocortisone; Glucocorticoid needed to replace cortisol deficiency. Reduced hydrocortisone dose might normalize the growth and adult stature of children with congenital adrenal hyperplasia; Drug: Testolactone; Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.
Experimental: Standard therapy; 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; Mineralocorticoid needed to replace aldosterone deficiency. Patients will continue to receive an optimal fludrocortisone dose; Drug: Hydrocortisone; Glucocorticoid needed to replace cortisol deficiency. Reduced hydrocortisone dose might normalize the growth and adult stature of children with congenital adrenal hyperplasia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adult Height Relative to Mid-parental Height	Adult height expressed in standard deviation score (SDS) units relative to the mid-parental height for the general population. Adult height is 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. Mid-parental height was calculated based on reported parental heights calculated as (father's height (cm) + mother's height (cm))/ 2 ± 6.5 (cm).	Followed to attainment of adult height, average of 11 years from date of randomization
Predicted Adult Height	Predicted adult height was calculated using the bone age at the baseline visit or the first available bone age, using the Bayley-Pinneau method. Predicted adult height was calculated as the standard deviation score (SDS) units relative to the general population based on the National Health and Nutrition Examination Survey data (Centers for Disease Control and Prevention (CDC), National Center for Health Statistics) at 20 years old. Baseline was defined as time of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys).	At date of randomization and at pubertal onset (average of seven years from date of randomization)
Predicted Adult Height Change	Changes in predicted adult height from baseline to pubertal onset, pubertal onset to final visit, and baseline to final visit. Adult height standard deviation score (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. Predicted adult height at baseline was calculated using the bone age at the baseline visit or the first available bone age according to the Bayley-Pinneau method. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	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	Number of prepubertal and pubertal years bone age remained unchanged. Baseline bone age was calculated using the bone age at the baseline visit or the first available bone age according to the Bayley-Pinneau method. Change in bone age from baseline to pubertal onset and pubertal onset to final visit was measured in years. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	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)	Changes in body mass index (BMI) were evaluated from baseline to puberty onset and puberty onset to final visit. BMI calculation was based on average of three early morning height measurements by stadiometer and weight measurement by scale for each timepoints. BMI was calculated as the standard deviation score (SDS) units relative to the general population based on the National Health and Nutrition Examination Survey data (Centers for Disease Control and Prevention (CDC), National Center for Health Statistics) at 20 years old. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was time at attainment of adult height, defined as incremental growth < 1.5 cm over 12 months.	From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Body Mass Index (BMI)	Body mass index (BMI) was calculated based on average of three early morning height measurements by stadiometer and weight measurement by scale. BMI was calculated as the standard deviation score (SDS) units relative to the general population based on the National Health and Nutrition Examination Survey data (Centers for Disease Control and Prevention (CDC), National Center for Health Statistics) at 20 years old. Measures evaluated at pubertal onset and at final visit. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
Average Annual Growth Velocity	Average annual growth (height) velocity, measured as the change in height over time relative to the population mean and adjusted for age and sex. Measured during the study period from baseline visit to pubertal onset visit (visits occurring approximately every 6 months) and from pubertal onset to adult height. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Dose of Oral Hydrocortisone	Dose of oral hydrocortisone participant was taking adjusted for body surface area. Dose was recorded at baseline (first visit), pubertal onset, and at adult height (final visit). Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	At date of randomization, pubertal onset (average of seven years from date of randomization), and at final visit (average of 11 years from date of randomization)
Average Daily Dose of Oral Hydrocortisone	Average daily dose of oral hydrocortisone adjusted for body surface area. Dose was measured by developmental periods and for differences between sexes. Doses recorded at every visit, approximately every 6 months. Average dose measured from baseline to pubertal onset, from pubertal onset visit to adult height (final visit), and from baseline to adult height. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	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)
Percent of Visits With 17-hydroxyprogesterone in the Optimal Range (<1,200 ng/dL)	Percentage of visits where early morning (pre-medication) 17-hydroxyprogesterone measurements fell within the optimal range (<1,200 ng/dL) during the study period from baseline to pubertal onset and pubertal onset visit to final visit, with visits occurring approximately every 6 months. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Percent of Visits With Androstenedione in Normal Range	Percentage of visits where early morning (pre-medication) androstenedione measurements fell within the normal range based on age and sex-specific ranges during the study period. Measurements done from baseline to pubertal onset visit, and from pubertal onset visit to adult height (final visit), with visits occurring approximately every 6 months. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Average Testosterone	Average testosterone based on early morning (pre-medication) testosterone levels measured for participants approximately every six months. Average testosterone measured from baseline to pubertal onset and from pubertal onset visit to adult height (final visit) by sex. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Number of Participants With Onset of Early Central Puberty	Number of participants with onset of early central puberty, defined as testicular volume ≥ 4 mL in males before age 10, and breast Tanner stage 2 in females before age 9.	Measured from date of randomization to onset of early central puberty
Average Age at Menarche	Average age at menarche (years) in female participants only.	Followed from date of randomization to onset of menarche
Number of Female Participants With Normal Menstrual Cyclicity at Final Visit	Number of female participants with normal menstrual cyclicity at final visit. Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	Measured at single time point at final visit, average of 11 years from date of randomization
Number of Participants With Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) > 2.5	Number of participants with Insulin resistance based on Homeostasis model assessment of insulin resistance (HOMA-IR) > 2.5 at the final visit. Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	Final visit, average of 11 years from date of randomization
Average (Median) Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)	Homeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, measured as insulin (μU/mL) × glucose (mmol/L)/22.5 at final visit. HOMA-IR value ≤ 2.5 is considered normal. HOMA-RI value > 2.5 is considered abnormal. Higher HOMA-IR value indicates greater insulin resistance. Final visit was attainment of adult, defined as height with incremental growth <1.5 cm over 12 months.	Measured at single time point at final visit, average of 11 years from date of randomization
Number of Male Participants With Testicular Adrenal Rest Tumors (TART)	Number of male participants with testicular adrenal rest tumors (TART), measured by scrotal ultrasound, at pubertal onset visit and final visit. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
Anterior Posterior Spine Bone Mineral Density (BMD) at Final Visit	Anterior posterior spine bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DEXA) scan at final visit. The instrument specific comparisons (in standard deviations) were made to the average peak bone mass of a normal population, i.e. to the average bone mass of persons of the same age and sex as the patient. Final visit is defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	Final visit, average of 11 years from date of randomization
Femoral Neck Bone Mineral Density (BMD) at Final Visit	Femoral neck bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DEXA) scan at final visit. The instrument specific comparisons (in standard deviations) were made to the average peak bone mass of a normal population, i.e. to the average bone mass of persons of the same age and sex as the patient. Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.	Final visit, average of 11 years from date of randomization

Collaborators and Investigators

• Sponsor: 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)

Publications and helpful links

General Publications

• 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. 2024 Dec 3:dgae824. doi: 10.1210/clinem/dgae824. Online ahead of print.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 1995
• Primary Completion (Actual): April 1, 2024
• Study Completion (Actual): April 1, 2024

Study Registration Dates

• First Submitted: November 3, 1999
• First Submitted That Met QC Criteria: November 3, 1999
• First Posted (Estimated): November 4, 1999

Study Record Updates

• Last Update Posted (Actual): June 12, 2025
• Last Update Submitted That Met QC Criteria: May 28, 2025
• Last Verified: May 8, 2024

More Information

Terms related to this study

• Keywords: Children; Intervention; Congenital Adrenal Hyperplasia (CAH)
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Gonadal Disorders; Congenital Abnormalities; Adrenal Gland Diseases; Disorders of Sex Development; Urogenital Abnormalities; Steroid Metabolism, Inborn Errors; Hyperplasia; Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Androgen Antagonists; Letrozole; Hydrocortisone; Fludrocortisone; Flutamide; Testolactone
• Other Study ID Numbers: 960033; 96-CH-0033

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data is being used for secondary analyses.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No